PHARMACOLOGY: Pointers for Final Exam

TOPICS POINTERS

CHEMOTHER
APEUTIC
DRUGS

Principles of What are the factors to consider when selecting an antimicrobial agent?
Antimicrobial Selection of the most appropriate antimicrobial agent requires knowledge of
Therapy 1)the organism's identity
2)the organism's susceptibility to a particular agent
3)the site of the infection
4)patient factors
5)the safety of the agent
6)the cost of therapy However, some critically ill patients require empiric therapy - that is,
immediate administration of drug(s) prior to bacterial identification and susceptibility testing

What factors influence the penetration and concentration of an antibacterial agent in the CSF?
•Lipid solubility of the drug ➢For example, lipid-soluble drugs, such as the quinolones
and metronidazole, have significant penetration into the CNS

•Molecular weight of the drug ➢A compound with a low molecular weight has an
enhanced ability to cross the blood-brain barrier, whereas compounds with a high
molecular weight (for example, vancomycin) penetrate poorly, even in the presence of
meningeal inflammation

•Protein binding of the drug ➢High degree of protein binding of a drug in the serum
restricts its entry into the CSF. Therefore, the amount of free (unbound) drug in serum,
rather than the total amount of drug present, is important for CSF penetration.
 Know how antibacterials are categorized according to spectra.
A. Narrow-spectrum antibiotics
•Chemotherapeutic agents acting only on a single or a limited group of microorganisms
are said to have a narrow spectrum. •For example, isoniazid is active only against
mycobacteria

B. Extended-spectrum antibiotics
•Extended spectrum is the term applied to antibiotics that are effective against gram-
positive organisms and also against a significant number of gram-negative bacteria. •For
example, ampicillin is considered to have an extended spectrum, because it acts against
gram-positive and some gram-negative bacteria.

C. Broad-spectrum antibiotics
•Drugs such as tetracycline and chloramphenicol affect a wide variety of microbial
species and are referred to as broad-spectrum antibiotics •Administration of broad-
spectrum antibiotics can drastically alter the nature of the normal bacterial flora and
precipitate a superinfection of an organism such as Candida albicans, the growth of
which is normally kept in check by the presence of other microorganisms.

Beta-Lactam Describe the mechanism of antibacterial action of beta-lactam antibiotics.

Antibiotics & Beta-lactam antibiotics are bactericidal drugs. They act to inhibit cell wall synthesis by the following steps:
Other Cell 1) binding of the drug to specific enzymes (penicillin-binding proteins [PