PHARMACOLOGY

1)Bevacizumab
It is a humanized monoclonal antibody that binds
VEGF-A and hinders its access to the VEGF receptor,
interrupting angiogenic signalling. Combined with 5-FU,
bevacizumab is used in metastatic colorectal cancer. Added to
conventional chemotherapy, it improves survival in metastatic
non-small cell lung cancer, breast cancer, clear cell renal
carcinoma and glioblastoma. Deafness due to
neurofibromatosis can be reversed by growth inhibitory effect of
bevacizumab. Being an antibody, bevacizumab is administered
by i.v. infusion every 2–3 weeks.
Adverse effects are—rise in BP, arterial thromboembolism
leading to heart attack and stroke, vessel injury and
haemorrhages, heart failure, proteinurea, gastrointestinal
perforations, and healing defects.

2)Dopamine (DA)
It is a dopaminergic (D1 and D2) as well as adrenergic α and
β1 (but not β2) agonist. The D1 receptors in renal and
mesenteric blood vessels are the most sensitive: i.v. infusion of
low dose of DA dilates these vessels (by raising intracellular
cAMP). This increases g.f.r. In addition DA exerts natriuretic
effect by D1 receptors on proximal tubular cells. Moderately
high doses produce a positive inotropic (direct β1 and D1
action + that due to NA release), but little chronotropic effect on
heart.
Vasoconstriction (α1 action) occurs only when large
doses are infused. At doses normally employed, it raises
cardiac output and systolic BP with little effect on diastolic BP. It
has practically no effect on nonvascular α and β receptors;
does not penetrate blood-brain barrier—no CNS effects.
Dopamine is used in patients of cardiogenic or septic
shock and severe CHF wherein it increases BP and urine
outflow. It is administered by i.v. infusion (0.2–1 mg/min) which
is regulated by monitoring BP and rate of urine formation.
DOPAMINE, INTROPIN, DOPACARD 200 mg in 5 ml amp

3)Dobutamine
A derivative of DA, but not a D1 or D2 receptor agonist. Though
it acts on both α and β adrenergic receptors, the only prominent
action of clinically employed doses (2–8 µg/kg/ min i.v. infusion)
is increased force of cardiac contraction and output, without
significant change in heart rate, peripheral resistance and BP.
As such, it is considered to be a relatively selective β1 agonist.
It is used as an inotropic agent in pump failure
accompanying myocardial infarction, cardiac surgery, and for
short term management of severe congestive heart failure. It is
less arrhythmogenic than Adr.
CRDIJECT 50 mg/4 ml and 250 mg per 20 ml amp,
DOBUTREX, DOBUSTAT 250 mg vial.
4)Tacrolimus (FK506)
This immunosuppressant is chemically different from
cyclosporine, but has the same mechanism of action, and is
~100 times more potent. It binds to a different cytoplasmic
immunophilin protein labelled ‘FK 506 binding protein (FKBP)’,
but the subsequent steps are the same, i.e. inhibition of helper
T cells via calcineurin. Tacrolimus is administered orally as well
as by i.v. infusion.
Oral absorption is variable and decreased by food. It
is metabolized by CYP3A4 and excreted in bile with a t½ of 12
hour. Therapeutic application, clinical efficacy as well as toxicity
profile are similar to cyclosporine. Tacrolimus also requires
blood level monitoring for dose adjustment. However, due to
higher potency and easier monitoring of blood levels, it is
generally preferred now for organ transplantations.
Tacrolimus may be useful in patients whose
rejection reaction is not suppressed by cyclosporine. It is
particularly valuable in liver transplantation because its
absorption is not dependent on bile. Being more potent, it is
also suitable for suppressing acute rejection that has set in.
Tacrolimus has been used in fistulating
Crohn’s disease. A 10 week course may induce remission.
Topically, it is useful in atopic dermatitis. Hypertension,
hirsutism, gum hyperplasia and hyperuricaemia are less
marked than with cyclosporine, but tacrolimus is more likely to
precipitate diabetes, cause neurotoxicity, alopecia and
diarrhoea. Dose limiting toxicity is renal.
Dose: 0.05–0.1 mg/kg BD oral (for renal transplant), 0.1–0.2
mg/kg BD (for liver transplant). It can also be given i.v. (no i.v.
preparation is available in India); 0.03–0.1% topically.
TACROMUS, PANGRAF 0.5, 1.0, 5.0 mg caps; TACRODERM,
TACREL 0.03, 0.1% oint.

5)PROTON PUMP INHIBITORS (PPIs)

These are the most effective drugs, both for symptomatic relief
as well as for healing of esophageal lesions.
Intragastric pH >4 maintained for ~18 hr/day is considered
optimal for healing of esophagitis. This level of acid
suppression can be consistently achieved only by PPIs.
Therefore, PPIs are the drugs of choice for patients with all
stages of GERD, particularly stage 2 and 3 cases. Symptom
relief is rapid and 80–90% esophageal lesions heal in 4–8
weeks. Dose titration is needed according to response in
individual patients. Some patients, especially stage 2 and 3
cases, need twice daily dosing. Prolonged (often indefinite)
therapy is required in chronic cases because symptoms recur a
few days after drug stoppage. PPIs have no effect on LES tone.

6)ANTI CANCER ANTIBIOTICS

These are products obtained from microorganisms and have
prominent antitumour activity. Practically all of them intercalate
between DNA strands and interfere with its template function.
 Actinomycin D (Dactinomycin) It is a very potent
antineoplastic drug, highly efficacious in Wilms’ tumour and
childhood rhabdomyosarcoma. Good results have also been
obtained in Mtx resistant choriocarcinoma, Ewing’s sarcoma
and metastatic testicular carcinoma. In addition to blocking
RNA transcription (due to interference with template function of
DNA) dactinomycin causes single strand breaks in DNA.
Prominent adverse effects are vomiting, stomatitis, diarrhoea,
erythema and desquamation of skin, alopecia and bone marrow
depression.
Dose: 15 µg/kg i.v. daily for 5 days. DACMOZEN 0.5 mg/vial inj.
Daunorubicin (Rubidomycin), Doxorubicin These
are anthracycline antibiotics having antitumour activity.
However, utility of daunorubicin is limited to acute myeloid as
well as lymphoblastic leukaemia (in which it is highly active),
while doxorubicin, in addition, is effective in manysolid tumours,
such as breast, thyroid, ovary, bladder and lung cancers,
sarcomas and neuroblastoma. They intercalate between DNA
strands and block DNA as well as RNA synthesis. They are
also capable of causing breaks in DNA strands by activating
topoisomerase-2 and generating quinone type free radicals. As
such, they have mutagenic and carcinogenic potential.
Maximum action is exerted at S phase, but toxicity is usually
exhibited in G2 phase. Both these antibiotics produce
cardiotoxicity as a unique adverse effect.
This can manifest either acutely within 2–3 days,
causing ECG changes, arrhythmias and hypotension, all of
which are reversible; or be delayed—congestive heart failure
(related to the total dose administered). CHF is due to
cardiomyopathy and may be fatal. Marrow depression,
alopecia, stomatitis, vomiting and local tissue damage (on
extravasation) are other adverse effects. Urine may be
coloured red.
Daunorubicin: 30–50 mg/m2 BSA i.v. daily for 3 days, repeat
every 3–4 weeks. DAUNOCIN, DAUNOMYCIN 20 mg/vial inj.
Doxorubicin: 60–75 mg/m2 BSA slow i.v. injection every 3
weeks; ADRIAMYCIN, DOXORUBICIN, ONCODRIA 10 mg, 50
mg per vial inj.
Epirubicin This is a recently introduced anthracycline
with mechanism of action and properties similar to doxorubicin.
Epirubicin has been primarily used as a component of regimen
for adjuvant therapy of breast carcinoma. Other indications are
gastroesophageal, pancreatic, hepatic and bladder carcinoma.
Alopecia, hyperpigmentation of skin and oral mucosa, painful
oral ulcers, fever and g.i. symptoms are the common adverse
effects. Urine may turn red. Cardiotoxicity is dose related.
Dose: 60–90 mg/m2 i.v. over 5 min, repeated at 3 weeks, total
dose < 900 mg/m2 to avoid cardiotoxicity. ALRUBICIN,
EPIRUBITEC 10, 50 mg vials, for reconstitution as 2 mg/ml
soln. with diluent.
Mitoxantrone It is an anthracycline derivative related to
doxorubicin with lower cardiotoxicity, probably because it does
not produce quinone type free radicals. However, it does bind
to DNA causing strand breaks and inhibiting DNA as we as
RNA synthesis. Clinical utility is relatively narrow, restricted
mostly to acute myeloid leukaemia, advanced hormone
refractory prostate cancer and occasionally in breast and
hepatic carcinoma, non-Hodgkin lymphoma. It has been found
useful in late stage multiple sclerosis as well. Though
cardiomyopathy can occur, major toxicity is marrow depression
and mucosal inflammation. Discolouration of nails and eye may
occur.
ONCOTRON 20 mg/10 ml inj; 14 mg/m2 single i.v. dose, repeat
at 3 weeks. For induction in acute leukaemia 12 mg/ m2/day for
5 days.
Bleomycin This is a mixture of closely related glycopeptide
antibiotics having potent antitumour activity. It chelates copper
or iron, produces superoxide ions and intercalates between
DNA strands—causes chain scission and inhibits repair. It is
highly effective in testicular tumour and squamous cell
carcinoma of skin, oral cavity, head and neck, genitourinary
tract and esophagus; also useful in Hodgkin’s lymphoma. Rate
of fluid collection in malignant pleural or peritoneal effusion can
be reduced by intrapleural/intraperitoneal injection of
bleomycin.
Mucocutaneous toxicity and pulmonary fibrosis, but
minimal myelosuppression are the special features. Allergic
and hypotensive reaction can occur after bleomycin injection. It
can be injected i.m. as well.
Dose: 30 mg twice weekly i.v. or i.m. (total dose 300–400 mg);
BLEOCIN, ONCOBLEO 15 mg inj.

Mitomycin C This highly toxic drug is used only

in resistant cancers of stomach, cervix, colon, rectum, breast,
etc. It is usually combined with 5-FU and radiation. Superficial
bladder tumours are treated by intravesical instillation of
mitomycin C. It is transformed intracellularly to a form which
acts as an alkylating agent and crosslinks DNA. It also
generates free radicals which damage DNA. Bone marrow and
g.i.t. are the primary targets of toxicity. Myelosuppression is
typically delayed. Injections are repeated only after 6 weeks or
more. A haemolytic-uremic syndrome is reported.
Dose: 10 mg/m2 BSA, infused i.v. in one day or divided in 5
and infused over 5 days. MITOCIN, ALMITO, LYOMIT 2, 10

7)AROMATASE INHIBITORS
Aromatization of ‘A’ ring of testosterone and
androstenedione is the final and key step in the production of
estrogens (estradiol/estrone) in the body. In addition to the
circulating hormone, locally produced estrogens appear to play
an important role in the development of breast cancer. Though
some aromatase inhibitors (AIs) were produced in the past,
three recent ‘third generation’ AIs Letrozole, Anastrozole and
Exemestane have demonstrated clinical superiority and are
widely used now in the treatment of breast cancer. Properties of
AIs are compared with that of tamoxifen
 Letrozole It is an orally active nonsteroidal (type 2)
compound that reversibly inhibits aromatization all over the
body, including that within the breast cancer cells, resulting in
nearly total estrogen deprivation. Proliferation of estrogen
dependent breast carcinoma cells is suppressed to a greater
extent than with tamoxifen. Letrozole is rapidly absorbed with
100% oral bioavailability, large volume of distribution, slow
metabolism and a t½ of ~40 hours. Randomized clinical trials
have established its utility in:
(a) Early breast cancer: Letrozole is a first line drug for adjuvant
therapy after mastectomy in ER+ive postmenopausal women.
Extended adjuvant therapy with letrozole beyond the standard
5 year tamoxifen treatment continues to afford protection,
whereas continuation of tamoxifen is not useful. Replacement
of tamoxifen by an AI is now recommended after 2 years
(sequential therapy). Survival is prolonged in patients who have
positive axillary lymph nodes.
(b) Advanced breast cancer: Current guidelines recommend
letrozole as first line therapy because of longer time to disease
progression and higher response rate obtained with it
compared to tamoxifen. It is also effective as second line
treatment when tamoxifen has failed.
Adverse effects Hot flushes, nausea, diarrhoea, dyspepsia
and thinning of hair are the side effects. Joint pain is common
and bone loss may be accelerated. However, there is no
endometrial hyperplasia or increased risk of endometrial
carcinoma. Risk of venous thromboembolism is also not
increased, and there is no deterioration of lipid profile.
Dose: 2.5 mg OD oral. LETOVAL, LETROZ, FEMARA,
ONCOLET 2.5 mg tab.
Though contraindicated in premenopausal women, letrozole
was clandestinely promoted and tested as an ovulation
inducing fertility drug. Use of letrozole for inducing ovulation in
infertile women has been banned in India since Oct. 2011.
Anastrozole Another nonsteroidal and reversible (Type 2) AI,
more potent than letrozole and suitable for single daily dosing.
It accumulates in the body to produce peak effect after 7–10
days.
Anastrozole is useful as adjuvant therapy in early ER+ive
breast cancer as well as for palliation of advanced cases in
postmenopausal women. In early cases, tumor recurrence time
was found to be longer than with tamoxifen. Risk of new tumor
appearing in the contralateral breast was also lower with
anastrozole. A longer time to disease progression compared to
tamoxifen has been obtained in advanced ER+ive breast
cancer. Many tamoxifen resistant cases responded with
increased survival. Like letrozole, it is also a first line drug for
early as well as advanced breast carcinoma in postmenopausal
women. Side effects are hot flushes, vaginal dryness, vaginal
bleeding, nausea, diarrhoea, thinning of hair. Arthralgia and
acceleration of osteoporosis are prominent. However, it does
not predispose to endometrial carcinoma or to venous
thromboembolism.
Dose: 1 mg OD. ALTRAZ, ARMOTRAZ, ANABREZ 1 mg tab.

Exemestane: This steroidal and irreversible (Type 1) inhibitor

of aromatase acts like a suicide substrate by covalent binding
to the enzyme. As a result >90% suppression of estradiol
production is obtained. However, it has weak androgenic
activity similar to androstenedione. Exemestane has been
found beneficial in early breast cancer by reducing the risk of
disease progression when it was substituted for tamoxifen as
adjuvant therapy. In advanced breast cancer, longer survival,
increased time to disease progression and fewer treatment
failures have been obtained with exemestane. It is administered
orally and is well tolerated. Adverse effects are similar to other
AIs.

8)GEMCITABINE
9)ADRIYAMYCIN
10)RADIOMIMETIC DRUGS
ALKYLATING AGENTS These compounds
produce highly reactive carbonium ion intermediates which
transfer alkyl groups to cellular macromolecules by forming
covalent bonds. The position 7 of guanine residues in DNA is
especially susceptible, but other molecular sites are also
involved. They may react with carboxyl, hydroxyl, amino,
sulfhydryl and phosphate groups of biomacromolecules.
Alkylation results in cross linking/abnormal base
pairing/scission of DNA strand. Cross linking of nucleic acids
with proteins can also take place. Alkylating agents have
cytotoxic and radiomimetic (like ionizing radiation) actions. Most
are cell cycle non-specific, i.e. act on dividing as well as resting
cells. Some have CNS stimulant and cholinergic properties.
Mechlorethamine (Mustine HCl) It is the first
nitrogen mustard; highly reactive and local vesicant—can be
given only by i.v. route. It produces many acute effects like
nausea, vomiting and haemodynamic changes. Extravasation
during i.v. injection may cause sloughing. Hodgkin and non-
Hodgkin lymphomas are the main indications. It has been a
component of erstwhile MOPP regimen.
Dose: 0.1 mg/kg i.v. daily × 4 days; courses may be repeated at
suitable intervals. MUSTINE 10 mg dry powder in vial.
Cyclophosphamide It is inactive as such:
produces few acute effects and is not locally damaging.
Transformation into active metabolites(aldophosphamide,
phosphoramide mustard) occurs in the liver, and a wide range
of antitumour actions is exerted. It has prominent
immunosuppressant property. Thus, it is one of the most
popular alkylating agents useful in many solid tumours. It is less
damaging to platelets, but alopecia and cystitis (due to another
metabolite acrolein) are prominent.
Chloramphenicol retards the metabolism of
cyclophosphamide.
Dose: 2–3 mg/kg/day oral; 10–15 mg/kg i.v. every 7–10 days,
i.m. use also possible. ENDOXAN, CYCLOXAN 50 mg tab;
200, 500, 1000 mginj.
Ifosfamide This congener of cyclophosphamide
has a longer and dose-dependent t½. It has found utility in
bronchogenic, breast, testicular, bladder, head and neck
carcinomas, osteogenic sarcoma and some lymphomas. The
dose limiting toxicity of ifosphamide is haemorrhagic cystitis. To
prevent the same, mesna is routinely given with it. Is a –SH
compound that is excreted in urine—binds and inactivates the
vasicotoxic metabolites of ifosfamide and cyclophosphamide.
Ifosfamide causes less alopecia and is less emetogenic than
cyclophosphamide.
HOLOXAN-UROMITEXAN 1 g vial + 3 amps of mesna 200 mg
inj.; HOLOXAN, IPAMIDE 1 g inj.

Chlorambucil It is a very slow acting alkylating

agent, especially active on lymphoid tissue: Myeloid tissue is
largely spared. It is the drug of choice for long-term
maintenance therapy for chronic lymphatic leukaemia; non-
Hodgkin lymphoma and few solid tumours also resolve. It has
some immunosuppressant property.
Dose: 4–10 mg (0.1–0.2 mg/kg) daily for 3–6 weeks, then 2 mg
daily for maintenance; LEUKERAN 2, 5 mg tab.
Melphalan It is very effective in multiple myeloma
and has been used in advanced ovarian cancer. Bone marrow
depression is the most important toxicity. Infections, diarrhoea
and pancreatitis are the complications.
Dose: 10 mg daily for 7 days or 6 mg/day for 2–3 weeks—4
weeks gap—2 to 4 mg daily for maintenance orally. Also used
for regional perfusion in malignant melanoma. ALKERAN 2, 5
mg tab, 50 mg per vial for inj.
Thio-TEPA It is an ethylenimine: does not require to
form an active intermediate. It has hightoxicity: seldom used
now in ovarian and bladder cancer.
Dose: 0.3–0.4 mg/kg i.v. at 1–4 week intervals. THIOTEPA 15
mg per vial inj.
Busulfan It is highly specific for myeloid elements;
granulocyte precursors being the most sensitive, followed by
those of platelets and RBC. It produces little effect on lymphoid
tissue and g.i.t. Hyperuricaemia is common; pulmonary fibrosis
and skin pigmentation are the specific adverse effects. Sterility
also occurs. It is the drug of choice for chronic myeloid
leukaemia.
Dose: 2–6 mg/day (0.06 mg/kg/day) orally. MYLERAN,
BUSUPHAN 2 mg tab.
Nitrosoureas These are highly lipid soluble
alkylating agents with a wide range of antitumour activity. They
cross blood-brain barrier—are effective in meningeal
leukaemias and brain cancer. Nausea, vomiting are common
and CNS effects also occur. Bone marrow depression is
peculiarly delayed, taking nearly 6 weeks to develop. Visceral
fibrosis and renal damage can occur: Lomustine (CCNU): 100–
130 mg/m2 BSA single oral dose every 6 weeks; LOMUSTINE
40, 100 mg cap.
Dacarbazine (DTIC) After activation in liver, it acts
by methylating DNA and interfering with its function. The most
important indication is malignant melanoma; also used in
Hodgkin’s disease. Nausea, vomiting, flu-like symptoms,
neuropathy and myelosuppression are the prominent adverse
effects.
Dose: 3.5 mg/kg/day i.v. for 10 days, repeat after 4 weeks.
DACARIN 100, 200, 500 mg inj; DACARZINE 200 mg/vial inj.
Temozolamide This orally active triazine methylating agent is
the drug of choice for glioma and other malignant brain
tumours; also utilized in melanoma. Adverse effects are similar
to dacarbazine.
Dose: 100–250 mg/day; GLIOZ 20, 100, 250 mg caps.
Procarbazine It is not a classical alkylating agent, but has
similar properties. After metabolic activation (it is inactive as
such), procarbazine methylates and depolymerizes DNA
causingchromosomal damage. Inhibition of nucleic acid
synthesis also occurs. Beause of damage to DNA, mutagenic
and carcinogenic potential has been detected. It is a
component of MOPP regimen for Hodgkin’s and related
lymphomas, and is an alternative drug for brain tumours.
Procarbazine is a weak MAO inhibitor; produces sedation and
other CNS effects, and can interact with foods and drugs.
Alcohol causes hot flushing and a disulfiram-like reaction in
patients taking procarbazine. Males may suffer sterility.
Vomiting, leucopenia, thrombocytopenia are the prominent
toxicities.
Dose: 100 mg/m2/day for 14 days in 28 days cycles.
INDICARB 20 mg cap, NEOZINE, P-CARZINE 50 mg cap

11)H.PYLORI TREARMEMNT
It is treated with antibiotics and other drugs with different
combinations
Clarithromycin 500 Metronidazole 400 Omeprazole 20 mg
mg B mg BD BD
OR OR OR
Amoxycillin 500-750 Tinidazole 600 mg Lansoprazole 30 mg
mg BD BD BD
OR OR
Tetracyclines, or Pantoprazole 40 mg
Bismuth. BD
The above regime is given for 7-14 days and then only
proton pump inhibitors are continued.

12)Fluorouracil (5-FU) is converted in the body to the

corresponding nucleotide 5-fluoro2-deoxyuridine
monophosphate, which forms a covalent ternary complex with
methyl-THFA and tymidylate synthase (TS) resulting in
irreversible inhibition of TS. Consequently conversion of
deoxyuridilic acid to deoxythymidylic acid is blocked. Selective
failure of DNA synthesis occurs due to non-availability of
thymidylate. Accordingly, thymidine can partially reverse 5-FU
toxicity. 5-FU itself gets incorporated into RNA, interferes with
RNA synthesis and function contributing to its cytotoxicity. Even
resting cells are affected, though rapidly multiplying ones are
more susceptible. Since inhibition of TS by
5-FU is dependednt on the prsence of
THFA, concurrent infusion of leucovorin enhances the efficacy
of 5-FU. Cisplatin and oxaliplatin also synergise with 5-FU.
Most protocols now employ 5-FU along with leucovorin and
cisplatin/ oxaliplatin. Currently, 5-FU is a commonly used
anticancer drug for many solid malignancies, especially of
colon, rectum, stomach, pancreas, liver, urinary bladder, head
and neck. Oral absorption of 5-FU is unreliable. It is primarily
used by i.v. infusion. 5-FU is rapidly metabolized by
dihydropyrimidine dehydrogenase (DPD) resulting in a plasma
t½ of 15–20 min after i.v. infusion. Genetic deficiency of DPD
predisposes to severe 5-FU toxicity.
Major toxicity of 5-FU is exerted on the
bone marrow and g.i.t. causing myelosuppression, mucositis,
diarrhoea, nausea and vomiting. Peripheral neuropathy (hand-
foot syndrome) also occurs.
Dose: 500 mg/m2 i.v. infusion over 1–3 hours weekly for 6–8
weeks, or 12 mg/kg/day i.v. for 4 days followed by 6 mg/kg i.v.
on alternate days, 3–4 doses. FLURACIL, FIVE FLURO,
FIVOCIL 250 mg/5 ml and 500 mg/10 ml vial. A 1% topical
solution applied twice daily for 3–6 weeks has yielded gratifying
results in superficial basal cell carcinoma, and in actinic
keratosis.

13)ANTI-RETROVIRUS DRUGS
These are drugs active against human immunodeficiency virus
(HIV) which is a retrovirus. They are useful in prolonging and
improving the quality of life and postponing complications of
acquired immunodeficiency syndrome (AIDS) or AIDSrelated
complex (ARC), but do not cure the infection.
The clinical efficacy of antiretrovirus drugs is
monitored primarily by plasma HIV-RNA assays and CD4
lymphocyte count carried out at regular intervals. HIV is a
single stranded RNA retrovirus which uniquely carries out
reverse transcription of proviral DNA from viral RNA (normally
RNA is transcripted from DNA) with the help of a viral RNA-
dependent DNA polymerase (reverse transcriptase)
The primary cell type attacked by HIV is the CD4+
helper T-lymphocyte, but later macrophages and some other
cell types may also be infected. When population of CD4 cells
declines markedly (<200 cells/µL), cell mediated immunity
(CMI) is lost and opportunistic infections abound, to which the
victim ultimately succumbs, unless treated. Because the HIV
genome integrates with the host DNA, eradication of the virus
from the body of the victim appears impossible at present.
Over the past 30 years, a number of virus specific targets have
been identified and drugs for these developed. We now have
drugs which effectively suppress HIV replication and restore
CMI for variable periods of time.
The two established targets for anti-HIV attack are:
(a) HIV reverse transcriptase: Which transcripts HIV-RNA into
proviral DNA.
(b) HIV protease: Which cleaves the large virus directed
polyprotein into functional viral proteins. In addition, some
newer targets being exploited are:
• Fusion of viral envelope with plasma membrane of CD4 cells
through which HIVRNA enters the cell. • Chemokine coreceptor
(CCR5) on host cells which provide anchorage for the surface
proteins of the virus.
• HIV-integrase: Viral enzyme which integrates the proviral DNA
into host DNA. The first anti-retrovirus (ARV) drug zidovudine
was made available for use in 1987.
Over the past 25 years a large number of drugs
belonging to 3 classes viz. Nucleoside or Non-nucleoside
reverse transcriptase inhibitors (NRTIs and NNRTIs) and HIV-
protease inhibitors (PIs) have been produced and extensively
used. Recently few drugs for the newer targets have also
become available for use in patients who have failed several
regimens employing the 3 major groups of drugs, and have
viral multiplication despite optimized background therapy. The
aim of anti-HIV therapy is to cause maximal suppression of viral
replication for the maximal period of time that is possible. For
this, ARV drugs are always used in combination of at least 3
drugs and regimens have to be changed over time due to
development of resistance. Life long therapy is required. Over
the past 35 years, HIV infection has emerged as a major global
health problem.
Though, with the use of effective antiretroviral
therapy (ART) the prevalence is declining in the present
century, WHO estimate in 2009 showed that 33.3 million people
world wide were living with HIV, and HIV/AIDS killed 1.8 million
people in 2010, most of them in subsaharan Africa. India is a
relatively low HIV prevalence country, but it has the 3rd largest
number of people living with HIV, which was 2.4 million in 2009,
concentrated mostly among female sex workers, injection drug
abusers, transgenders, etc. India launched its National AIDS
Control Programme (NACP) in 1992, but the prevalence and
annual death rate has declined steadily only after 2004 when
the National AIDS Control Organization (NACO) rolled-out free
combination ART to eligible registered patients. Currently ~ 5
lac patients are alive on ART*, and new infections have
declined by > 50% during the last decade, which in a large
measure, is due to effective use of combination ART.

(a) Nucleoside reverse transcriptase inhibitors (NRTIs):

Zidovudine (AZT),Didanosine, Stavudine,

Lamivudine, Abacavir, Emtricitabine, Tenofovir (Nt RTI)
(b) Nonnucleoside reverse transcriptase inhibitors
(NNRTIs): Nevirapine, Efavirenz, Delavirdine
(c) Protease inhibitors: Ritonavir, Atazanavir, Indinavir,
Nelfinavir, Saquinavir, Amprenavir, Lopinavir (d) Entry (Fusion)
inhibitor: Enfuvirtide
(e) CCR5 receptor inhibitor: Maraviroc 9578367180
(f) Integrase inhibitor: Raltegravir

14)Nonselective COX inhibitors (traditional NSAIDs)

1.Salicylates: Aspirin.
2. Propionic acid derivatives: Ibuprofen, Naproxen, Ketoprofen,
Flurbiprofen.
3. Fenamate: Mephenamic acid.
4. Enolic acid derivatives: Piroxicam, Tenoxicam.
5. Acetic acid derivatives: Ketorolac, Indomethacin,
Nabumetone.
6. Pyrazolone derivatives: Phenylbutazone, Oxyphenbutazone.
NSAIDs and prostaglandin (PG) synthesis inhibition In 1971
Vane and coworkers made the landmark observation that
aspirin and some NSAIDs blocked PG generation. This is now
considered to be the major mechanism of action of NSAIDs.
Prostaglandins, prostacyclin (PG I2) and thromboxane A2
(TXA2) are produced from arachidonic acid by the enzyme
cyclooxygenase (see p. 182) which exists in a constitutive
(COX-1) and an inducible (COX-2) isoforms; the former serves
physiological ‘house keeping’ functions, while the latter,
normally present in minute quantities, is induced by cytokines
and other signal molecules at the site of inflammation →
generation of PGs locally which mediate many of the
inflammatory changes. However, COX-2 is constitutively
present at some sites in brain, in juxtaglomerular cells and in
the foetus; it may serve physiological role at these sites. Most
NSAIDs inhibit COX-1 and COX-2 nonselectively, but now
some selective COX-2 inhibitors have been produced.
Features of nonselective COX-1/COX-2 inhibitors
(traditional NSAIDs) and selective COX-2 inhibitors are
compared in Table 14.1 Aspirin inhibits COX irreversibly by
acetylating one of its serine residues; return of COX activity
depends on synthesis of fresh enzyme
Analgesia
PGs induce hyperalgesia by affecting the
transducing property of free nerve endings so that stimuli that
normally do not elicit pain are able to do so. NSAIDs do not
affect the tenderness induced by direct application of PGs, but
block the pain sensitizing mechanism induced by bradykinin,
TNFα, interleukins (ILs) and other algesic substances primarily
by inhibiting COX-2. This constitutes the peripheral component
of the analgesic action of NSAIDs. They are, therefore, more
effective against inflammation associated pain. Lately the
central component of analgesic action of NSAIDs has also
been shown to involve inhibition of PG synthesis in the spinal
dorsal horn neurones as well as in brain.
Antipyresis
NSAIDs reduce body temperature in fever, but do
not cause hypothermia in normothermic individuals. Fever
during infection and tissue injury is produced through the
generation of pyrogens including, ILs, TNFα, interferons which
induce PGE2 production in hypothalamus— raise its
temperature set point. NSAIDs block the action of pyrogens but
not that also). However, fever can occur through non-PG
mediated mechanisms as well. of PGE2 injected into the
hypothalamus. The isoform present at this site appears to be
COX-2 (possibly COX-3 also). However, fever can occur
through non-PG mediated mechanisms as well.

Antiinflammatory
The most important mechanism of
antiinflammatory action of NSAIDs is considered to be inhibition
of COX-2 mediated enhanced PG synthesis at the site of injury.
However, there is some evidence that inhibition of the
constitutive COX-1 also contributes to suppression of
inflammation, especially in the initial stages. The
antiinflammatory potency of different compounds roughly
corresponds with their potency to inhibit COX. However,
nimesulide is a potent antiinflammatory but relatively weak
COX inhibitor.
PGs are only one of the mediators of inflammation;
inhibition of COX does not depress the production of other
mediators like LTs, PAF, cytokines, etc. Inflammation is the
result of concerted participation of a large number of
vasoactive, chemotactic and proliferative factors at different
stages, and there are many targets for antiinflammatory action.
Activated endothelial cells express adhesion
molecules (ELAM-1, ICAM-1) on their surface and play a key
role in directing circulating leucocytes to the site of
inflammation (chemotaxis). Similarly, inflammatory cells
express selectins and integrins. Certain NSAIDs may act by
additional mechanisms including inhibition of expression/
activity of some of these molecules and generation of
superoxide/other free radicals. Growth factors like GM-CSF, IL-
6 as well as lymphocyte transformation factors and TNFα may
also be affected. Stabilization of leucocyte lysosomal
membrane and antagonism of certain actions of kinins may be
contributing to NSAID action.
Dysmenorrhoea
Involvement of PGs in dysmenorrhoea has been
clearly demonstrated: level of PGs in menstrual flow,
endometrial biopsy and that of PGF2α metabolite in circulation
are raised in dysmenorrhoeic women. Intermittent ischaemia of
the myometrium is probably responsible for menstrual cramps.
NSAIDs lower uterine PG levels—afford excellent relief in 60–
70% and partial relief in the remaining. Ancillary symptoms of
headache, muscle ache and nausea are also relieved. Excess
flow may be normalized.
Antiplatelet aggregatory NSAIDs inhibit synthesis of both
proaggregatory (TXA2) and antiaggregatory (PGI2)
prostanoids, but effect on platelet TXA2 (COX-1 generated)
predominates → therapeutic doses of most NSAIDs inhibit
platelet aggregation: bleeding time is prolonged. Aspirin is
highly active; acetylates platelet COX irreversibly in the portal
circulation before it is deacetylated by first pass metabolism in
liver. Small doses are therefore able to exert antithrombotic
effect for several days. Risk of surgical and anticoagulant
associated bleeding is enhanced.
Ductus arteriosus closure During foetal circulation ductus
arteriosus is kept patent by local elaboration of PGE2 by COX-
2. Unknown mechanisms switch off this synthesis at birth and
the ductus closes. When this fails to occur, small doses of
indomethacin or aspirin bring about closure in majority of cases
within a few hours by inhibiting PG production. Administration
of NSAIDs in late pregnancy has been found topromote
premature closure of ductus in some cases. Risk of post-
partum haemorrhage is increased. Prescribing of NSAIDs near
term should be avoided. Parturition Sudden spurt of PG
synthesis by uterus occurs just before labour begins. This is
believed to trigger labour as well as facilitate its progression.
Accordingly, NSAIDs have the potential to delay and retard
labour. However, labour can occur in the absence of PGs.
Gastric mucosal damage Gastric pain, mucosal
erosion/ulceration and blood loss are produced by all NSAIDs
to varying extents: relative gastric toxicity is a major
consideration in the choice of NSAIDs. Inhibition of COX-1
mediated synthesis of gastroprotective PGs (PGE2, PGI2) is
clearly involved, though local action inducing back diffusion of
H+ ions in gastric mucosa also plays a role. Deficiency of PGs
reduces mucus and HCO3¯ secrection, tends to enhance acid
secretion and may promote mucosal ischaemia. Thus, NSAIDs
enhance aggressive factors and contain defensive factors in
gastric mucosa—are ulcerogenic. Paracetamol, a very weak
inhibitor of COX is practically free of gastric toxicity and
selective COX-2 inhibitors are relatively safer. Stable PG
analogues (misoprostol) administered concurrently with
NSAIDs counteract their gastric toxicity.
Renal effects Conditions leading to hypovolaemia, decreased
renal perfusion and Na+ loss induce renal PG synthesis which
brings about intrarenal adjustments by promoting
vasodilatation, inhibiting tubular Cl¯ reabsorption (Na+ and
water accompany) and opposing ADH action. NSAIDs produce
renal effects by at least 3 mechanisms:
• COX-1 dependent impairment of renal blood flow and
reduction of g.f.r. → can worsen renal insufficiency.
• Juxtaglomerular COX-2 (probably COX-1 also) dependent
Na+ and water retention.
• Ability to cause papillary necrosis on habitual intake.
Renal effects of NSAIDs are not marked in normal individuals,
but become significant in those with CHF, hypovolaemia,
hepatic cirrhosis, renal disease and in patients receiving
diuretics or antihypertensives. In them Na+ retention and
edema can occur; diuretic and antihypertensive drug effects
are blunted. Involvement of PG synthesis inhibition in analgesic
nephropathy is uncertain. Analgesic nephropathy occurs after
years of heavy ingestion of analgesics. Such individuals
probably have some personality defect.
Regular use of combinations of NSAIDs and
chronic/ repeated urinary tract infections increase the risk of
analgesic nephropathy. Pathological lesions are papillary
necrosis, tubular atrophy followed by renal fibrosis. Urine
concentrating ability is lost and the kidneys shrink. Because
phenacetin was first implicated, it went into disrepute, though
other analgesics are also liable to produce similar effects.
Anaphylactoid reactions Aspirin precipitates asthma,
angioneurotic swellings, urticaria or rhinitis in certain
susceptible individuals. These subjects react similarly to
chemically diverse NSAIDs, ruling out immunological basis for
the reaction. Inhibition of COX with consequent diversion of
arachidonic acid to LTs and other products of lipoxygenase
pathway may be involved, but there is no proof.

15)Antioxidant vitamins (vit E, β β β β β carotene, vit C) in

prevention of cardiovascular disease and cancer
Antioxidants are believed to quench free
radicals. Free radicals are atoms or molecules with ‘singlet’, i.e.
unpaired electron which makes them highly reactive. Oxidative
free radicals are generated by metabolic reactions—create a
chain reaction leading to membrane lipid peroxidation, DNA
damage, etc. Free radical oxidation has been implicated in
atherosclerosis (oxidized LDL is more atherogenic), cancers,
neurodegenerative diseases and inflammatory bowel diseases.
Many endogenous and dietary compounds like superoxide
dismutase, ferritin, transferrin, ceruloplasmin, α tocopherol, β
carotene and ascorbic acid have antioxidant and free radical
scavenging properties.
On this theoretical basis supported by some
epidemiological observations, cohort studies and prospective
trials β carotene, vit C and especially vit E have been claimed
to protect against atherosclerosis leading to coronary artery
disease as well as many types of cancers (lung, breast, mouth,
skin, esophagus, stomach, etc.).
As a result, vit E and others are being aggressively
promoted and many physicians are prescribing them for
prophylaxis of these conditions. Learning from mass media,
people on their own also are consuming them on a large scale.
However, the evidence of a beneficial effect is highly
contradictory. Several large observational studies (involving
tens of thousands of subjects) and their metaanalysis have
failed to demonstrate any benefit of antioxidant vitamins in
terms of cardiovascular event/cancer prevention in well
nourished population.
On the other hand, there is some indication of
increased risk of CHF with >400 mg/day α tocopherol and
increased risk of hip fracture among postmenopausal women
with high dose of vit A. Therefore, it would be well advised to
adopt a healthy lifestyle, viz. eating sufficient fruits and
vegetables, doing regular exercise, avoiding overweight and
smoking, rather than consuming antioxidant medications. A
large number of antioxidant proprietary preparations
(ANTOXID, CAROFIT, GLACE, VITOXID, REVOX, CARNITOR,
CARNIVIT-E, etc.) containing widely variable amounts of β-
carotene, vit A acetate, vit E, vit C, selenium, zinc, copper,
manganese, carnitine (a substance synthesized in liver and
kidney, and involved in intracellular transport of long-chain fatty
acids) are briskly promoted and consumed, but with no credible
evidence of benefit, and may be some potential harm.

16)Lidocaine (Lignocaine)
Introduced in 1948, it is currently the most widely
used LA. It is a versatile LA, good both for surface application
as well as injection and is available in a variety of forms.
Injected around a nerve it blocks conduction within 3 min,
whereas procaine may take 15 min; also anaesthesia is more
intense and longer lasting. Vasodilatation occurs in the injected
area. It is used for surface application, infiltration, nerve block,
epidural, spinal and intravenous regional block anaesthesia.
Cross sensitivity with ester LAs is not seen. In contrast to other
LAs, early central effects of lidocaine are depressant, i.e.
drowsiness, mental clouding, dysphoria, altered taste and
tinnitus. Overdose causes muscle twitching, convulsions,
cardiac arrhythmias, fall in BP, coma and respiratory arrest like
other LAs. Lidocaine is a popular antiarrhythmic .
XYLOCAINE, GESICAIN 4% topical solution, 2% jelly, 2%
viscous, 5% ointment, 1% and 2% injection (with or without
adrenaline), 5% heavy (for spinal anaesthesia); 100 mg/ml
spray (10 mg per actuation).

17)ANTACIDS
These are basic substances which neutralize gastric acid and
raise pH of gastric contents.
Peptic activity is indirectly reduced if the pH rises above 4,
because pepsin is secreted as a complex with an inhibitory
terminal moiety that dissociates below pH 5: optimum peptic
activity is exerted between pH 2 to 4. Antacids do not decrease
acid production; rather, agents that raise the antral pH to > 4
evoke reflex gastrin release → more acid is secreted,
especially in patients with hyperacidity and duodenal ulcer;
“acid rebound” occurs and gastric motility is increased.
The potency of an antacid is generally expressed
in terms of its acid neutralizing capacity (ANC), which is defined
as number of mEq of 1N HCl that are brought to pH 3.5 in 15
min (or 60 min in some tests) by a unit dose of the antacid
preparation. This takes into consideration the rate at which the
antacid dissolves and reacts with HCl. This is important
because a single dose of any antacid taken in empty stomach
acts for 30–60 min only, since in this time any gastric content is
passed into duodenum. Taken with meals antacids may act for
at the most 2–3 hr.
Systemic Antacids
Sodium bicarbonate It is water soluble, acts instantaneously,
but the duration of action is short. It is a potent neutralizer (1 g
→ 12 mEq HCl), pH may rise above 7.
However, it has several demerits:
(a) Absorbed systemically: large doses will induce alkalosis.
(b) Produces CO2 in stomach → distention, discomfort,
belching, risk of ulcer perforation.
(c) Acid rebound occurs, but is usually short lasting.
(d) Increases Na+ load: may worsen edema and CHF. Use of
sod. bicarbonate is restricted to casual treatment of heartburn.
It provides quick symptomatic relief. Other uses are to
alkalinize urine and to treat acidosis.
Sodium citrate Properties similar to sod. bicarbonate; 1 g
neutralizes 10 mEq HCl; CO2 is not evolved.
Nonsystemic Antacids
These are insoluble and poorly absorbed basic compounds;
react in stomach to form the corresponding chloride salt. The
chloride salt again reacts with the intestinal bicarbonate so that
HCO3 ¯ is not spared for absorption—no acid-base disturbance
occurs. However, small amounts that are absorbed have the
same alkalinizing effect as NaHCO3.
Mag. hydroxide has low water solubility: its aqueous
suspension (milk of magnesia) has low concentration of OH¯
ions and thus low alkalinity. However, it reacts with HCl
promptly and is an efficacious antacid (1 g → 30 mEq HCl).
Rebound acidity is mild and brief. MILK OF MAGNESIA 0.4 g/5
ml suspension: 5 ml neutralizes 12 mEq acid.
Magnesium trisilicate has low solubility and reactivity; 1 g can
react with 10 mEq acid, but in clinical use only about 1 mEq is
neutralized.
About 5% of administered Mg is absorbed systemically
—may cause problem if renal function is inadequate. All Mg
salts have a laxative action by generating osmotically active
MgCl2 in the stomach and through Mg2+ ion induced
cholecystokinin release. Soluble Mg salts are used as osmotic
purgatives.
Aluminium hydroxide gel It is a bland, weak and slowly
reacting antacid. On keeping it slowly polymerizes to variable
extents into still less reactive forms. Thus, the ANC of a
preparation gradually declines on storage. Also, the product
from different manufacturers may have differing ANCs; usually
it varies from 1–2.5 mEq/g. Thus, 5 ml of its suspension may
neutralize just 1 mEq HCl. As such, little worthwhile acid
neutralization is obtained at conventional doses. The Al3+ ions
relax smooth muscle. Thus, it delays gastric emptying. Alum.
hydrox. frequently, causes constipation due to its smooth
muscle relaxant and mucosal astringent action.
Alum. hydrox. binds phosphate in the intestine and prevents its
absorption—hypophosphatemia occurs on regular use. This
may:
(a) cause osteomalacia
(b) be used therapeutically in hyperphosphatemia and
phosphate stones. Small amount of Al3+ that is absorbed is
excreted by kidney. This is impaired in renal failure—aluminium
toxicity (encephalopathy, osteoporosis) can occur.
ALUDROX 0.84 g tab, 0.6 g/10 ml susp.
Magaldrate It is a hydrated complex of hydroxymagnesium
aluminate that initially reacts rapidly with acid and releases
alum. hydrox. which then reacts more slowly. The freshly
released alum. hydrox. is in the unpolymerized more reactive
form. Thus, magaldrate cannot be equated to a physical
mixture of mag. and alum. hydroxides. It is a good antacid with
prompt and sustained neutralizing action. Its ANC is estimated
to be 28 mEq HCl/g.
STACID 400 mg tab, 400 mg/5 ml susp.; ULGEL 400 mg with
20 mg simethicone per tab or 5 ml susp.
Calcium carbonate It is a potent and rapidly acting acid
neutralizer (1 g → 20 mEq HCl), but ANC of commercial
preparations is less and variable due to differing particle size
and crystal structure. Though it liberates CO2 in the stomach at
a slower rate than NaHCO3, it can cause distention and
discomfort. The Ca2+ ions are partly absorbed.
The greatest drawback of CaCO3 as an antacid is
that Ca2+ ions diffuse into the gastric mucosa—increase HCl
production directly by parietal cells as well as by releasing
gastrin. Acid rebound occurs. Mild constipation or rarely loose
motions may be produced. The absorbed calcium can be
dangerous in renal insufficiency.
Milk alkali syndrome In the past, large quantity of
milk was prescribed with CaCO3 (or NaHCO3) for peptic ulcer.
Such regimen often produced a syndrome characterized by
headache, anorexia, weakness, abdominal discomfort,
abnormal Ca deposits and renal stones due to concurrent
hypercalcaemia and alkalosis. It is rare now.
Antacid combinations
A combination of two or more antacids is frequently used.
These may be superior to any single agent on the following
accounts:
(a) Fast (Mag. hydrox.) and slow (Alum. hydrox.) acting
components yield prompt as well as sustained effect.
(b) Mag. salts are laxative, while alum. salts are constipating:
combination may annul each other’s action and bowel
movement may be least affected.
(c) Gastric emptying is least affected; while alum. salts tend to
delay it, mag./cal. salts tend to hasten it.
(d) Dose of individual components is reduced; systemic toxicity
(dependent on fractional absorption) is minimized.
Some available antacid combinations are:
ACIDIN: Mag. carb. 165 mg, dried alum. hydrox. gel 232 mg,
cal. carb. 165 mg, sod. bicarb. 82 mg, with kaolin 105 mg and
belladonna herb 30 µg per tab. ALMACARB: Dried alum.
hydrox. gel 325 mg, mag. carb. 50 mg, methyl polysilox. 40 mg,
deglycyrrhizinated liquorice 380 mg per tab. ALLUJEL-DF:
Dried alum. hydrox. gel 400 mg, mag. hydrox. 400 mg, methyl
polysilox. 30 mg per 10 ml susp. DIGENE: Dried alum. hydrox.
gel 300 mg, mag. alum. silicate 50 mg, mag. hydrox. 25 mg,
methylpolysilox. 10 mg per tab. DIGENE GEL: Mag. hydrox.
185 mg, alum. hydrox. gel 830 mg, sod. carboxymethyl
cellulose 100 mg, methylpolysilox. 25 mg per 10 ml susp.
GELUSIL: Dried alum. hydrox. gel 250 mg, mag. trisilicate 500
mg per tab. GELUSIL LIQUID: Mag. trisilicate 625 mg, alum.
hydrox. gel 312 mg per 5 ml susp. MUCAINE: Alum. hydrox.
290 mg, mag. hydrox. 98 mg, oxethazaine 10 mg per 5 ml
susp.

18) ANTITUBERCULAR DRUGS

First line: These drugs have high antitubercular efficacy as well
as low toxicity; are used routinely. Second line: These drugs
have either low antitubercular efficacy or higher toxicity or both;
and are used as reserve drugs.
First line drugs 1. Isoniazid (H)
2. Rifampin (R)
3. Pyrazinamide (Z)
4. Ethambutol (E)
5. Streptomycin (S)
Second line drugs
• Ethionamide (Eto)
• Rifabutin
• Prothionamide (Pto)
• Cycloserine (Cs)
• Terizidone (Trd)
• Para-aminosalicylic

Fluoroquinolones
• Ofloxacin (Ofx)
• Levofloxacin (Lvx/Lfx)
• Moxifloxacin (Mfx)
• Ciprofloxacin (Cfx) acid (PAS)
Injectable drugs
• Kanamycin (Km)
• Thiacetazone (Thz)
• Amikacin (Am)
• Capreomycin (Cm)

Alternative grouping of
antitubercular drugs*
Group I First line oral anti-TB drugs Isoniazid (INH), Rifampin,
Pyrazinamide, Ethambutol
Group II Injectable anti-TB drugs Streptomycin, Kanamycin,
Amikacin, Capreomycin
Group III Fluoroquinolones Ofloxacin, Levofloxacin,
Moxifloxacin, Ciprofloxacin
Group IV Second line oral anti-TB drugs Ethionamide,
Prothionamide, Cycloserine, Terizidone, Para-aminosalicylic
acid
Group V Drugs with unclear efficacy£ Thiacetazone,
Clarithromycin, Clofazimine, Linezolid, Amoxicillin/clavulanate,
Imipenem/cilastatin

20) H2 ANTAGONISTS
These are the first class of highly
effective drugs for acid-peptic disease, but have been
surpassed by proton pump inhibitors (PPIs). Four H2
antagonists cimetidine, ranitidine, famotidine and roxatidine are
available in India; many others are marketed elsewhere. Their
interaction with H2 receptors has been found to be competitive
in case of cimetidine, ranitidine and roxatidine, but competitive-
noncompetitive in case of famotidine.
Cimetidine was the first H2 blocker to be
introduced clinically and is described as the prototype, though
other H2 blockers are more commonly used now.
Pharmacological actions
1.H2 blockade
Cimetidine and all other H2 antagonists block
histamine-induced gastric secretion, cardiac stimulation
(prominent inisolated preparations, especially in guinea
pig), uterine relaxation (in rat) and bronchial relaxation (H2
blockers potentiate histamine induced bronchospasm).
They attenuate fall in BP due to histamine, especially the
late phase response seen with high doses. They are
highly selective: have no effect on H1 mediated responses
or on the action of other transmitters/autacoids.
2. Gastric secretion
The only significant in vivo action of H2 blockers
is marked inhibition of gastric secretion. All phases (basal,
psychic, neurogenic, gastric) of secretion are suppressed dose-
dependently, but the basal nocturnal acid secretion is
suppressed more completely. Secretory responses to not only
histamine but all other stimuli (ACh, gastrin, insulin, alcohol,
food) are attenuated. This reflects the permissive role of
histamine in amplifying responses to other secretagogues. The
volume, pepsin content and intrinsic factor secretion are
reduced, but the most marked effect is on acid. However,
normal vit B12 absorption is not interfered: no vit B12
deficiency occurs even after prolonged use.
The usual ulcer healing doses produce 60–70%
inhibition of 24 hr acid output. The H2 blockers have
antiulcerogenic effect. Gastric ulceration due to stress and
drugs (NSAIDs, cholinergic, histaminergic) is prevented. They
do not have any direct effect on gastric or esophageal motility
or on lower esophageal sphincter (LES) tone.
Pharmacokinetics
Cimetidine is adequately absorbed orally,
though bioavailability is 60–80% due to first pass hepatic
metabolism. Absorption is not interfered by presence of food in
stomach. It crosses placenta and reaches milk, but penetration
in brain is poor because of its hydrophilic nature. About 2/3 of a
dose is excreted unchanged in urine and bile, the rest as
oxidized metabolites. The elimination t½ is 2–3 hr. Dose
reduction is needed in renal failure.
Interactions
Cimetidine inhibits several cytochrome P-450
isoenzymes and reduces hepatic blood flow. It inhibits the
metabolism of many drugs so that they can accumulate to toxic
levels, e.g. theophylline, phenytoin, carbamazepine,
phenobarbitone, sulfonylureas, metronidazole, warfarin,
imipramine, lidocaine, nifedipine, quinidine. Metabolism of
propranolol and diazepam is also retarded, but this may not be
clinically significant. Antacids reduce absorption of all H2
blockers. When used concurrently a gap of 2 hr should be
allowed. Ketoconazole absorption is decreased by H2 blockers
due to reduced gastric acidity.
Dose:
For ulcer healing—400 mg BD or 800 mg at bed time orally;
maintenance—400 mg at bed time.
For stress ulcer—50 mg/hr i.v. infusion. Rapid or higher dose
i.v. injection can cause confusional state, hallucinations,
convulsions, bradycardia, arrhythmias, coma or cardiac arrest.
CIMETIDINE 200 mg, 400 mg, 800 mg tabs, 200 mg/2 ml inj.,
LOCK-2 200 mg tab.
Ranitidine
A nonimidazole (has a furan ring) H2 blocker, it has several
desirable features compared to cimetidine:
• About 5 times more potent than cimetidine. Though its
pharmacokinetic profile and t½ of 2–3 hr is similar to cimetidine,
a longer duration of action with greater 24 hr acid suppression
is obtained clinically because of higher potency.
• No antiandrogenic action, does not increase prolactin
secretion or spare estradiol from hepatic metabolism—no effect
on male sexual function or gynaecomastia.
• Lesser permeability into the brain: lower propensity to cause
CNS effects. In fact, little effect outside g.i.t. has been
observed.
• Less marked inhibition of hepatic metabolism of other drugs;
drug interactions mostly have no clinical relevance.
• Overall incidence of side effects is lower: headache,
diarrhoea/constipation, dizziness have an incidence similar to
placebo.
Dose: for ulcer healing 300 mg at bed time or 150 mg BD; for
maintenance 150 mg at bed time. Parenteral dose—50 mg i.m.
or slow i.v. inj. every 6–8 hr (rapid i.v. injection can cause
hypotension), 0.1–0.25 mg/kg/hr by i.v. infusion has been used
for prophylaxis of stress ulcers. For gastrinoma 300 mg 3–4
times a day. ULTAC, ZINETAC 150 mg, 300 mg tabs; HISTAC,
RANITIN, ACILOC, RANTAC 150 mg, 300 mg tabs, 50 mg/2 ml
inj.
Famotidine
A thiazole ring containing H2 blocker which binds
tightly to H2 receptors and exhibits longer duration of action
despite an elimination t½ of 2.5–3.5 hr. Some inverse agonistic
action on H2 receptors (in the absence of histamine) has been
demonstrated. It is 5–8 times more potent than ranitidine.
Antiandrogenic action is absent. Because of low affinity for
cytochrome P450 and the low dose, drug metabolism modifying
propensity is minimal. The oral bioavailability of famotidine is
40–50%, and it is excreted by the kidney, 70% in the
unchanged form. Incidence of adverse effects is low: only
headache, dizziness, bowel upset, rarely disorientation and
rash have been reported. Because of the higher potency and
longer duration, it has been considered more suitable for ZE
syndrome and for prevention of aspiration pneumonia.
Dose: 40 mg at bed time or 20 mg BD (for healing); 20 mg at
bed time for maintenance; upto 480 mg/day in ZE syndrome;
parenteral dose 20 mg i.v. 12 hourly or 2 mg/hr i.v. infusion.
FAMTAC, FAMONITE, TOPCID 20 mg, 40 mg tabs; FAMOCID,
FACID 20, 40 mg tabs, 20 mg/2 ml inj.
Roxatidine
The pharmacodynamic, pharmacokinetic and
side effect profile of roxatidine is similar to that of ranitidine, but
it is twice as potent and longer acting. It has no antiandrogenic
or cytochrome P450 inhibitory action.

Uses
The H2 blockers are used in conditions in which it is profitable
to suppress gastric acid secretion. Used in appropriate doses,
all available agents have similar efficacy. However, PPIs,
because of higher efficacy and equally good tolerability, have
outstripped H2 blockers.
1. Duodenal ulcer H2 blockers produce rapid and marked pain
relief (within 2–3 days); 60–85% ulcers heal at 4 weeks and
70–95% ulcers at 8 weeks, but they are seldom used now to
heal existing ulcers. Suppression of nocturnal secretion by
single high bed time dose is equally efficacious and
physiologically more sound. About ½ of the patients relapse
within 1 year of healing with H2 blockers. Maintenance therapy
with bed time dose reduces the relapse rate to 15–20% per
year as long as given.
2. Gastric ulcer Healing rates obtained in gastric ulcer are
somewhat lower (50–75% at 8 weeks). However, doses remain
the same. H2 blockers can heal NSAID associated ulcers, but
are less effective than PPIs or misoprostol.
3. Stress ulcers and gastritis Acutely stressful situations like
hepatic coma, severe burns and trauma, prolonged surgery,
prolonged intensive care, renal failure, asphyxia neonatorum,
etc. are associated with gastric erosions and bleeding. Mucosal
ischaemia along with acid is causative. Intravenous infusion of
H2 blockers successfully prevents the gastric lesions and
haemorrhage as well as promotes healing of erosions that have
occurred.
4. Zollinger-Ellison syndrome It is a gastric hypersecretory state
due to a rare tumour secreting gastrin. H2 blockers in high
doses control hyperacidity and symptoms in many patients, but
PPIs are the drugs of choice. Definitive treatment is surgical.
5. Gastroesophageal reflux disease (GERD) H2 blockers afford
symptomatic relief and facilitate healing of esophageal
erosions, but are less effective than PPIs. They are indicated
only in mild or stage-1 cases of GERD (see p. 659).
6. Prophylaxis of aspiration pneumonia H2 blockers given
preoperatively (preferably evening before also) reduce the risk
of aspiration of acidic gastric contents during anaesthesia and
surgery.
7. Other uses H2 blockers have adjuvant beneficial action in
certain cases of urticaria who do not adequately respond to an
H1 antagonist alone.

21)ANTITHYROID DRUGS (Thioamides)

Propylthiouracil, Methimazole, Carbimazole
By convention, only the hormone synthesis
inhibitors are called antithyroid drugs, though this term has also
been applied to all thyroid inhibitors. Thiourea derivatives were
found to produce goiter and hypothyroidism in rats in the
1940s.
Open chain compounds were found to be toxic.
Subsequently, methyl and propyl thiouracil and thioimidazole
derivatives methimazole and carbimazole were found to be
safe and effective. Antithyroid drugs bind to the thyroid
peroxidase and prevent oxidation of iodide/ iodotyrosyl
residues, thereby;
(i) Inhibit iodination of tyrosine residues in thyroglobulin
(ii) Inhibit coupling of iodotyrosine residues to form T3 and T4.
Action has been observed at lower concentration of
antithyroid drugs than action
(iii) Thyroid colloid is depleted over time and blood levels of
T3/T4 are progressively lowered

Thioamides do not interfere with trapping of iodide and do not

modify the action of T3 and T4 on peripheral tissues or on
pituitary.
Goiter is not the result of potentiation of TSH action on thyroid,
but is due to increased TSH release as a consequence of
reduction in feedback inhibition. No goiter occurs if antithyroid
drugs are given to hypophysectomised animals or if T4 is given
along with them. Antithyroid drugs do not affect release of T3
and T4—their effects are not apparent till thyroid is depleted of
its hormone content.
Propylthiouracil also inhibits peripheral conversion of T4 to T3
by D1 type of 5’DI, but not by D2 type. This may partly
contribute to its antithyroid effects.
Methimazole and carbimazole do not have this action and may
even antagonize that of propylthiouracil.
Pharmacokinetics
All antithyroid drugs are quickly absorbed orally,
widely distributed in the body, enter milk and cross placenta;
are metabolized in liver and excreted in urine primarily as
metabolites. All are concentrated in thyroid: intrathyroid t½ is
longer: effect of a single dose lasts longer than would be
expected from the plasma t½. Carbimazole acts largely by
getting converted to methimazole in the body and is longer
acting than propythiouracil.

Adverse effects
Hypothyroidism and goiter can occur due to
overtreatment, but is reversible on stopping the drug. It is
indicated by enlargement of thyroid, and is due to excess TSH
production. Goiter does not develop with appropriate doses
which restore T4 concentration to normal so that feedback TSH
inhibition is maintained. Important side effects are: g.i.
intolerance, skin rashes and joint pain. Loss or graying of hair,
loss of taste, fever and liver damage are infrequent. A rare but
serious adverse effect is agranulocytosis (1 in 500 to 1000
cases); It is mostly reversible. There is partial cross reactivity
between propylthiouracil and carbimazole.
Preparations and dose
Propylthiouracil: 50–150 mg TDS followed by 25–50 mg BD–
TDS for maintenance. PTU 50 mg tab. Methimazole: 5–10 mg
TDS initially, maintenance dose 5–15 mg daily in 1–2 divided
doses. Carbimazole: 5–15 mg TDS initially, maintenance dose
2.5–10 mg daily in 1–2 divided doses, NEO MERCAZOLE,
THYROZOLE, ANTITHYROX 5 mg tab.
Carbimazole is more commonly used in India. Propylthiouracil
(600–900 mg/day) may be preferred in thyroid storm for its
inhibitory action on peripheral conversion of T4 to more active
T3. It is also used in patients developing adverse effects with
carbimazole.
Use Antithyroid drugs control thyrotoxicosis in both Graves’
disease and toxic nodular goiter. Clinical improvement starts
after 1–2 weeks or more (depending on hormone content of
thyroid gland). Iodide loaded patients (who have received
iodide containing contrast media/cough mixtures, amiodarone)
are less responsive.
Maintenance doses are titrated on the basis of clinical status of
the patient. The following strategies are adopted.
(i) As definitive therapy
(a) Remission may occur in upto half of the patients of
Graves’ disease after 1–2 years of treatment: the drug can
then be withdrawn. If symptoms recur—treatment is
reinstituted. This is preferred in young patients with a
short history of Graves’ disease and a small goiter. (b)
Remissions are rare in toxic nodular goiter: surgery (or
131I) is preferred. However, in frail elderly patient with
multinodular goiter who may be less responsive to 131I,
permanent maintenance therapy with antithyroid drugs
can be employed.
(ii) (ii) Preoperatively Surgery in thyrotoxic patients is risky.
 Young patients with florid hyperthyroidism and substantial
goiter are rendered euthyroid with carbimazole before
performing subtotal thyroidectomy.
(iii) (iii) Along with 131I Initial control with antithyroid drug—1
to 2 weeks gap—radioiodine dosing— resume antithyroid
drug after 5–7 days and gradually withdraw over 3 months
as the response to 131I develops. This approach is
preferred in older patients who are to be treated with 131I,
but require prompt control of severe hyperthyroidism. This
will also prevent initial hyperthyroidism following 131I due
to release of stored T4. Advantages of antithyroid drugs
over surgery/131I are:
(a) No surgical risk, scar or chances of injury to
parathyroid glands or recurrent laryngeal nerve.
(b) Hypothyroidism, if induced, is reversible.
(c) Can be used even in children and young adults.
Disadvantages are: (a) Prolonged (often life-long)
treatment is needed because relapse rate is high. (b) Not
practicable in uncooperative/unintelligent patient. (c) Drug
toxicity.
Thyroidectomy and 131I are contraindicated during pregnancy.
With antithyroid drugs risk of foetal hypothyroidism and goiter is
there. However, low doses of propylthiouracil are preferred: its
greater protein binding allows less transfer to the foetus. For
the same reason it is to be preferred in the nursing mother.
However, methimazole has also now been found to be safe
during pregnancy. Propylthiouracil is used in thyroid storm as
well

22)Local anaesthetics
(LAs) are drugs which upon topical application
or local injection cause reversible loss of sensory perception,
especially of pain, in a restricted area of the body. They block
generation and conduction of nerve impulse at any part of the
neurone with which they come in contact, without causing any
structural damage. Thus, not only sensory but also motor
impulses are interrupted when a LA is applied to a mixed nerve,
resulting in muscular paralysis and loss of autonomic control as
well.

CLASSIFICATION
(i) Injectable anaesthetic
• Low potency, short duration = Procaine ,Chloroprocaine,
• Intermediate potency and duration Lidocaine (Lignocaine)
Prilocaine
• High potency, long duration Tetracaine (Amethocaine)
Bupivacaine Ropivacaine Dibucaine (Cinchocaine)
(ii) Surface anaesthetic
• Soluble
Cocaine
Lidocaine
Benoxinate
• Insoluble
Benzocaine
Butylaminobenzoate
Tetracaine (Butamben)
Oxethazaine
MECHANISM OF ACTION
LAs block nerve conduction by decreasing the entry of
Na+ ions during upstroke of action potential (AP). As the
concentration of the LA is increased, the rate of rise of AP
and maximum depolarization decreases causing
slowing of conduction. Finally, local depolarization fails to
reach the threshold potential and conduction block
ensues. The LAs interact with a receptor situated within
the voltage sensitive Na+ channel and raise the threshold
of channel opening: Na+ permea
Effect of progressively increasing concentrations of a
local anaesthetic on the generation of an action potential
in a nerve fibre,
(a) Untreated nerve fibre ability fails to increase in
response to an impulse or stimulus. Impulse conduction is
interrupted when the Na+ channels over a critical length
of the fibre (2–3 nodes of Ranvier in case of myelinated
fibres) are blocked. The details are explained in . At
physiological pH, the LA molecule is partly ionized. The
equilibrium between the unionized base form
(B) and the ionized cationic form (BH+) depends on the
pKa of the LA. Potency of a LA generally corresponds to
the lipid solubility of its base form (B), because it is this
form which penetrates the axon. However, the
predominant active species is the cationic form of the LA
which is able to approach its receptor only when the
channel is open at the inner face, and it binds more avidly
to the activated and inactivated states of the channel, than
to the resting state. Binding of the LA prolongs the
inactivated state. The channel takes longer to recover →
refractory period of the fibre is increased.
A resting nerve is rather resistant to
blockade. Blockade develops rapidly when the nerve is
stimulated repeatedly. The degree of blockade is
frequency dependent: greater blockade occurs at higher
frequency of stimulation. Moreover, exposure to higher
concentration of Ca2+ reduces inactivation of
Na+channels and lessens the degree of block. Blockade
of conduction by LA is not due to hyperpolarization; in
fact, resting membrane potential is unaltered because K+
channels are blocked only at higher concentrations of LA.
The onset time of blockade is related primarily to the pKa
of the LA.
Those with lower pKa , e.g. lidocaine,
mepivacaine are fast acting, because 30–40% LA is in the
undissociated base form at pH 7.4 and it is this form
which penetrates the axon. Procaine, tetracaine,
bupivacaine have higher pKa (8.1–8.9), only 15% or less
is unionized at pH 7.4; these are slow acting.
Chloroprocaine is an exception, having rapid onset
despite high pKa

23)LINCOSAMIDE ANTIBIOTICS
Clindamycin
This potent lincosamide antibiotic is similar in mechanism
of action (inhibits protein synthesis by binding to 50S
ribosome) and spectrum of activity to erythromycin with
which it exhibits partial cross resistance. Modification of
the ribosomal binding site by the constitutive methylase
enzyme confirs resistance to both, but not the inducible
enzyme. Antibiotic efflux is not an important mechanism of
clindamycin resistance.
Clindamycin inhibits most grampositive cocci
(including most species of streptococci, penicillinase
producing Staph., but not MRSA), C. diphtheriae,
Nocardia, Actinomyces, Toxoplasma and has slow action
on Plasmodia. However, the distinctive feature is its high
activity against a variety of anaerobes, especially Bact.
fragilis. Aerobic gram-negative bacilli, spirochetes,
Chlamydia, Mycoplasma and Rickettsia are not affected.
Oral absorption of clindamycin is good. It penetrates into
most skeletal and soft tissues, but not in brain and CSF;
accumulates in neutrophils and macrophages.
It is largely metabolized and metabolites are
excreted in urine and bile. The t½ is 3 hr. Side effects are
rashes, urticaria, abdominal pain, but the major problem is
diarrhoea and pseudomembranous enterocolitis due to
Clostridium difficile superinfection which is potentially
fatal. The drug should be promptly stopped and oral
metronidazole (alternatively vancomycin) given to treat it.
Thrombophlebitis of the injected vein can
occur on i.v. administration. Because of the potential
toxicity, use of clindamycin is restricted to anaerobic and
mixed infections, especially those involving Bact. fragilis
causing abdominal, pelvic and lung abscesses. It is a first
line drug for these conditions, and is generally combined
with an aminoglycoside or a cephalosporin.
Metronidazole and chloramphenicol are the
alternatives to clindamycin for covering the anaerobes.
Skin and soft tissue infections in patients allergic to
penicillins can be treated with clindamycin. Anaerobic
streptococcal and Cl. perfringens infections, especially
those involving bone and joints respond well.
It has also been employed for prophylaxis
of endocarditis in penicillin allergic patients with valvular
defects who undergo dental surgery, as well as to prevent
surgical site infection in colorectal/pelvic surgery. In AIDS
patients, it has been combined with pyrimethamine for
toxoplasmosis and with primaquine for Pneumocystis
jiroveci pneumonia. It is an alternative to doxycycline for
supplementing quinine/artesunate in treating multidrug
resistant falciparum malaria. Topically it is used for
infected acne vulgaris.

23)BETA-LACTAMASE INHIBITORS
β-lactamases are a family of enzymes produced by many
gram-positive and gram-negative bacteria that inactivate
β-lactam antibiotics by opening the β-lactam ring. Different
β-lactamases differ in their substrate affinities. Three
inhibitors of this enzyme clavulanic acid, sulbactam and
tazobactam are available for clinical use.
Clavulanic acid Obtained from
Streptomyces clavuligerus, it has a β-lactam ring but no
antibacterial activity of its own. It inhibits a wide variety
(class II to class V) of β-lactamases (but not class I
cephalosporinase) produced by both gram-positive and
gram-negative bacteria. Clavulanic acid is a ‘progressive’
inhibitor: binding with β-lactamase is reversible initially,
but becomes covalent later—inhibition increasing with
time. Called a ‘suicide’ inhibitor, it gets in activated after
binding to the enzyme. It permeates the outer layers of
the cell wall of gram-negative bacteria and inhibits the
periplasmically located β-lactamase.
Pharmacokinetics:
Clavulanic acid has rapid oral
absorption and a bioavailability of 60%; can also be
injected. Its elimination t½ of 1 hr and tissue distribution
matches amoxicillin, with which it is combined (called
coamoxiclav). However, it is eliminated mainly by
glomerular filtration and its excretion is not affected by
probenecid.
Moreover, it is largely hydrolysed and
decarboxylated before excretion, while amoxicillin is
primarily excreted unchanged by tubular secretion. Uses
Addition of clavulanic acid re-establishes the activity of
amoxicillin against β-lactamase producing resistant Staph.
aureus (but not MRSA that have altered PBPs), H.
influenzae, N. gonorrhoeae, E. coli, Proteus, Klebsiella,
Salmonella and Shigella. Though Bact. fragilis and
Branhamella catarrhalis are not responsive to amoxicillin
alone, they are inhibited by the combination. Clavulanic
acid does not potentiate the action of amoxicillin against
strains that are already sensitive to it. Coamoxiclav is
indicated for:
• Skin and soft tissue infections, intraabdominal and
gynaecological sepsis, urinary, biliary and respiratory tract
infections: especially when empiric antibiotic therapy is to
be given for hospital acquired infections.
• Gonorrhoea (including PPNG) single dose amoxicillin 3
g + clavulanic acid 0.5 g + probenecid 1 g is highly
curative.
AUGMENTIN, ENHANCIN, AMONATE:
Amoxicillin 250 mg + clavulanic acid 125 mg tab; also 500
mg + 125 mg tab; 125 mg + 31.5 mg per 5 ml dry syr;
CLAVAM 250 + 125 mg tab, 500 + 125 mg tab, 875 + 125
mg tab, 125 mg + 32 mg per 5 ml dry syr, 1–2 tab TDS.
Also AUGMENTIN, CLAVAM: Amoxicillin 1 g + clavulanic
acid 0.2 g vial and 0.5 g + 0.1 g vial; inject 1 vial deep i.m.
or i.v. 6–8 hourly for severe infections.
It is more expensive than amoxicillin alone.
Adverse effects are the same as for amoxicillin alone; but
g.i. tolerance is poorer—especially in children. Other
adverse effects are Candida stomatitis/vaginitis and
rashes. Some cases of hepatic injury have been reported
with the combination.
Sulbactam
It is a semisynthetic β-lactamase
inhibitor, related chemically as well as in activity to
clavulanic acid. It is also a progressive inhibitor, highly
active against class II to V but poorly active against class I
β-lactamase. On weight basis, it is 2–3 times less potent
than clavulanic acid for most types of the enzyme, but the
same level of inhibition can be obtained at the higher
concentrations achieved clinically. Sulbactam does not
induce chromosomal β-lactamases, while clavulanic acid
can induce some of them.
Oral absorption of sulbactam is
inconsistent. Therefore, it is preferably given parenterally.
It has been combined with ampicillin for use against β-
lactamase producing resistant strains. Absorption of its
complex salt with ampicillin— sultamicillin tosylate is
better, which is given orally.

Indications are:
• PPNG gonorrhoea; sulbactam per se also inhibits N.
gonorrhoeae.
• Mixed aerobic-anaerobic infections, intraabdominal,
gynaecological, surgical and skin/ soft tissue infections,
especially those acquired in the hospital.
SULBACIN, AMPITUM: Ampicillin 1 g + sulbactam 0.5 g
per vial inj; 1–2 vial deep i.m. or i.v. injection 6–8 hourly.
Sultamicillin tosylate: BETAMPORAL, SULBACIN 375 mg
tab.
Sulbactam has been combined with cefoperazone and
ceftriaxone also (see p.728). Pain at site of injection,
thrombophlebitis of injected vein, rash and diarrhoea are
the main adverse effects.

Tazobactam
It is another β-lactamase inhibitor
similar to sulbactam. Its pharmacokinetics matches with
piperacillin with which it has been combined for use in
severe infections like peritonitis, pelvic/urinary/respiratory
infections caused by β-lactamase producing bacilli.
However, the combination is not active against
piperacillin-resistant Pseudomonas, because tazobactam
(like clavulanic acid and sulbactam) does not inhibit
inducible chromosomal βlactamase produced by
Enterobacteriaceae. It is also of no help against
Pseudomonas that develop resistance by losing
permeability to piperacillin.
Dose: 0.5 g combined with piperacillin 4 g injected i.v.
over 30 min 8 hourly. PYBACTUM, TAZACT, TAZOBID,
ZOSYN 4 g + 0.5 g vial for inj. Tazobactam has been
combined with ceftriaxone as well (see p. 728).

24)CALCINEURIN INHIBITORS (Specific T-cell inhibitors)

Cyclosporine It is a cyclic polypeptide with 11
amino acids, obtained from a fungus and introduced in
1977 as a highly selective immunosuppressant which has
markedly increased the success of organ transplantations.
It profoundly and selectively inhibits T lymphocyte
proliferation, IL-2 and other cytokine production as well as
response of inducer T cells to IL-1, without any effect on
suppressor T-cells. Lymphocytes are arrested in G0 or G1
phase.
The CD4 molecule associated with T cell
receptor on helper T cells anchors the major
histocompatibility complex class II (MHC II) carrying the
antigen peptide so that it is able to activate the T cell
receptor (Fig. 63.2). Stimulation of T cell receptor
phosphorylates PLc, which hydrolyses PIP2 to generate
DAG and IP3. While DAG activates PKc to produce
MAPkinase dependent and other actions, IP3 releases
intracellular Ca2+. After binding to calmodulin this Ca2+
activates a membrane associated serine/ threonine
phosphatase called calcineurin which dephosphorylates
regulatory protein ‘nuclear factor of activated T-cell’
(NFAT), permitting its intranuclear migration and
transcription of cytokine genes leading to production of IL-
2 along with other interleukins, GM-CSF, TNFα, interferon,
etc. IL-2 is the major cytokine for T-cell multiplication and
differentiation.
Cyclosporine enters target cells and binds to
cyclophilin, an immunophilin class of protein. The complex
then binds to and inactivates calcineurin → response of
the helper T cell to antigenic stimulation fails.
Cyclosporine also enhances expression of transforming
growth factor β (TGFβ), an inhibitor of IL-2 which
attenuates IL-2 stimulated T-cell proliferation and
production of killer lymphocytes. Cyclosporine is most
active when administered before antigen exposure, but
can, in addition, suppress the responses of primed helper
T cells; hence useful in autoimmune diseases as well.

Cyclosporine selectively suppresses cell

mediated immunity (CMI), prevents graft rejection and yet
leaves the recipient with enough immune activity to
combat bacterial infection. Unlike cytotoxic
immunosuppressants, it is free of toxic effects on bone
marrow and RE system. Humoral immunity remains intact.
However, it is nephro toxic—the major limitation, and
impairs liver function. Other adverse effects are sustained
rise in BP, precipitation of diabetes, anorexia, lethargy,
hyperkalaemia, hyperuricaemia, opportunistic infections,
hirsutism, gum hyperplasia, tremor and seizures.
Cyclosporine is the most effective drug for
prevention and treatment of graft rejection reaction. It is
routinely used in renal, hepatic, cardiac, bone marrow and
other transplantations. For induction it is started orally 12
hours before the transplant and continued for as long as
needed.
When graft rejection has started, it can be
given i.v., because oral bioavailability is low, dependent on
presence of bile and is highly variable. Blood level
monitoring is required for effective therapy. It is
concentrated in WBCs and RBCs, metabolized in liver by
CYP3A4 and excreted in bile. The plasma t½ is biphasic
4–6 hr and 12–18 hr.
Dose: 10–15 mg/kg/day with milk or fruit juice till 1–2
weeks after transplantation, gradually reduced to
maintenance dose of 2–6 mg/kg/day. Therapy may be
started with 3–5 mg/kg i.v. infusion.
Cyclosporine is a second line drug in
autoimmune diseases, like severe rheumatoid arthritis,
uveitis, bronchial asthma, inflammatory bowel disease,
dermatomyositis, etc. and in psoriasis, especially to
suppress acute exacerbations. It is generally used along
with corticosteroids or Mtx. Good results have been
obtained in some cases of aplastic anaemia. For these
conditions, lower doses (2–5 mg/kg/day) are needed and
adverse effects are milder. However, it is not curative and
relapses occur when the drug is withdrawn. Drug
interactions Cyclosporine can interact with a large number
of drugs.
All nephrotoxic drugs like aminoglycosides, vancomycin,
amphotericin B and NSAIDs enhance its toxicity.
By depressing renal function, it can reduce
excretion of many drugs. Phenytoin, phenobarbitone,
rifampin and other enzyme inducers lower its blood levels
so that transplant rejection may result. On the other hand,
CYP3A4 inhibitors erythromycin, ketoconazole and
related drugs inhibit its metabolism to increase
bioavailability and cause toxicity. Potassium supplements
and K+ sparing diuretics can produce marked
hyperkalaemia in patients on cyclosporine

25)Ketamine
This unique anaesthetic is
pharmacologically related to the hallucinogen
phencyclidine. It induces a so called ‘dissociative
anaesthesia’ characterized by profound analgesia,
immobility, amnesia with light sleep. The patient appears
to be conscious, i.e. opens his eyes, makes swallowing
movements and his muscles are stift, but he is unable to
process sensory stimuli and does not reeact to them.
Thus, the patient appears to be dissociated from his body
and surroundings. The primary site of action is in the
cortex and subcortical areas; not in the reticular activating
system, which is the site of action of barbiturates.
Respiration is not depressed, bronchi
dilate, airway reflexes are maintained, muscle tone
increases. Non-purposive limb movements occur. Heart
rate, cardiac output and BP are elevated due to
sympathetic stimulation. A dose of 1–2 (average 1.5)
mg/kg i.v. or 3–5 mg/kg i.m. produces the above effects
within a minute, and recovery starts after 10–15 min, but
patient remains amnesic for 1–2 hr.
Emergence delirium, hallucinations and
involuntary movements occur in upto 50% patients during
recovery; but the injection is not painful. Children tolerate
the drug better. Ketamine is rapidly metabolized in the
liver and has an elimination t½ of 2–4 hr. Ketamine has
been used for operations on the head and neck, in
patients who have bled, in asthmatics (relieves
bronchospasm), in those who do not want to lose
consciousness and for short operations.
It is good for repeated use; particularly
suitable for burn dressing. Combined with diazepam, it
has found use in angiographies, cardiac catheterization
and trauma surgery. It may be dangerous for
hypertensives, in ischaemic heart disease (increases
cardiac work), in congestive heart failure and in those with
raised intracranial pressure (ketamine increases cerebral
blood flow and O2 consumption), but is good for
hypovolemic patients. KETMIN, KETAMAX, ANEKET 50
mg/ml in 2 ml amp, 10 ml vial. Clandestinely mixed in
drinks, ketamine has been misused as rape drug.

26)ANTIAMOEBIC DRUGS
These are drugs useful in infection
caused by the anaerobic protozoa Entamoeba histolytica.
Other Entamoeba species are generally nonpathogenic.
Amoebiasis has a worldwide distribution (over 50 million
people are infected), but it is endemic in most parts of
India and other developing countries. Poor environmental
sanitation and low socio-economic status are important
factors in the spread of the disease, which occurs by
faecal contamination of food and water. Amoebic cysts
reaching the intestine transform into trophozoites which
either live on the surface of colonic mucosa as
commensals— form cysts that pass into the stools
(luminal cycle) and serve to propagate the disease, or
invade the mucosa—form amoebic ulcers (Fig. 60.1) and
cause acute dysentery (with blood and mucus in stools) or
chronic intestinal amoebiasis (with vague abdominal
symptoms, amoeboma).
Occasionally the trophozoites pass
into the bloodstream, reach the liver via portal vein and
cause amoebic liver abscess. Other organs like lung,
spleen, kidney and brain are rarely involved in
extraintestinal amoebiasis. In the tissues, only
trophozoites are present; cyst formation does not occur.
Tissue phase is always secondary to intestinal
amoebiasis, which may be asymptomatic. In fact, most
chronic cyst passers are asymptomatic. In the colonic
lumen, the Entamoebae live in symbiotic relationship with
bacteria, and a reduction in colonic bacteria reduces the
amoebic population.
The ‘Brazil root’ or Cephaelis
ipecacuanha was used for the treatment of dysentery in
the 17th century. The pure alkaloid emetine obtained from
it was found to be a potent antiamoebic in 1912. Emetine
remained the most efficacious and commonly used drug
for amoebiasis till 1960. Many 8hydroxyquinolines
(quiniodochlor, etc.) became very popular drugs for
diarrhoea and amoebic dysentery, but have come under a
cloud since they were held responsible for causing
epidemics of ‘Subacute myelo-optic neuropathy’ (SMON)
in Japan in 1970s.

CLASSIFICATION
1. Tissue amoebicides
a) For both intestinal and extraintestinal amoebiasis:
Nitroimidazoles: Metronidazole, Tinidazole, Secnidazole,
Ornidazole, Satranidazole Alkaloids: Emetine,
Dehydroemetine
(b) For extraintestinal amoebiasis only: Chloroquine
2. Luminal amoebicides
(a) Amide : Diloxanide furoate, Nitazoxanide
(b) 8-Hydroxyquinolines: Quiniodochlor
(Iodochlorohydroxyquin, Clioquinol), Diiodohydroxyquin
(Iodoquinol)
(c)Antibiotics: Tetracyclines, Paromomycin

Uses
1. Amoebiasis: Metronidazole is a first line drug for all
forms of amoebic infection. Many dosage regimens have
been tried; the current recommendations are:
For invasive dysentery and liver abscess—800 mg
TDS (children 30–50 mg/kg/day) for 7–10 days. In severe
cases of amoebic dysentery or liver abscess 500 mg may
be infused i.v. slowly every 6–8 hours for 7–10 days or till
oral therapy can be instituted. For mild intestinal disease
—400 mg TDS for 5–7 days. Metronidazole is less
effective than many luminal amoebicides in eradicating
amoebic cysts from the colon, because it is nearly
completely absorbed from the upper bowel.
2. Giardiasis It is highly effective in a dose of 400 mg TDS
for 7 days. A shorter course of 3 days with 2 g/day is
equally effective.
3. Trichomonas vaginitis It is the drug of choice; 2.0 g
single dose is preferred. Alternatively 400 mg BD–TDS
may be used for 7 days. Additional intravaginal treatment
is needed only in refractory cases. Repeated courses may
be necessary in some patients, but should be given with
gaps of 4–6 weeks. The male partner should be treated
concurrently in cases of recurrent infections. Nonspecific
bacterial vaginosis also responds.
4. Anaerobic bacterial infections They occur mostly after
colorectal or pelvic surgery, appendicectomy, etc. Brain
abscesses and endocarditis may be caused by anaerobic
organisms. Metronidazole is an effective drug for these
and is generally used in combination with gentamicin or
cephalosporins (many are mixed infections). For serious
cases i.v. administration is recommended: 15 mg/kg
infused over 1 hr followed by 7.5 mg/kg every 6 hrs till oral
therapy can be instituted with 400–800 mg TDS.
Prophylactic use in high risk situations (colorectal/biliary
surgery) is recommended. Other drugs effective in
anaerobic infections are clindamycin and
chloramphenicol.
5. Helicobacter pylori gastritis/peptic ulcer (see p. 657)
Metronidazole or tinidazole alone are ineffective in
eradicating H. pylori; resistance develops. Metronidazole
400 mg TDS or tinidazole 500 mg BD are combined with
amoxicillin/clarithromycin and a proton pump inhibitor in
triple drug 2 week regimens
27)ASA Mesalazine (Mesalamine)
These are the official names given to 5-ASA.
Realizing that 5-ASA is the active moiety in UC, but is not
effective orally because of inability to reach the large
bowel (it is absorbed in the small intestine), it has been
formulated as a delayed release preparation or has been
coated with pH sensitive acrylic polymer. The pattern of
release over the length of jejunum, ileum and colon differs
among the different formulations. The coated formulation
(ASACOL, MESACOL) delivers 5-ASA to the distal small
bowel and colon.
A daily dose of 2.4 g has been found to improve
over 50% patients of UC (upto 80% mild-to-moderate
cases). Less than half of the 5-ASA released from these
preparations is absorbed systemically, acetylated in the
liver and excreted in urine. Like sulfasalazine, the primary
use of mesalazine is in preventing relapse of UC, though
it may also be employed to treat mild-tomoderate
exacerbations or as adjunct to corticosteroid in more
severe active disease. Higher dose of coated mesalazine
may induce remission in mild cases of Crohn’s colitis as
well, but efficacy is uncertain. It is not useful in
maintaining remission in CrD. MESACOL 400 mg, 800 mg
tab, 0.5 g suppository; ASACOL, TIDOCOL 400 mg tab;
ETISA 500 mg sachet.
Adverse effects Coated mesalazine is much better
tolerated than sulfasalazine. Side effects noted are
nausea, diarrhoea, abdominal pain and headache, but are
mild and less frequent. Serious adverse effects are fever,
itching and leucopenia. Rashes and hypersensitivity
reactions are rare. Bone marrow depression and
decreased sperm count has not occurred.
Mesalazine has nephrotoxic potential,
because 30–40% of 5-ASA is released in the ileum and is
absorbed. It is contraindicated in renal and hepatic
impairment.
 Drug interactions Coated mesalazine may
enhance the gastric toxicity of glucocorticoids and
hypoglycaemic action of sulfonylureas. Interaction with
coumarins, furosemide, spironolactone, methotrexate and
rifampicin are possible. 5-ASA enema Another mode of
delivery of 5-ASA to colon is to administer it by a retention
enema: 4 g enema once or twice daily is effective in distal
ulcerative colitis and proctitis, including some refractory
cases.5-ASA enema is not useful for maintenance of
remission. MESACOL ENEMA 4 g/60 ml.
28)SUCCINYLCHOLINE
DEPOLARIZING BLOCK
Decamethonium and SCh have affinity
as well as submaximal intrinsic activity at the NM
cholinoceptors. They depolarize muscle end plates by
opening Na+ channels (just as ACh does) and initially
produce twitching and fasciculations. Because in the
focally innervated mammalian muscle, stimulation is
transient; longer lasting depolarization of muscle end plate
produces repetitive excitation of the fibre. In the multiplely
innervated contracture muscle (rectus abdominis of frog)
stimulation is prolonged resulting in sustained contraction.
These drugs do not dissociate rapidly from the receptor
and are not hydrolysed by AChE.
They induce prolonged partial
depolarization of the region around muscle end plate →
Na+ channels get inactivated (because transmembrane
potential drops to about –50 mV) → ACh released from
motor nerve endings is unable to generate propagated
MAP → flaccid paralysis in mammals. In other words a
zone of inexcitability is created around the end plate
preventing activation of the muscle fibre. In birds, the area
of depolarization is more extensive and spastic paralysis
occurs. Depolarizing blockers also have 2 quaternary N+
atoms, but the molecule is long, slender and flexible—
termed Leptocurare by Bovet.
 The features of classical depolarizing block
differ markedly from that of nondepolarizing block (see
Fig. 25.2 and Table 25.1). However, in many species, e.g.
dog, rabbit, rat, monkey, in slow contracting soleus
muscle of cat, and under certain conditions in man the
depolarizing agents injected in high doses or infused
continuously produce dual mechanism neuromuscular
blockade which can be divided into two phases:
Phase I block It is rapid in onset, results from persistent
depolarization of muscle end plate and has features of
classical depolarization blockade. This depolarization
declines shortly afterwards and repolarization occurs
gradually despite continued presence of the drug at the
receptor, but neuromuscular transmission is not restored
and phase II block supervenes.
Phase II block It is slow in onset and results from
desensitization of the receptor to ACh. It, therefore,
superficially resembles block produced by d-TC.
The muscle membrane is nearly
repolarized, recovery is slow, contraction is not sustained
during tetanic stimulation (‘fade’ occurs) and the block is
partially reversed by anticholinesterases. In man and fast
contracting muscle (tibialis anterior) of cat, normally only
phase I block is seen. Phase II block may be seen in man
when SCh is injected in high dose or infused
Succinylcholine
Despite its propensity to cause muscle
fasciculations and soreness, changes in BP and HR,
arrhythmias, histamine release and K+ efflux from
muscles causing hyperkalaemia and its complications,
SCh is the most commonly used muscle relaxant for
passing tracheal tube.
It induces rapid, complete and
predictable paralysis with spontaneous recovery in ~5
min. Excellent intubating condition viz. relaxed jaw, vocal
cords apart and immobile with no diaphragmatic
movements, is obtained within 1–1.5 min. Occasionally
SCh is used by continuous i.v. infusion for producing
controlled muscle relaxation of longer duration. It should
be avoided in younger children unless absolutely
necessary, because risk of hyperkalaemia and cardiac
arrhythmia is higher. Risk of regurgitation and aspiration
of gastric contents is increased by SCh in GERD patients
and in the obese, especially if stomach is full. MIDARINE,
SCOLINE, MYORELEX, ENTUBATE 50 mg/ml inj, 2 ml
amp.

29)CYCLOPHOSPHAMIDE
It is inactive as such: produces few acute
effects and is not locally damaging. Transformation into
active metabolites (aldophosphamide, phosphoramide
mustard) occurs in the liver, and a wide range of
antitumour actions is exerted. It has prominent
immunosuppressant property.
Thus, it is one of the most popular
alkylating agents useful in many solid tumours. It is less
damaging to platelets, but alopecia and cystitis (due to
another metabolite acrolein) are prominent.
Chloramphenicol retards the metabolism of
cyclophosphamide. Dose: 2–3 mg/kg/day oral; 10–15
mg/kg i.v. every 7–10 days, i.m. use also possible.
ENDOXAN, CYCLOXAN 50 mg tab; 200, 500, 1000
mginj.
30)PLATINUM COORDINATION COMPLEXES
Cisplatin
It is hydrolysed intracellularly to produce a
highly reactive moiety which causes cross linking of DNA.
The favoured site is N7 of guanine residue. It can also
react with –SH groups of cytoplasmic and nuclear
proteins. Effects resemble those of alkylating agents and
radiation. It is bound to plasma proteins, penetrates
tissues and is slowly excreted unchanged in urine witha
t½ of about 72 hrs. Negligible amounts enter brain. A
copper transporter CTR1 is involved in the entry of
platinum complexes into the tumour cells. The same are
extruded from the cells by the transporter MRP1 as well
as by copper efflux proteins. Resistance to cisplatin can
be imparted by variation in the levels of these proteins.
Cisplatin is very effective in metastatic testicular and
ovarian carcinoma.
It is widely used in many other solid
tumours like lung, bladder, esophageal, gastric, hepatic,
head and neck carcinomas. Cisplatin is administered by
slow i.v. infusion 50–100 mg/m2 BSA every 3–4 weeks;
CISPLATIN, CISPLAT, PLATINEX 10 mg/10 ml, 50 mg/50
ml vial. Cisplatin is a highly emetic drug. Antiemetics are
routinely administered before infusing it. The most
important toxicity is renal impairment which is dependent
on total dose administered. Renal toxicity can be reduced
by maintaining good hydration. Tinnitus, deafness,
sensory neuropathy and hyperuricaemia are other
problems. A shock like state sometimes occurs during i.v.
infusion

31)Pentoxiphylline (Oxpentifylline) An analogue of

theophylline and a weak phosphodiesterase (PDE)
inhibitor, it has been shown to increase blood flow in
ischaemic areas by reducing whole blood viscosity and by
improving flexibility of RBCs. The rheological (dealing with
property of flow) action rather than vasodilatation is said
to be responsible for improving passage of blood through
microcirculation. Thus, the ‘steal’ phenomenon is not
likely. Oral doses do not affect heart rate, t.p.r. or BP.
Pentoxiphylline is usually well
tolerated: side effects are nausea, vomiting, dyspepsia
and bloating which can be minimized by taking the drug
after meals. Dose: 400 mg BD–TDS; TRENTAL-400,
FLEXITAL 400 mg SR tab, 300 mg/15 ml for slow i.v.
injection.
Pentoxiphylline is mainly used in
intermittent claudication (calf pain on walking) due to
occlusive vascular disease (Buerger’s disease); walking
distance is increased. Other conditions claimed to be
improved are: trophic leg ulcers, transient ischaemic
attacks (TIAs), nonhaemorrhagic stroke, and chronic
cerebrovascular insufficiency. However, overall benefits
are modest and restricted to a fraction of patients.

32)IMMUNOSUPPRESSANTS are drugs which inhibit

cellular/humoral or both types of immune responses, and
have their major use in organ transplantation and
autoimmune diseases. The important drugs are:
1. Calcineurin inhibitors (Specific T-cell inhibitors)
Cyclosporine (Ciclosporin), Tacrolimus
2. m-TOR inhibitors Sirolimus, Everolimus
3. Antiproliferative drugs (Cytotoxic drugs) Azathioprine,
Methotrexate, Cyclophosphamide, Chlorambucil,
Mycophenolate mofetil (MMF)
4. Glucocorticoids Prednisolone and others
5. Biological agents
o TNF α inhibitors: Etanercept, Infliximab,
Adalimumab
o IL-1 receptor antagonist: Anakinra
o IL-2 receptor antagonists: Daclizumab, (anti CD-25
antibodies) Basiliximab
o Anti CD-3 antibody: Muromonab CD3
o Polyclonal antibodies: Antithymocyte antibody
(ATG), Rho (D) immune globulin.
33)INTRAVENOUS ANAESTHETICS FAST ACTING
DRUGS
Thiopentone sod. It is an ultrashort acting
thiobarbiturate, highly soluble in water yielding a very
alkaline solution, which must be prepared freshly before
injection. Extravasation of the solution or inadvertent
intraarterial injection produces intense pain; necrosis and
gangrene can occur. Injected i.v. (3–5 mg/kg) as a 2.5%
solution, it produces unconsciousness in 15–20 sec. Its
undissociated form has high lipid solubility— enters brain
almost instantaneously. Initial distribution depends on
organ blood flow—brain gets large amounts. However, as
other less vascular tissues (muscle, fat) gradually take up
the drug, blood concentration falls and it back diffuses
from the brain: consciousness is regained in 6– 10 min
(t½ of distribution phase is 3 min).

On repeated injection, the extracerebral

sites are gradually filled up—lower doses produce
anaesthesia which lasts longer. Its ultimate disposal
occurs mainly by hepatic metabolism (elimination t½ is 8–
12 hr), but this is irrelevant for termination of action of a
single dose. Residual CNS depression may persist for >
12 hr. The patient should not be allowed to leave the
hospital without an attendant before this time.
Thiopentone is a poor analgesic. Painful procedures
should not be carried out under its influence unless an
opioid or N2O has been given; otherwise, the patient may
struggle, shout and show reflex changes in BP and
respiration.
It is a weak muscle relaxant; does not
irritate air passages. Respiratory depression with inducing
doses of thiopentone is generally marked but transient.
With large doses it can be severe. BP falls immediately
after injection mainly due to vasodilatation, but recovers
rapidly. Cardiovascular collapse may occur if
hypovolemia, shock or sepsis are present. Reflex
tachycardia occurs, but thiopentone does not sensitize the
heart to Adr, arrhythmias are rare.
Cerebral blood flow is reduced, both
due to fall in BP as well as constriction of cerebral
vessels. However, cerebral oxygenation does not suffer,
because there is greater decrease in cerebral O2
consumption and cerebral perfusion is maintained. A
comparative summary of effects of i.v. anaesthetics is
presented in Table 27.2. Thiopentone is a commonly used
inducing agent. It can be employed as the sole
anaesthetic for short operations that are not painful.
Adverse effects Laryngospasm occurs generally when
respiratory secretions or other irritants are present, or
when intubation is attempted while anaesthesia is light.
This can be prevented by atropine premedication and
administration of succinylcholine immediately after
thiopentone. Succinylcholine and thiopentone react
chemically—should not be mixed in the same syringe.
Shivering and delirium may occur during recovery.
Pain in the postoperative period is likely
to induce restlessness; adequate analgesia should be
provided. Postanaesthetic nausea and vomiting are
uncommon. It can precipitate acute intermittent porphyria
in susceptible individuals, therefore contraindicated. Other
uses Occasionally used for rapid control of convulsions.
Gradual i.v. infusion of subanaesthetic doses can be used
to facilitate verbal communication with psychiatric patients
and for ‘narcoanalysis’ of criminals; acts by knocking off
guarding.

34)Buprenorphine It is a synthetic thebaine congener,

highly lipid-soluble µ analgesic that is 25 times more
potent than morphine but with lower intrinsic activity and
ceiling effect. The onset of action is slower and duration
longer. After a single dose, analgesia lasts for 6–8 hours;
but with repeated dosing, duration of action
increases to ~24 hours due to accumulation in tissues.
Certain other effects last still longer. Sedation, vomiting,
miosis, subjective and cardiovascular effects are similar to
morphine, but constipation is less marked. Postural
hypotension is prominent. Respiratory depression (and
analgesia) exhibit ceiling effect. It substitutes for morphine
at low levels of morphine dependence, but precipitates
withdrawal in highly morphine dependent subjects,
reflecting its partial agonistic action at µ receptors.
Antagonistic action on κ receptor
has also been detected. Lower degree of tolerance and
physical as well as psychological dependence develops
with buprenorphine on chronic use. Its withdrawal
syndrome resembles that of morphine, but is delayed for
several days, is milder and longer lasting. ‘Drug seeking’
is present. Abuse liability is rated lower than morphine.
Naloxone (high dose) can prevent buprenorphine effect,
but does not reverse it when given afterwards; does not
precipitate buprenorphine withdrawal; probably because
of more tight binding of buprenorphine to opioid receptors.
Buprenorphine has good efficacy by sublingual route, is
highly plasma protein bound and remains in tissues for
several days; terminal t½ is 40 hours. It is mostly excreted
unchanged in bile and finds its way out of the body in
faeces.
Dose: 0.3–0.6 mg i.m., s.c. or slow i.v., also sublingual
0.2–0.4 mg 6–8 hourly. NORPHIN, TIDIGESIC 0.3 mg/ml
inj. 1 and 2 ml amps. 0.2 mg sublingual tab;
BUPRIGESIC, PENTOREL 0.3 mg/ml inj in 1, 2 ml amp.
Use: Buprenorphine is indicated for long-lasting painful
conditions requiring an opioid analgesic, e.g. cancer pain.
It has also been recommended for premedication,
postoperative pain, in myocardial infarction and in the
treatment of morphine dependence. Buprenorphine is not
suitable for use during labour, because if respiratory
depression occurs in the neonate, it cannot be effectively
reversed by naloxone. Nalbuphine, Meptazinol and
Dezocine are other agonistantagonist opioids introduced
in some countries.

35)CEFOTAXIME It is the prototype of the third

generation cephalosporins; exerts potent action on
aerobic gram-negative as well as some grampositive
bacteria, but is not active on anaerobes (particularly Bact.
fragilis), Staph. aureus and Ps. aeruginosa. Prominent
indications are meningitis caused by gram-negative bacilli
(attains relatively high CSF levels), life-threatening
resistant/ hospital-acquired infections, septicaemias and
infections in immunocompromised patients. It is an
alternative to ceftriaxone for typhoid fever, and can be
utilized for single dose therapy (1 g i.m. + 1 g probenecid
oral) of PPNG urethritis, but is not dependable for
Pseudomonas infections. Cefotaxime is deacetylated in
the body; the metabolite exerts weaker but synergistic
action with the parent drug. The plasma t½ of cefotaxime
is 1 hr, but is longer for the deacetylated metabolite—
permitting 12 hourly doses in many situations. Penetration
into CSF is good.
Dose: 1–2 g i.m./i.v. 6–12 hourly, children 50–100
mg/kg/day. OMNATAX, ORITAXIM, CLAFORAN 0.25, 0.5,
1.0 g per vial inj.

36)PREANAESTHETIC MEDICATION Preanaesthetic

medication refers to the use of drugs before anaesthesia
to make it more pleasant and safe. The aims are:
1. Relief of anxiety and apprehension preoperatively and
to facilitate smooth induction. 2. Amnesia for pre- and
postoperative events. 3. Supplement analgesic action
of anaesthetics and potentiate them so that less
 anaesthetic is needed. 4. Decrease secretions and
vagal stimulation that may be caused by the
anaesthetic. 5. Antiemetic effect extending to the
postoperative period. 6. Decrease acidity and volume of
gastric juice so that it is less damaging if aspirated.
Different drugs achieve different purposes. One or
more drugs may be used in a patient depending on the
needs
2. Sedative-antianxiety drugs Benzodiazepines like
diazepam (5–10 mg oral) or lorazepam (2 mg oral or
0.05 mg/kg i.m. 1 hour before) have become popular
drugs for preanaesthetic medication because they
produce tranquility and smoothen induction; there is
loss of recall of perioperative events (especially with
lorazepam) with little respiratory depression or
accentuation of postoperative vomiting. They
counteract CNS toxicity of local anaesthetics and are
being used along with pethidine/fentanyl for a variety of
minor surgical and endoscopic procedures. Midazolam
is a good amnesic with potent and shorter lasting
action; it is also better suited for i.v. injection, due to
water solubility. Promethazine (50 mg i.m.) is an
antihistaminic with sedative, antiemetic and
anticholinergic properties. It causes little respiratory
depression.
3. Opioids Morphine (10 mg) or pethidine (50–100 mg),
i.m. allay anxiety and apprehension of the operation,
produce pre- and postoperative analgesia, smoothen
induction, reduce the dose of anaesthetic required and
supplement poor analgesics (thiopentone, halothane)
or weak anaesthetics (N2O). Postoperative
restlessness is also reduced. Disadvantages They
depress respiration, interfere with pupillary signs of
anaesthesia, may cause fall in BP during anaesthesia,
can precipitate asthma and tend to delay recovery.
Other disadvantages are lack of amnesia, flushing,
 delayed gastric emptying and biliary spasm. Some
patients experience dysphoria. Morphine particularly
contributes to postoperative constipation, vomiting and
urinary retention. Tachycardia sometimes occurs when
pethidine has been used. Use of opioids is now mostly
restricted to those having preoperative pain. When
indicated, fentanyl is mostly injected i.v. just before
induction.
4. Anticholinergics (see Ch. 8) Atropine or hyoscine (0.6
mg or 10–20 µg/kg i.m./i.v.) or glycopyrrolate (0.2–0.3
mg or 5–10 µg/kg i.m./ i.v.) have been used, primarily to
reduce salivary and bronchial secretions. This need is
infrequent now due to use of non-irritant anaesthetics.
However, they must be given beforehand when ether is
used. The main aim of their use now is to prevent vagal
bradycardia and hypotension (which occur reflexly due
to certain surgical procedures), and prophylaxis of
laryngospasm which is precipitated by respiratory
secretions. Hyoscine, in addition, produces amnesia
and antiemetic effect, but tends to delay recovery.
Some patients get disoriented; emergence delirium is
more common. \
Moreover, anti bradycardiac effect of
hyoscine is less marked. Therefore, it is infrequently
selected for use during anaesthesia. Glycopyrrolate is
twice as potent and longer acting quaternary
antimuscarinic which does not produce central effects.
Antisecretory action is more marked than atropine,
while tachycardia is less marked, especially after i.m.
injection. It acts rapidly when given i.v. and is the
preferred antimuscarinic in anaesthetic practice.

Antimuscarinics facilitate assisted ventilation

by reducing airway resistance, but tend to increase the
anatomic dead space. They dilate pupils, abolish the
pupillary signs and increase chances of gastric reflux
 by decreasing tone of lower esophageal sphincter
(LES). They should not be used in febrile patients.
Dryness of mouth

5. Neuroleptics Chlorpromazine (25 mg), triflupromazine

(10 mg) or haloperidol (2–4 mg) i.m. are infrequently
used in premedication. They allay anxiety, smoothen
induction and have antiemetic action. However, they
potentiate respiratory depression and hypotension
caused by the anaesthetics and delay recovery.
Involuntary movements and muscle dystonias can
occur, especially in children. 5. H2 blockers/proton
pump inhibitors Patients undergoing prolonged
operations, caesarian section and obese patients are at
increased risk of gastric regurgitation and aspiration
pneumonia. Ranitidine (150 mg)/famotidine (20 mg) or
omeprazole (20 mg)/pantoprazole (40 mg) given night
before and in the morning benefit by raising pH of
gastric juice and may also reduce its volume and thus
chances of regurgitation. The chances of reflux and
damage to lungs on aspiration is minimal
6. if volume of gastric juice is <25 ml and pH is >3.5.
Prevention of stress ulcers is another advantage. They
are now routinely used before prolonged surgery.
7. Antiemetics Metoclopramide 10–20 mg i.m.
preoperatively is effective in reducing postoperative
vomiting. By enhancing gastric emptying and tone of
LES, it reduces the chances of reflux and its aspiration.
Extrapyramidal effects and motor restlessness can
occur. Combined use of metoclopramide and H2
blockers is more effective. Domperidone is nearly as
effective and does not produce extrapyramidal side
effects. Ondansetron (4–8 mg i.v.) the selective 5-HT3
blocker has been found highly effective in reducing the
incidence of post-anaesthetic nausea and vomiting (see
Ch. 47). It is practically devoid of side effects and has
become the antiemetic of choice in anaesthetic
practice.

37)KETOROLAC
This arylacetic acid NSAID has
potent analgesic but modest anti inflammatory activity.
In postoperative pain it has equalled the efficacy of
morphine, but does not interact with opioid receptors
and is free of opioid side effects. Like other NSAIDs, it
inhibits PG synthesis and relieves pain primarily by a
peripheral mechanism. In short-lasting pain, it has
compared favourably with aspirin. Ketorolac is rapidly
absorbed after oral and i.m. administration. It is highly
plasma protein bound and 60% excreted unchanged in
urine.
Major metabolic pathway is
glucuronidation; plasma t½ is 5–7 hours. Adverse
effects Nausea, abdominal pain, dyspepsia, ulceration,
loose stools, drowsiness, headache, dizziness,
nervousness, pruritus, pain at injection site, rise in
serum transaminase and fluid retention have been
noted. Ketorolac has been used concurrently with
morphine to keep its dose low. However, it should not
be given to patients on anticoagulants.
Use Ketorolac is frequently used
in postoperative, dental and acute musculoskeletal
pain: 15– 30 mg i.m. or i.v. every 4–6 hours (max. 90
mg/ day). It may also be used for renal colic, migraine
and pain due to bony metastasis. Orally it is used in a
dose of 10–20 mg 6 hourly for short-term management
of moderate pain.
Ketorolac has been rated superior to
aspirin (650 mg), paracetamol (600 mg) and equivalent
to ibuprofen (400 mg). Continuous use for more
than 5 days is not recommended. It should not be used
for preanaesthetic medication or for obstetric analgesia.
Topical ketorolac is quite popular for noninfective ocular
conditions.

KETOROL, ZOROVON, KETANOV,

TOROLAC 10 mg tab, 30 mg in 1 ml amp. KETLUR,
ACULAR 0.5% eye drops; 1–2 drops 2–4 times a day
for noninfective ocular inflammatory conditions.

38)METHOTREXATE
1. Folate antagonist
(Mtx) This folic acid analogue is one of the
oldest and highly efficacious antineoplastic drugs which
acts by inhibiting dihydrofolate reductase (DHFRase)—
blocking the conversion of dihydrofolic acid (DHFA) to
tetrahydrofolic acid (THFA). Utilizing the folate carrier it
enters into cells and is transformed to more active
polyglutamate form by the enzyme folypolyglutamate
synthase (FPGS). Tetrahydrofolic acid is an essential
coenzyme required for one carbon transfer reactions in
de novo purine synthesis and amino acid
interconversions. The inhibition is pseudoirreversible
because Mtx has 50,000 times higher affinity for the
enzyme than the normal substrate.

Methotrexate has cell cycle specific

action— kills cells in S phase; In addition to DHFRase it
inhibits thymidylate synthase as well so that DNA
synthesis is primarily affected. However, synthesis of
RNA and protein also suffers. It exerts major toxicity on
bone marrow—low doses given repeatedly cause
megaloblastic anaemia, but high doses produce
pancytopenia.
Mucositis and diarrhoea are
common side effects. Desquamation and bleeding may
occur in g.i.t. Methotrexate is absorbed orally, 50%
plasma protein bound, little metabolized and largely
excreted unchanged in urine. Salicylates, sulfonamides,
dicumerol displace it from protein binding sites. Aspirin
and sulfonamides enhance toxicity of Mtx by
decreasing its renal tubular secretion. The toxicity of
Mtx cannot be overcome by folic acid, because it will
not be converted to the active coenzyme form.
However, Folinic acid (N5 formyl THFA,
cirtrovorum factor) rapidly reverses the effects.
Thymidine also counteracts Mtx toxicity.

Methotrexate is apparently curative in

choriocarcinoma: 15–30 mg/day for 5 days orally or 20–
40 mg/m2 BSA i.m. or i.v. twice weekly.

In a dose of 2.5–15 mg/day it is highly effective

in maintaining remission in children with acute
leukaemias, but it is not good for inducing remission:
Mtx is widely used in non-Hodgkin lymphoma, breast,
bladder, head and neck cancers, osteogenic sarcoma,
etc. It has prominent immunosuppressant property
useful in rheumatoid arthritis, psoriasis and many other
antoimmune disorders (see Ch. 63). NEOTREXATE 2.5
mg tab, 50 mg/2 ml inj; BIOTREXATE 2.5 mg tab, 5,
15, 50 mg/vial inj.

The use of folinic acid rescue has

permitted much higher doses of Mtx and has enlarged
its scope to many difficult-to-treat neoplasms. A nearly
100 times higher dose (250–1000 mg/m2 BSA) of Mtx
is infused i.v. over 6 hours, followed by 3–15 mg i.v.
calcium leucovorin within 3 hours, repeated as
required. This procedure can be repeated weekly.
39)DIAZEPAM It is the oldest and all purpose BZD,
used as anxiolytic, hypnotic, musclerelaxant,
premedicant, anaesthetic and for emergency control of
seizures due to its broad spectrum activity. It generates
active metabolites (desmethyl-diazepam, oxazepam).
On occasional use it is free of residual effects. With
regular use accumulation occurs and prolonged
anxiolytic effect may be obtained. It is less likely to
cause rebound insomnia on discontinuation of chronic
use. Withdrawal phenomena are mild.
VALIUM 2, 5, 10 mg tab., 10 mg/2 ml inj.,
CALMPOSE 2.5, 5, 10 mg tab, 2 mg/5 ml syr, 10 mg/2
ml inj, PLACIDOX 2, 5, 10 mg tab, 10 mg/2 ml inj.

40)AMINOGLYCOSIDES
These are a group of natural and semisynthetic
antibiotics having polybasic amino groups linked
glycosidically to two or more aminosugar (streptidine, 2-
deoxy streptamine, garosamine) residues. Unlike
penicillin, which was a chance discovery,
aminoglycosides are products of deliberate search for
drugs effective against gram-negative bacteria.
Streptomycin was the first member discovered in 1944
by Waksman and his colleagues. It assumed great
importance because it was active against tubercle
bacilli. Others were produced later, and now
aminoglycosides are a sizable family.

All aminoglycosides are produced by soil

actinomycetes and have many common properties (see
box).
Systemic aminoglycosides Streptomycin Amikacin
Gentamicin Sisomicin Kanamycin Netilmicin
Tobramycin Paromomycin
Topical aminoglycosides Neomycin Framycetin

MECHANISM OF ACTION The aminoglycosides are

bactericidal antibiotics, all having the same general
pattern of action which may be described in two main
steps: (a) Transport of the aminoglycoside through the
bacterial cell wall and cytoplasmic membrane. (b)
Binding to ribosomes resulting in inhibition of protein
synthesis. Transport of aminoglycoside into the
bacterial cell is a multistep process. They diffuse across
the outer coat of gram-negative bacteria through porin
channels. Entry from the periplasmic space across the
cytoplasmic membrane is carrier mediated which is
linked to the electron transport chain. Thus, penetration
is dependent upon maintenance of a polarized
membrane and on oxygen dependent active processes
(energy dependent phase I or EDP1 entry).
These processes are inactivated
under anaerobic conditions; anaerobes are not
sensitive and facultative anaerobes are more resistant
when O2 supply is deficient, e.g. inside big abscesses.
Penetration is also favoured by high pH;
aminoglycosides are ~20 times more active in alkaline
than in acidic medium. Inhibitors of bacterial cell wall
(β-lactams, vancomycin) enhance entry of
aminoglycosides and exhibit synergism. Once inside
the bacterial cell, streptomycin binds to 30S ribosomes,
but other aminoglycosides bind to additional sites on
50S subunit, as well as to 30S-50S interface. They
freeze initiation of protein synthesis (see Fig. 52.1),
prevent polysome formation and promote their
disaggregation to monosomes so that only one
ribosome is attached to each strand of mRNA. Binding
of aminoglycoside to 30S-50S juncture causes
distortion of mRNA codon recognition resulting in
misreading of the code: one or morewrong amino acids
are entered in the peptide chain and/or peptides of
abnormal lengths are produced.
Different aminoglycosides cause
misreading at different levels depending upon their
selective affinity for specific ribosomal proteins. The
cidal action of these drugs appears to be based on
secondary changes in the integrity of bacterial cell
membrane, because other antibiotics which inhibit
protein synthesis (tetracyclines, chloramphenicol,
erythromycin) are only static. After exposure to
aminoglycosides, sensitive bacteria become more
permeable; ions, amino acids and even proteins leak
out followed by cell death. This probably results from
incorporation of the defective proteins into the cell
membrane.
One of the consequences of
aminoglycoside induced alteration of cell membrane is
augmentation of the carriermediated energy-dependent
phase II (EDP2) entry of the antibiotic. This reinforces
their lethal action. The cidal action of aminoglycosides
is concentration dependent, i.e. rate of bacterial cell
killing is directly related to the ratio of the peak
antibiotic concentration to the MIC value. They also
exert a long and concentration dependent
‘postantibiotic effect’ (see p. 697). It has, therefore,
been argued that despite their short t½ (2–4 hr), single
injection of the total daily dose of aminoglycoside may
be more effective and possibly less toxic than its
conventional division into 2–3 doses.

MECHANISM OF RESISTANCE Resistance to

aminoglycosides is acquired by one of the following
mechanisms:
(a) Acquisition of cell membrane bound inactivating
enzymes which phosphorylate/ adenylate or acetylate
the antibiotic. The conjugated aminoglycosides do not
bind to the target ribosomes and are incapable of
enhancing active transport like the unaltered drug.
These enzymes are acquired mainly by conjugation
and transfer of plasmids. Nosocomial microbes have
become
rich in such plasmids, some of which encode for
multidrug resistance. This is the most important
mechanism of development of resistance to
aminoglycosides. Susceptibility of different
aminoglycosides to these enzymes differs. Thus, cross
resistance was found between gentamicin and
tobramycin or netilmicin, but not between these and
streptomycin. Many nosocomial gram-negative bacilli
resistant to gentamicin/tobramycin respond to amikacin.

(b) Mutation decreasing the affinity of ribosomal

proteins that normally bind the aminoglycoside: this
mechanism can confer high degree resistance, but
operates to a limited extent, e.g. E. coli that develop
streptomycin resistance by single step mutation do not
bind the antibiotic on the polyribosome. Only a few
other instances are known. This type of resistance is
specific for a particular aminoglycoside.

(c) Decreased efficiency of the aminoglycoside

transporting mechanism: either the pores in the outer
coat become less permeable or the active transport is
interfered. This again is not frequently encountered in
the clinical setting. In some Pseudomonas which
develop resistance, the antibiotic induced 2nd phase
active transport has been found to be deficient.

SHARED TOXICITIES The aminoglycosides produce

toxic effects which are common to all members, but the
relative propensity differs1. Ototoxicity This is the most
important dose and duration of treatment related
adverse effect. The vestibular or the cochlear part may
be primarily affected by a particular aminoglycoside.
These drugs are concentrated in the labyrinthine fluid
and are slowly removed from it when the plasma
concentration falls.
1.Ototoxicity is greater when plasma concentration of
the drug is persistently high and above a threshold
value. For gentamicin this is estimated to be ~ 2 µg/ml;
if the trough level is above this value, vestibular
damage becomes concentration dependent. It is
recommended that dosing of gentamicin should be
such that the measured trough plasma concentration is
< 1 µg/ml to avoid toxicity.
The vestibular/cochlear sensory cells
and hairs undergo concentration dependent destructive
changes. Aminoglycoside ear drops can cause
ototoxicity when instilled in patients with perforated
eardrum; are contraindicated in them. Cochlear
damage It starts from the base and spreads to the
apex; hearing loss affects the high frequency sound
first, then progressively encompasses the lower
frequencies. No regeneration of the sensory cells
occurs; auditory nerve fibres degenerate in a retrograde
manner—deafness is permanent. Older patients and
those with preexisting hearing defect are more
susceptible. Initially, the cochlear toxicity is
asymptomatic and can be detected only by audiometry.
Tinnitus then appears, followed by progressive hearing
loss.
On stopping the drug, tinnitus
disappears in 4–10 days, but frequency loss persists.
Vestibular damage Headache is usually first to appear,
followed by nausea, vomiting, dizziness, nystagmus,
vertigo and ataxia. When the drug is stopped at this
stage, it passes into a chronic phase lasting 6 to 10
weeks in which the patient is asymptomatic while in bed
and has difficulty only during walking. Compensation by
visual and proprioceptive positioning and recovery
(often incomplete) occurs over 1–2 years. Permanency
of changes depends on the extent of initial damage and
the age of the patient (elderly have poor recovery).
2. Nephrotoxicity It manifests as tubular damage
resulting in loss of urinary concentrating power, low
g.f.r., nitrogen retention, albuminuria and casts.
Aminoglycosides attain high concentration in the renal
cortex (proximal tubules) and toxicity is related to the
total amount of the drug received by the patient.
However, in patients with normal renal function, single
daily dosing regimen appears to cause lesser
nephrotoxicity than the conventional thrice daily dosing.
It is more in the elderly and in those with preexisting
kidney disease. Provided the drug is promptly
discontinued renal damage caused by aminoglycosides
is totally reversible. It has been postulated that
aminoglycosides interfere with the production of PGs in
the kidney and that this is causally related to the
reduced g.f.r.
An important implication of
aminoglycosideinduced nephrotoxicity is reduced
clearance of the antibiotic resulting in higher and more
persistent blood levels causing enhanced ototoxicity.
Streptomycin and possibly tobramycin are less
nephrotoxic than the other aminoglycosides. 3.
Neuromuscular blockade All aminoglycosides reduce
ACh release from the motor nerve endings. They
interfere with mobilization of centrally located synaptic
vesicles to fuse with the terminal membrane (probably
by antagonizing Ca2+) as well as decrease the
sensitivity of the muscle endplates to ACh. The effect of
this action is not manifested ordinarily in the clinical use
of these drugs.
However, apnoea and fatalities have
occurred when streptomycin/neomycin was put into
peritoneal or pleural cavity after an operation,
especially if a curare-like muscle relaxant was
administered during surgery. Rapid absorption form the
peritoneum/pleura produces high blood levels and adds
to the residual action of the neuromuscular blocker.
Neomycin and streptomycin have higher propensity
than kanamycin, gentamicin or amikacin, while
tobramycin is least likely to produce this effect. The
neuromuscular block produced by aminoglycosides can
be partially antagonized by i.v. injection of a calcium
salt. Neostigmine has inconsistent reversing action.
Myasthenic weakness is accentuated by these drugs.
Neuromuscular blockers should be used cautiously in
patients receiving aminoglycosides.

PRECAUTIONS AND INTERACTIONS

1. Avoid aminoglycosides during pregnancy: risk of
foetal ototoxicity.
2. Avoid concurrent use of other nephrotoxic drugs, e.g.
NSAIDs, amphotericin B, vancomycin, cyclosporine and
cisplatin.
3. Cautious use of other potentially ototoxic drugs like
vancomycin, minocycline and furosemide, though
clinical evidence of potentiated ototoxicity is meagre
4. Cautious use in patients >60 years age and in those
with kidney damage.
5. Cautious use of muscle relaxants in patients
receiving an aminoglycoside.
6. Do not mix aminoglycoside with any drug in the
same syringe/infusion bottle.

PHARMACOKINETICS
All systemically administered aminoglycosides have
similar pharmacokinetic features. They are highly
ionized, and are neither absorbed nor destroyed in the
g.i.t. However, absorption from injection site in muscles
is rapid: peak plasma levels are attained in 30–60
minutes. They are distributed only extracellularly, so
that volume of distribution (~0.3 L/kg) is nearly equal to
the extracellular fluid volume. Low concentrations are
attained in serous fluids like synovial, pleural and
peritoneal, but these levels may be significant after
repeated dosing. Relatively higher concentrations are
present in endolymph and renal cortex, which are
responsible for ototoxicity and nephrotoxicity.
Penetration in respiratory secretions is poor.
Concentrations in CSF and
aqueous humour are nontherapeutic even in the
presence of inflammation. Aminoglycosides cross
placenta and can be found in foetal blood/amniotic fluid.
Their use during pregnancy can cause hearing loss in
the offspring, and must be avoided unless absolutely
essential. The plasma protein binding of
aminoglycosides is clinically insignificant, though
streptomycin is bound to some extent. Aminoglycosides
are not metabolized in the body, and are excreted
unchanged in urine. Glomerular filtration is the main
channel, because tubular secretion as well as
reabsorption are negligible. The plasma t½ ranges
between 2–4 hours, but small amount of drug persists
longer in tissues.
After chronic dosing, the drug may
be detectable in urine for 2–3 weeks. Renal clearance
of aminoglycosides parallels creatinine clearance
(CLcr), and is approximately 2/3 of it. The t½ is
prolonged and accumulation occurs in patients with
renal insufficiency, in the elderly and in neonates who
have low g.f.r. Reduction in dose or increase in dose-
interval is essential in these situations. This should be
done according to the measured CLcr. Nomograms are
available to help calculation of CLcr, but actual
measurement in the individual patient is preferable.
Generally, there is no need to reduce the daily dose till
CLcr is above 70 ml/min.

DOSING REGIMENS Because of low safety margin,

the daily dose of systemically administered
aminoglycosides must be precisely calculated
accordingly to body weight and level of renal function.
For an average adult with normal renal function (CLcr
>70 ml/min),
the usual doses are:
o Gentamicin/tobramycin/ sisomicin/netilmicin 3–5
mg/kg/day Streptomycin/
o kanamycin/amikacin 7.5–15 mg/kg/day Considering
the short t½ (2–4 hr) of aminoglycosides the daily
doses are conventionally divided into 3 equal parts
and injected i.m. (or i.v. slowly over 60 min) every 8
hours. However, most authorities now recommend a
single total daily dose regimen for patients with
normal renal function. This is based on the
considerations that:

• Aminoglycosides exert concentration dependent

bactericidal action and a long postantibiotic effect,
therefore higher plasma concentrations attained after
the single daily dose will be equally or more effective
than the divided doses.

• With the single daily dose, the plasma concentration

will remain subthreshold for ototoxicity and
nephrotoxicity for a longer period each day allowing
washout of the drug from the endolymph and the renal
cortex. Several comparative studies with gentamicin
and few other aminoglycosides and meta-analyses of
these studies have validated this concept. The single
daily dose regimen has been found to be less
nephrotoxic, but no dosing regimen appears to be less
ototoxic than another. Both regimens are equally
effective. Single daily doses are also more convenient
and cheaper (require less man power).

o However, the safety of the high dose extended

interval regimen in patients with renal insufficiency
and in children is not established, and is therefore
avoided. It is also not recommended when
gentamicin is combined with a β-lactam antibiotic for
obtaining cidal effect in bacterial endocarditis, etc.

Gentamicin It was the 3rd systemically administered

aminoglycoside antibiotic to be introduced for clinical
use, and was obtained from Micromonospora purpurea
in 1964. It quickly surpassed streptomycin because of
higher potency and broader spectrum of activity.
Currently, it is the most commonly used aminoglycoside
for acute infections and may be considered prototype of
the class. It is active mainly against aerobic
gramnegative bacilli, including E. coli, Klebsiella
pneumoniae, Enterobacter, H. influenzae, Proteus,
Serratia and Pseudomonas aeruginosa. Many strains of
Brucella, Campylobacter, Citrobacter, Fransisella and
Yersinia are also sensitive. Limited number of gram-
positive bacteria are susceptible, especially Staph.
aureus, Strep. faecalis and some Listeria, but Strep.
pyogenes, Strep. pneumoniae and enterococci are
usually insensitive. Gentamicin is ineffective against
Mycobacterium tuberculosis and other mycobacteria.

It is more potent (its MIC are lower) than streptomycin,

kanamycin and amikacin, but equally potent as
tobramycin, sisomicin and netilmicin. Bacteria that
acquire resistance against gentamicin generally exhibit
cross resistance to tobramycin and sisomicin also. It
synergises with β-lactam antibiotics, especially against
Enterococcus (endocarditis) and Pseudomonas
(meningitis). Dose: 3–5 mg/kg/day (single dose or
divided in 3 doses) i.m. or in an i.v. line over 30–60 min.
GARAMYCIN, GENTASPORIN, GENTICYN20, 60, 80,
240 mg per vial inj; also 0.3% eye/ear drops, 0.1% skin
cream.

Uses
Gentamicin is the cheapest (other than streptomycin)
and the first line aminoglycoside antibiotic.
It is often added when a
combination antibiotic regimen is used empirically to
treat serious infections by extending the spectrum of
coverage. Because of low therapeutic index, its use
should be restricted to serious gram-negative bacillary
infections. 1. Gentamicin is very valuable for preventing
and treating respiratory infections in critically ill patients;
in those with impaired host defence (receiving
anticancer drugs or high-dose corticosteroids; AIDS;
neutropenic), patients in resuscitation wards, with
tracheostomy or on respirators; postoperative
pneumonias; patients with implants and in intensive
care units. It is often combined with a
penicillin/cephalosporin or another antibiotic in these
situations.
However, resistant strains have emerged in
many hospitals and nosocomial infections are less
amenable to gentamicin now. Another aminoglycoside
(tobramycin, amikacin, netilmicin) is then selected on
the basis of the local sensitivity pattern, but strains
resistant to gentamicin are generally cross resistant to
tobramycin and sisomicin.
Aminoglycosides should not be used to
treat community acquired pneumonias which are mostly
caused by gram-positive cocci and anaerobes.

41)HALOTHANE (FLUOTHANE)
It is a volatile liquid with sweet odour,
nonirritant and noninflammable. Solubility in blood is
intermediate— induction is reasonably quick and
pleasant.
It is a potent anaesthetic—precise control of
administered concentration is essential. For induction
2–4% and for maintenance 0.5–1% is delivered by the
use of a special vaporizer. It is not a good analgesic or
muscle relaxant, but it potentiates competitive
neuromuscular blockers. Halothane causes direct
depression of myocardial contractility by reducing
intracellular Ca2+ concentration. Moreover,
sympathetic activity fails to increase reflexly.
Cardiac output is reduced with deepening
anaesthesia. BP starts falling early and parallels the
depth. A 20–30 mm Hg drop in BP is common. Many
vascular beds dilate but total peripheral resistance is
not significantly reduced. Heart rate is reduced by vagal
stimulation, direct depression of SA nodal automaticity
and absence of baroreceptor activation even when BP
falls. It tends to sensitize the heart to the
arrhythmogenic action of Adr.
The electrophysiological effects are
conducive to reentry—tachyarrhythmias occur
occasionally. Halothane causes relatively greater
depression of respiration; breathing is shallow and
rapid— PP of CO2 in blood rises if respiration is not
assisted. Cerebral blood flow increases. Ventilatory
support with added oxygen is frequently required. It
tends to accentuate perfusionventilation mismatch in
the lungs by causing vasodilatation in hypoxic alveoli.
Pharyngeal and laryngeal reflexes are abolished early
and coughing is suppressed while bronchi dilate. As
such, halothane is preferred for asthmatics. It inhibits
intestinal and uterine contractions. This property is
utilized for facilitating external or internal version during
late pregnancy.

However, its use during labour can prolong

delivery and increase postpartal blood loss. Urine
formation is decreased during halothane anaesthesia—
primarily due to low g.f.r. as a result of fall in BP.
Hepatitis occurs in rare susceptible individuals (1 in
35000 to 1 in 10,000) especially after repeated use
and in those with familial predisposition. A metabolite of
halothane is probably involved— causes chemical or
immunological injury. A genetically determined reaction
malignant hyperthermia occurs rarely. Many susceptible
subjects have an abnormal RyR1 (Ryanodine receptor)
calcium channel at the sarcoplasmic reticulum of
skeletal muscles. This channel is triggered by
halothane to release massive amounts of Ca2+
intracellularly causing persistent muscle contraction
and increased heat production.
Succinylcholine accentuates the condition
(see Ch. 25). Rapid external cooling, bicarbonate
infusion, 100% O2 inhalation and i.v. dantrolene (see
p. 356) are used to treat malignant hyperthermia. About
20% of halothane that enters blood is metabolized in
the liver, the rest is exhaled out. Elimination may
continue for 24–48 hours after prolonged administration
due to accumulation in fatty and other tissues.
Recovery from halothane anaesthesia is smooth and
reasonably quick; shivering may occur but nausea and
vomiting are rare.
Psychomotor performance and mental
ability remain depressed for several hours after
regaining consciousness. Halothane is a popular
anaesthetic in developing countries, because it is
relatively cheap and nonirritant, noninflammable,
pleasant with relatively rapid action. It is particularly
suitable for use in children, both for induction as well as
maintenance. In adults, it is mainly used as a
maintenance anaesthetic after i.v. induction. Halothane
toxicity is less frequent in children. However, in affluent
countries it has been largely replaced by the newer
agents which are costlier. Its deficiencies in terms of
poor analgesia and muscle relaxation are compensated
by concomitant use of N2O or opioids and
neuromuscular blockers.

43)DESFLURANE
It is a newer all fluorinated congener of
isoflurane which has gained popularity as an
anaesthetic for out patient surgery. Though it is highly
volatile, a thermostatically heated special vapourizer is
used to deliver a precise concentration of pure
desflurane vapour in the carrier gas (N2O + O2)
mixture. Its distinctive properties are lower lipid
solubility as well as very low solubility in blood and
tissues, because of which induction and recovery are
very fast.
Depth of anaesthesia changes rapidly
with change in inhaled concentration giving the
anaesthetist better control. Postanaesthetic cognitive
and motor impairment is shortlived, so that patient can
be discharged a few hours after surgery.
Desflurane is 5 times less potent than
isoflurane; higher concentration has to be used for
induction which irritates air passage and may induce
coughing, breath-holding and laryngospasm. A
somewhat pungent odour makes it unsuitable for
induction. Rapid induction sometimes causes brief
sympathetic stimulation and tachycardia which may be
risky in those with cardiovascular disease. Degree of
respiratory depression, muscle relaxation,
vasodilatation and fall in BP are similar to isoflurane.
Cardiac contractility and coronary blood flow are
maintained.

Lack of seizure provoking potential

arrhythmogenicity and absence of liver as well as
kidney toxicity are also similar to isoflurane. It is rapidly
exhaled unchanged. As such, desflurane can serve as
a good alternative to isoflurane for routine surgery as
well, especially prolonged operations. If closed circuit is
used, soda lime should be fresh and well hydrated.

45)SULFONYLUREAS (KATP CHANNEL

BLOCKERS)
All SUs have similar pharmacological
profile, their sole significant action being lowering of
blood glucose level in normal subjects and in type 2
diabetics, but not in type 1 diabetics. Being more potent
and clinically superior, only the second generation SUs
are employed now. All first generation compounds have
been discontinued except tolbutamide which is
infrequently used. Mechanism of action Sulfonylureas
provoke a brisk release of insulin from pancreas, The
rate of insulin secretion at any glucose concentration is
increased, i.e. insulin release is provoked even at low-
glucose concentration risking production of severe and
unpredictable hypoglycaemia. In type 2 DM the kinetics
of insulin release in response to glucose or meals is
delayed and subdued.
The SUs primarily augment the 2nd phase
insulin secretion with little effect on the 1st phase. That
they do not cause hypoglycaemia in pancreatectomised
animals and in type 1 diabetics (presence of at least
30% functional β cells is essential for their action),
confirms their indirect action through pancreas. A minor
action reducing glucagon secretion, probably by
increasing insulin and somatostatin release has been
demonstrated. Hepatic degradation of insulin is also
slowed. Extrapancreatic action
After few months of administration, the
insulinaemic action of SUs declines, probably due to
down regulation of sulfonylurea receptors (SUR1) on β
cells, but improvement in glucose tolerance is
maintained. In this phase, they sensitize the target
tissues (especially liver) to the action of insulin. This is
due to increase in number of insulin receptors and/or a
postreceptor action—improving translation of receptor
activation. It is hypothesized that long-term
improvement in carbohydrate tolerance leads to overall
lowering of circulating insulin concentration which
reverses the down regulation of insulin receptors.
An apparent increase in their number
occurs. A direct extrapancreatic action of SUs to
increase insulin receptors on target cells and to inhibit
gluconeogenesis in liver has been proposed, but
appears to have little clinical relevance.
Pharmacokinetics All SUs are well absorbed orally, and
are 90% or more bound to plasma proteins: have low
volumes of distribution (0.2–0.4 L/kg). They are
primarily metabolized— may produce active metabolite.
The metabolites (active/inactive) are excreted in urine.
As such, they should be used cautiously in patients with
liver or kidney dysfunction.
The distinctive features of different SUs are given in
Table 19.2. Interactions Drugs that enhance SU action
(may precipitate hypoglycaemia) are—
(a) Displace from protein binding: Phenylbutazone,
sulfinpyrazone, salicylates, sulfonamides.
(b) Inhibit metabolism/excretion: Cimetidine
ketoconazole, sulfonamides, warfarin, chloramphenicol,
acute alcohol intake (also synergises by causing
hypoglycaemia).
(c) Synergise with or prolong pharmacodynamic action:
Salicylates, propranolol (cardioselective β1 blockers
are less liable), sympatholytic antihypertensives,
lithium, theophylline, alcohol (by inhibiting
gluconeogenesis).
Drugs that decrease SU action (vitiate diabetes control)
are—
(a) Induce metabolism: Phenobarbitone,
phenytoin, rifampicin, chronic alcoholism.
(b) Opposite action/suppress insulin
release: Corticosteroids, thiazides, furosemide, oral
contraceptives. Adverse effects Incidence of adverse
effects is quite low (3–7%).
1. Hypoglycaemia It is the commonest problem, may
occasionally be severe and rarely fatal. It is more
common in elderly, liver and kidney disease patients
and when potentiating drugs are added. Tolbutamide
carries lowest risk due to its low potency and short
duration of action. Treatment of hypoglycaemic episode
is to give glucose, may be for a few days because
hypoglycaemia may recur.
2. Nonspecific side effects Majority of diabetics started
on SUs tend to gain 1–3 kg weight. This may be a
consequence of their insulinaemic action. Nausea,
vomiting, flatulence, diarrhoea or constipation,
headache and paresthesias are generally mild and
infrequent.
3. Hypersensitivity Rashes, photosensitivity, purpura,
transient leukopenia, rarely agranulocytosis. Flushing
and a disulfiram-like reaction after alcohol is reported to
occur in some individuals taking SUs. Tolbutamide
reduces iodide uptake by thyroid but hypothyroidism
does not occur. Safety of SUs during pregnancy is not
established. Change over to insulin is advised.

46)VINBLASTINE It is primarily employed along with

other drugs in Hodgkin’s disease, Kaposi sarcoma,
neuroblastoma, non-Hodgkin’s lymphoma, breast and
testicular carcinoma. Bone marrow depression is more
prominent, while neurotoxicity and alopecia are less
marked than with vincristine. SIADH has been noted. It
can cause local tissue necrosis if extravasation occurs
during i.v. infusion. Dose: 0.1–0.15 mg/kg i.v. weekly ×
3 doses. UNIBLASTIN, CYTOBLASTIN 10 mg/vial inj.

47)BLEOMYCIN This is a mixture of closely related

glycopeptide antibiotics having potent antitumour
activity. It chelates copper or iron, produces superoxide
ions and intercalates between DNA strands—causes
chain scission and inhibits repair. It is highly effective in
testicular tumour and squamous cell carcinoma of skin,
oral cavity, head and neck, genitourinary tract and
esophagus; also useful in Hodgkin’s lymphoma. Rate of
fluid collection in malignant pleural or peritoneal
effusion can be reduced by intrapleural/intraperitoneal
injection of bleomycin. Mucocutaneous toxicity and
pulmonary fibrosis, but minimal myelosuppression are
the special features. Allergic and hypotensive reaction
can occur after bleomycin injection. It can be injected
i.m. as well. Dose: 30 mg twice weekly i.v. or i.m. (total
dose 300–400 mg); BLEOCIN, ONCOBLEO 15 mg inj.

48)HEPARIN
McLean, a medical student, discovered in
1916 that liver contains a powerful anticoagulant.
Howell and Holt (1918) named it ‘heparin’ because it
was obtained from liver. However, it could be used
clinically only in 1937 when sufficient degree of
purification was achieved. Chemistry and occurrence
Heparin is a non-uniform mixture of straight chain
mucopolysaccharides with MW 10,000 to 20,000. It
contains polymers of two sulfated disaccharide units: D-
glucosamine-Liduronic acid D-glucosamine-Dglucuronic
acid Heparin carries strong electronegative charges
and is the strongest organic acid present in the body. It
occurs in mast cells as a much bigger
molecule (MW ~75,000) loosely bound to the granular
protein.
Thus, heparin is present in all tissues
containing mast cells; richest sources are lung, liver
and intestinal mucosa. Commercially it is produced
from ox lung and pig intestinal mucosa.
ACTIONS
1. Anticoagulant Heparin is a powerful and
instantaneously acting anticoagulant, effective both
in vivo and in vitro. It acts indirectly by activating
plasma antithrombin III (AT III, a serine proteinase
inhibitor). The heparin-AT III complex then binds to
clotting factors of the intrinsic and common pathways
(Xa, IIa, IXa, XIa, XIIa and XIIIa) and inactivates
them but not factor VIIa operative in the extrinsic
pathway. At low concentrations of heparin, factor Xa
mediated conversion of prothrombin to thrombin is
selectively affected. The anticoagulant action is
exerted mainly by inhibition of factor Xa as well as
thrombin (IIa) mediated conversion of fibrinogen to
fibrin. Low concentrations of heparin prolong aPTT
without significantly prolonging PT. High
concentrations prolong both. Thus, low
concentrations interfere selectively with the intrinsic
pathway, affecting amplification and continuation of
clotting, while high concentrations affect the common
pathway as well. Antithrombin III is itself a substrate
for the protease clotting factors; binds with the
protease to form a stable complex (suicide inhibitor).
2. However, in the absence of heparin, the two interact
very slowly. Heparin enhances the action of AT III in
two ways:
(a) Long heparin molecule provides a scaffolding for
the clotting factors (mainly Xa and IIa) as well as AT
III to get bound and interact with each other.
(b) Heparin induces conformational change in AT III
to expose its interactive sites. A specific
pentasaccharide sequence, which is present in only
some of the heparin molecules, binds to AT III with
high affinity to induce the conformational change
needed for rapid interaction with clotting factors. This
has been synthesized and named fondaparinux.
Inhibition of IIa requires both the mechanisms, but
Xa inhibition can occur by mechanism ‘b’ alone. This
probably explains why low molecular weight heparin,
which is insufficient to provide a long scaffolding,
selectively inhibits factor Xa.
Higher doses of heparin given for some time
cause reduction in AT-III levels, probably
acompensatory phenomenon. Sudden stoppage of
conventional-dose therapy may result in rebound
increase in coagulability for few days.
3. Antiplatelet Heparin in higher doses inhibits platelet
aggregation and prolongs bleeding time.
4. Lipaemia clearing Injection of heparin clears turbid
post-prandial lipaemic plasma by releasing a
lipoprotein lipase from the vessel wall and tissues,
which hydrolyses triglycerides of chylomicra and very
low density lipoproteins to free fatty acids. These
then pass into tissues and the plasma looks clear.
This action requires lower concentration of heparin
than that needed for anticoagulation. Facilitation of
fatty acid transport may be the physiological function
of heparin; but since, it is not found in circulating
blood and its storage form in tissues is much less
 active, this seems only conjectural.
PHARMACOKINETICS Heparin is a large, highly
ionized molecule; therefore not absorbed orally.
Injected i.v. it acts instantaneously, but after s.c.
injection anticoagulant effect develops after ~60 min.
Bioavailability of s.c. heparin is inconsistent. Heparin
does not cross blood-brain barrier or placenta (it is the
anticoagulant of choice during pregnancy). It is
metabolized in liver by heparinase and fragments are
excreted in urine. Heparin released from mast cells is
degraded by tissue macrophages—it is not a
physiologically circulating anticoagulant. After i.v.
injection of doses < 100 U/kg, the t½ averages 1 hr.

Beyond this, dose-dependent inactivation is

seen and t½ is prolonged to 1–4 hrs. The t½ is longer
in cirrhotics and kidney failure patients, and shorter in
patients with pulmonary embolism. Unitage and
administration Because of variable molecular size of
unfractionated heparin (UFH), it is standardized only by
bioassay: 1 U is the amount of heparin that will prevent
1 ml of citrated sheep plasma from clotting
for 1 hour after the addition of 0.2 ml of 1% CaCl2
solution. Heparin sod. 1 mg has 120–140 U of activity.
HEPARIN SOD., BEPARINE, NUPARIN 1000 and 5000
U/ ml in 5 ml vials for injection. Heparin should not be
mixed with penicillin, tetracyclines, hydrocortisone or
NA in the same syringe or infusion bottle. Heparinized
blood is not suitable for blood counts (alters the shape
of RBCs and WBCs), fragility testing and complement
fixation tests. Dosage Heparin is conventionally given
i.v. in a bolus dose of 5,000–10,000 U (children 50–100
U/kg), followed by continuous infusion of 750–1000
U/hr. Intermittent i.v. bolus doses of UFH are no longer
recommended. The rate of infusion is controlled by
aPTT measurement which is kept at 50–80 sec. or 1.5–
2.5 times the patient’s pretreatment value. If this test is
not available, whole blood clotting time should be
measured and kept at ~2 times the normal value
Deep s.c. injection of 10,000–20,000 U
every 8–12 hrs can be given if i.v. infusion is not
possible. Needle used should be fine and trauma
should be minimum to avoid haematoma formation.
Haematomas are more common with i.m. injection—
this route should not be used. Low dose (s.c.) regimen
5000 U is injected s.c. every 8–12 hours, started before
surgery and continued for 7–10 days or till the patient
starts moving about. This regimen has been found to
prevent postoperative deep vein thrombosis without
increasing surgical bleeding. It also does not prolong
aPTT or clotting time. However, it should not be used in
case of neurosurgery or when spinal anaesthesia is to
be given. The patients should not be receiving aspirin
or oral anticoagulants. It is ineffective in high-risk
situations, e.g. hip joint or pelvic surgery.

ADVERSE EFFECTS
1. Bleeding due to overdose is the most serious
complication of heparin therapy. Haematuria is
generally the first sign. With proper monitoring, serious
bleeding occurs only in 1–3% patients.

2. Thrombocytopenia is another common problem.

Generally it is mild and transient; occurs due to
aggregation of platelets. Occasionally serious
thromboembolic events result. In some patients
antibodies are formed to the heparinplatelet complex
and marked depletion of platelets occurs—heparin
should be discontinued in such cases. Even low
molecular weight (LMW) heparins are not safe in such
patients.
3. Transient and reversible alopecia is infrequent.
Serum transaminase levels may rise.

4. Osteoporosis may develop on long-term use of

relatively high doses.
5. Hypersensitivity reactions are rare; manifestations
are urticaria, rigor, fever and anaphylaxis. Patients with
allergic diathesis are more liable.

Contraindications
1. Bleeding disorders, history of heparin induced
thrombocytopenia.
2. Severe hypertension (risk of cerebral haemorrhage),
threatened abortion, piles, g.i. ulcers (risk of aggravated
bleeding).
3. Subacute bacterial endocarditis (risk of embolism),
large malignancies (risk of bleeding in the central
necrosed area of the tumour), tuberculosis (risk of
hemoptysis).
4. Ocular and neurosurgery, lumbar puncture.
5. Chronic alcoholics, cirrhosis, renal failure.
6. Aspirin and other antiplatelet drugs should be used
very cautiously during heparin therapy

49)ANTIPSEUDOMONAL PENICILLIN
Piperacillin This antipseudomonal
penicillin is about 8 times more active than carbenicillin.
It has good activity against Klebsiella, many
Enterobacteriaceae and some Bacteroides. It is
frequently employed for treating serious gramnegative
infections in neutropenic/immunocompromised or burn
patients. Elimination t½ is 1 hr. Concurrent use of
gentamicin or tobramycin is advised.

Dose: 100–150 mg/kg/day in 3 divided doses (max 16

g/day) i.m. or i.v. The i.v. route is preferred when > 2 g
is to be injected. PIPRAPEN 1 g, 2 g vials; PIPRACIL 2
g, 4 g vials for inj; contains 2 mEq Na+ per g.
Mezlocillin Another antipseudomonas penicillin, not
available in India

50)NONSPECIFIC ANTIDIARRHOEAL DRUGS These

drugs can be grouped into:
A. Absorbants and adsorbants
B. Antisecretory drugs
C. Antimotility drugs
A. Absorbants These are colloidal bulk forming
substances like ispaghula, methyl cellulose, carboxy
methyl cellulose which absorb water and swell. They
modify the consistency and frequency of stools and
give an impression of improvement, but do not reduce
the water and electrolyte loss. They are of value in
selected conditions like diarrhoea phase of IBS, and to
increase the consistency of faeces in colostomy
patients. Ispaghula and other bulk forming colloids are
useful in both constipation and diarrhoea phases of IBS
and reduce abdominal pain as well. Substances that do
not ferment in colon are preferred for diarrhoea.

Adsorbants like kaolin, pectin, attapulgite are

believed to adsorb bacterial toxins in the gut and
coat/protect the mucosa. They were ones very popular
ingredients of diarrhoea remedies, but are now banned
in India, because there is no objective proof of their
efficacy.

B. Antisecretory drugs Racecadotril This recently

introduced prodrugis rapidly converted to thiorphan, an
enkephalinase inhibitor.

It prevents degradation of endogenous

enkephalins (ENKs) which are mainly δ opioid receptor
agonists. Racecadotril decreases intestinal
hypersecretion, without affecting motility (motility
appears to be regulated through µ receptors) by
lowering mucosal cAMP due to enhanced ENK action.
It is indicated in the shortterm treatment of acute
secretory diarrhoeas. In contrast to
loperamide/diphenoxylate, it is not contraindicated in
children. The elimination t½ as thiorphan is 3 hr. Side
effects are nausea, vomiting, drowsiness, flatulence.

Dose: 100 mg (children 1.5 mg/kg) TDS for not more

than 7 days. CADOTRIL, RACIGYL 100 mg cap, 15 mg
sachet; REDOTIL 100 mg cap. ZEDOTT, ZOMATRIL
100 mg tab, 10 mg and 30 mg sachet and dispersible
tab. Bismuth subsalicylate Taken as suspension (60 ml
6 hourly) it is thought to act by decreasing PG synthesis
in the intestinal mucosa, thereby reducing Cl¯
secretion. It has some prophylactic value in travellers’
diarrhoea (probably due to weak antibacterial action as
well), but it is rather inconvenient to carry and
take.Though quite popular in USA, it is not used in India
and UK. Anticholinergics Atropinic drugs can reduce
bowel motility and secretion, but have poor efficacy in
secretory diarrhoeas. They may benefit nervous/drug
(neostigmine, metoclopramide) induced diarrhoeas and
provide some symptomatic relief in dysenteries,
diverticulitis.
Octreotide This somatostatin analogue
(see p. 238) has a long plasma t½ (90 min) as well as
potent antisecretory/ antimotility action on the gut. It
has been used to control diarrhoea in carcinoid and
vasoactive intestinal peptide (VIP) secreting tumours,
and for refractory diarrhoea in AIDS patients, but needs
to be given by s.c. injection. Opioids In addition to their
well recognized antimotility action, opioids reduce
intestinal secretion. Loperamide has been clearly
shown to reduce secretion, probably through specific
opioid receptors, but does not affect mucosal cAMP or
cGMP levels.
C. Antimotility drugs These are opioid drugs which
increase small bowel tone and segmenting activity,
reduce propulsive movements and diminish intestinal
secretions while enhancing absorption. They afford only
symptomatic relief in diarrhoea. The major action
appears to be mediated through µ opioid receptors
located on enteric neuronal network, but direct
action on intestinal smooth muscle and secretory/
absorptive epithelium has also been demonstrated.
The δ receptors are believed to promote
absorption and inhibit secretion, while the µ receptors
enhance absorption and decrease propulsive
movements. Overall they increase resistance to luminal
transit and allow more time for the absorptive
processes. No tolerance develops to their constipating
action. Codeine (see p. 474) This opium alkaloid has
prominent constipating action at a dose of 60 mg TDS.

The antidiarrhoeal effect is attributed

primarily to its peripheral action on small intestine and
colon. It does have central effects, but dependence
producing liability is low. Side effects are nausea,
vomiting and dizziness. Due to its abuse potential and
availability of loperamide, codeine is seldom, if ever,
used for diarrhoea. Diphenoxylate (2.5 mg) + atropine
(0.025 mg): LOMOTIL tab and in 5 ml liquid.

Dose: 5–10 mg, followed by 2.5–5 mg 6 hourly. It is a

synthetic opioid, chemically related to pethidine; used
exclusively as constipating agent; action is similar to
codeine.
 The antidiarrhoeal action is most
prominent, but because it is absorbed systemically and
crosses blood-brain barrier—CNS effects do occur.
Atropine is added in subpharmacological dose to
discourage abuse by taking several tablets. Abuse
liability is rated low, and overdose will produce
disturbing atropinic side effects. It has caused
respiratory depression, paralytic ileus and toxic
megacolon in children. Response is more variable in
them— contraindicated below 6 years of age.
Loperamide has largely superseded it.
Loperamide It is an opiate analogue with major
peripheral µ opioid and additional weak anticholinergic
property. As a constipating agent it is much more potent
than codeine. Because of poor water solubility—little is
absorbed from the intestines. Entry into brain is
negligible—CNS effects are rare and occur only with
high doses; no abuse liability. The duration of action is
longer (12 hr) than codeine and diphenoxylate. In
addition to its opiate like action on motility, loperamide
also inhibits secretion. Direct interaction with
calmodulin may be responsible for the antidiarrhoeal
action. Faecal continence is improved by enhancement
of anal sphincter tone.

Adverse effects Abdominal cramps and rashes are the

most common side effects. Paralytic ileus, toxic
megacolon with abdominal distension is a serious
complication in young children—fatalities have
occurred, probably due to absorption of toxins from the
intestines. Loperamide is contraindicated in children < 4
yr. However, it appears to be the most effective and
most suitable of the antimotility antidiarrhoeal drugs.

Dose: 4 mg followed by 2 mg after each motion (max.

10 mg in a day); 2 mg BD for chronic diarrhoea.
IMODIUM, LOPESTAL, DIARLOP: 2 mg tab, cap.
Liquid formulation has been withdrawn to prevent use
in young children.

The utility of antimotility drugs in diarrhoea is limited to

noninfective diarrhoea, mild traveller’s diarrhoea, and
when diarrhoea is exhausting or idiopathic diarrhoea in
AIDS patients.
Low doses may be used for chronic diarrhoea in IBS,
but higher doses must be avoided. Their use is a short-
term measure only.
Antimotility drugs are contraindicated in acute infective
diarrhoeas because they delay clearance
of the pathogen from the intestine. If invasive
organisms (Shigella, EPEC, EH, etc.) are present,
antimotility drugs can be disastrous by increasing the
risk of systemic invasion.
Careful use may be made in mild IBD when loose
motions and urgency are interfering with daily activities,
but antimotility drugs are contraindicated in severe
disease, since they may raise intraluminal pressure.

Antimotility drugs can be used to induce deliberate

short-term constipation, e.g. after anal surgery, and to
reduce the volume, fluidity and bag cleaning frequency
in ileostomy/colostomy patients

50)HIGH CEILING (LOOP) DIURETICS (INHIBITORS

OF NA+-K+-2CL¯ COTRANSPORT)

Furosemide (Frusemide) Prototype drug The

development of this rapidly acting highly efficacious oral
diuretic was a breakthrough. Its maximal natriuretic
effect is much greater than that of other classes. The
diuretic response goes on increasing with increasing
dose: upto 10 L of urine may be produced in a day. It is
active even in patients with relatively severe renal
failure.
The onset of action is prompt (i.v. 2–5 min.,
i.m. 10–20 min., oral 20–40 min.) and duration short (3–
6 hours). The major site of action is the thick AscLH
(therefore called loop diuretics) where furosemide
inhibits Na+- K+-2Cl¯ cotransport (site II, Fig. 41.1). A
minor component of action on PT has also been
indicated. It is secreted in PT by organic anion transport
and reaches AscLH where it acts from luminal side of
the membrane. The corticomedullary osmotic gradient
is abolished and positive as well as negative free water
clearance is blocked. K+ excretion is increased mainly
due to high Na+ load reaching DT.
However, at equinatriuretic doses, K+ loss is
less than that with thiazides Furosemide has weak
CAse inhibitory action; increases HCO3¯ excretion as
well; urinary pH may rise but the predominant urinary
anion is Cl¯. Therefore, acidosis does not develop. The
diuretic action is independent of acid-base balance of
the body and it causes little distortion of the same; mild
alkalosis occurs at high doses. In addition to its
prominent tubular action, furosemide causes acute
changes in renal and systemic haemodynamics. After 5
min of i.v. injection, renal blood flow is transiently
increased and there is redistribution of blood flow from
outer to midcortical zone; g.f.r. generally remains
unaltered due to compensatory mechanisms despite
increased renal blood flow.

Pressure relationship between vascular,

interstitial and tubular compartments is altered, the net
result of which is decreased PT reabsorption. The
intrarenal haemodynamic changes are brought about
by increased local PG synthesis. Furosemide also sets
in motion compensatory mechanisms which tend to
limit its diuretic action. Interference with Na+ entry into
maculadensa causes marked renin release. Activation
of the renin-angiotensin-aldosterone system is the
major compensatory mechanism. Reflex sympathetic
stimulation of the kidney reinforces renin release.
These mechanisms restore Na+ balance after
termination of the diuretic action. Because of this
phenomenon and short t½ of furosemide, its once daily
administration may have less marked overall effect on
Na+ status of the body. Intravenous furosemide causes
prompt increase in systemic venous capacitance and
decreases left ventricular filling pressure, even before
the saluretic response is apparent.
This action also appears to be PG mediated
and is responsible for the quick relief it affords in LVF
and pulmonary edema. Furosemide increases Ca2+
excretion (contrast thiazides which reduce it) as well as
Mg2+ excretion by abolishing transepithelial potential
difference in the thick AscLH which drives reabsorption
of these divalent cations. It tends to raise blood uric
acid level by competing with its proximal tubular
secretion as well as by increasing reabsorption in PT
which is a consequence of reduced e.c.f. volume.
The magnitude of hyperuricaemia is lower
than that with thiazides. A small rise in blood sugar
level may be noted after regular use of furosemide, but
is again less marked compared to thiazides

Molecular mechanism of action: A glycoprotein with

12 membrane spanning domains has been found to
function as the Na+-K+-2Cl¯ cotransporter in many
epithelia performing secretory/absorbing function,
including AscLH. Recently, distinct absorptive and
secretory isoforms of Na+-K+-2Cl¯ cotransporter have
been isolated. The former is exclusively expressed at
the luminal membrane of thick AscLH—furosemide
attaches to the Cl¯ binding site of this protein to inhibit
its transport function. The secretory form is expressed
on the basolateral membrane of most glandular and
epithelial cells.
Use of high ceiling diuretics
1. Edema Diuretics are used irrespective of etiology of
edema—cardiac, hepatic or renal. The high ceiling
diuretics are preferred in CHF for rapid mobilization
of edema fluid (see Ch. 37).
Thiazides may be used for maintenance,
but often prove ineffective and high ceiling drugs are
called in. For nephrotic and other forms of resistant
edema, only the high ceiling diuretics are effective,
and are the drugs of choice. In chronic renal failure
massive doses have to be used, but they continue to
be effective while thiazides just do not produce any
action. In impending acute renal failure, loop
diuretics may decrease the need for dialysis.
2. Acute pulmonary edema (acute LVF, following MI):
Intravenous administration of furosemide or its
congeners produces prompt relief. This is due to
vasodilator action that precedes the saluretic action.
Subsequently, decrease in blood volume and venous
return is responsible for the improvement.
3. Cerebral edema Though osmotic diuretics are
primarily used to lower intracranial pressure by
withdrawing water, furosemide may be combined to
improve efficacy.
4. Hypertension High ceiling diuretics are indicated in
hypertension only in the presence of renal insufficiency,
CHF, or in resistant cases and in hypertensive
emergencies; otherwise thiazides are preferred (see p.
460).
5. Along with blood transfusion in severe anaemia, to
prevent volume overload. Infused with hypertonic
saline, it may be helpful in hyponatraemia. 6.
Hypercalcaemia of malignancy This condition may
present as a medical emergency with severe volume
depletion. Rapid and large volume i.v. saline infusion is
the most important measure. Addition of furosemide
(10–20 mg/hour) to the i.v. drip after volume
replacement, augments Ca2+ excretion and prevents
volume overload. Forced diuresis with saline and
furosemide infusion is no longer recommended to treat
poisonings.

51)SELECTIVE ESTROGEN RECEPTOR

MODULATORS (SERMS)
These are drugs which exert
estrogenic as well as antiestrogenic actions in a tissue
selective manner. Tamoxifen citrate Though chemically
related to clomiphene, it has complex actions; acts as
potent estrogen antagonist in breast carcinoma cells,
blood vessels and at some peripheral sites, but as
partial agonist in uterus, bone, liver and pituitary.
Inhibition of human breast cancer cells and hot flushes
reflect antiestrogenic action, while the weak estrogen
agonistic action manifests as stimulation of endometrial
proliferation, lowering of Gn and prolactin levels in
postmenopausal women as well as improvement in
their bone density.
A decrease in total and LDL cholesterol
without any change in HDL and triglyceride level
reflects estrogenic action. Similar to estrogen HRT, it
increases the risk of deep vein thrombosis by 2–3
times.
Till recently tamoxifen has been the
standard hormonal treatment of breast cancer in both
preand post-menopausal women, but aromatase
inhibitors have now gained prominence. In early cases
tamoxifen is given as postmastectomy adjuvant
therapy, while in advanced cases, it is a constituent of
palliative treatment. Response rates are high in ER-
positive breast carcinomas, but some ER-negative
tumours also respond
suggesting additional nonhormonal mechanism of
action.
Tamoxifen is the only drug approved for
primary as well as metastatic breast carcinoma in
premenopausal women. It is also effective in surgically
treated cancer of male breast. Based on large
epidemiological studies which have shown 45%
reduction in the incidence of ER-positive breast cancer,
tamoxifen has been approved for primary prophylaxis of
breast cancer in high-risk women.
Recurrence rate in ipsilateral as well as
contralateral breasts is reduced by tamoxifen, but
benefits of prophylactic therapy beyond 5 years are not
proven; outcomes may even be worse. Adjuvant
therapy of breast carcinoma with tamoxifen when used
in postmenopausal women is now generally replaced
after 2 years by an aromatase inhibitor, while in
premenopausal women, tamoxifen itself is continued till
5 years postmastectomy. Improvement in bone mass
due to antiresorptive effect, and in lipid profile are the
other benefits of tamoxifen therapy. However,
endometrial thickening occurs and risk of endometrial
carcinoma is increased 2–3 fold due to estrogenic
action.
Tamoxifen is effective orally; has a biphasic
plasma t½ (10 hours and 7 days) and a long duration of
action. Some metabolites of tamoxifen are more potent
antiestrogens. The drug is excreted primarily in bile.

Dose 20 mg/day in 1 or 2 doses, max. 40 mg/day;

TAMOXIFEN, MAMOFEN, TAMODEX 10, 20 mg tabs.
Male infertility: May be used as alternative to
clomiphene.
Side effects Hot flushes, vomiting, vaginal bleeding,
vaginal discharge, menstrual irregularities are the side
effects. Increased risk of venous thromboembolism is
due to estrogenic action on clotting mechanism.
Dermatitis, anorexia, depression, mild leucopenia and
ocular changes are infrequent. Tamoxifen is much less
toxic than other anticancer drugs.

52)IODINE AND IODIDES

Though iodine is a constituent of thyroid
hormones, it is the fastest acting thyroid inhibitor. In
Grave’s disease the gland, if enlarged, shrinks,
becomes firm and less vascular. The thyroid status
starts returning to normal at a rate commensurate with
complete stoppage of hormone release from the gland.

The thyroid gland involutes and colloid is

restored. The response to iodine and iodides is
identical, because elemental iodine is reduced to iodide
in the intestines. With daily administration, peak effects
are seen in 10–15 days, after which ‘thyroid escape’
occurs and thyrotoxicosis may return with greater
vengeance. Worsening of hyperthyroidism especially
occurs in multinodular goiter. All facets of thyroid
function seem to be affected, but the most important
action is inhibition of hormone release—‘thyroid
constipation’. Endocytosis of colloid and proteolysis of
thyroglobulin comes to a halt. The mechanism of action
is not clear.
Excess iodide inhibits its own transport
into thyroid cells by interfering with expression of NIS
on the cell membrane. In addition, it attenuates TSH
and cAMP induced thyroid stimulation. Excess iodide
rapidly and briefly interferes with iodination of tyrosil
and thyronil residues of thyroglobulin (probably by
altering redox potential of thyroid cells) resulting in
reduced T3/T4 synthesis (Wolff-Chaikoff effect).
However, within a few days, the gland ‘escapes’ from
this effect and hormone synthesis resumes.

Preparations and dose Lugol’s solution (5% iodine in

10% Pot. iodide solution): LUGOL’S SOLUTION,
COLLOID IODINE 10%: 5–10 drops/day. COLLOSOL 8
mg iodine/5 ml liq. Iodide (Sod./Pot.) 100–300 mg/day
(therapeutic), 5–10 mg/ day (prophylactic) for endemic
goiter.
Uses
1. Preoperative preparation for thyroidectomy in
Graves’ disease: Iodine is generally given for 10 days
just preceding surgery. The aim is to make the gland
firm, less vascular and easier to operate on. Though
iodide itself will lower the thyroid status, it cannot be
relied upon to attain euthyroidism which is done by use
of carbimazole before starting iodide. Propranolol may
be given additionally for rapid control of symptoms.
2. Thyroid storm Lugol’s iodine (6–10 drops) or iodine
containing radiocontrast media (iopanoic acid/ipodate)
orally are used to stop any further release of T3/T4
from the thyroid and to decrease T4 to T3 conversion.
3. Prophylaxis of endemic goiter It is generally used as
“iodized salt”(see p. 251).
4. Antiseptic As tincture iodine, povidone iodine, etc.

Adverse effects
1. Acute reaction It occurs only in individuals sensitive
to iodine, and can be triggered even by a minute
quantity. Manifestations are swelling of lips, eyelids,
angioedema of larynx (may be dangerous), fever, joint
pain, petechial haemorrhages, thrombocytopenia,
lymphadenopathy. Further exposure to iodine should be
stopped immediately.
2. Chronic overdose (iodism) Inflammation of mucous
membranes, salivation, rhinorrhoea, sneezing,
lacrimation, swelling of eyelids, burning sensation in
mouth, headache, rashes, g.i. symptoms, etc. The
symptoms regress on stopping iodide ingestion. Long-
term use of high doses can cause hypothyroidism and
goiter. Iodide may cause flaring of acne in adolescents.
Given to pregnant or nursing mothers, it may be
responsible for foetal/infantile goiter and
hypothyroidism. Thyrotoxicosis may be aggravated in
multinodular goiter

53)CEFAZOLIN

It is the prototype first generation

cephalosporin that is active against most PnG sensitive
organisms, i.e. Streptococci (pyogenes as well as
viridans), gonococci, meningococci,
C. diphtheriae, H. influenzae, clostridia and
Actinomyces. Activity against Klebsiella, Moraxella
catarrhalis and E. coli is relatively high, but it is quite
susceptible to staphylococcal β-lactamase. It can be
given i.m. (less painful) as well as i.v. and has a longer
t½ (2 hours) due to slower tubular secretion; attains
higher concentration in plasma and in bile. It is the
preferred parenteral first generation cephalosporin,
especially for surgical prophylaxis.
Dose: 0.5 g 8 hourly (mild cases), 1 g 6 hourly (severe
cases), children 25–50 mg/kg/day i.m. or i.v.; surgical
prophylaxis 1.0 g 1/2 hour before surgery. REFLIN,
ALCIZON, ORIZOLIN 0.25 g, 0.5 g, 1 g per vial inj.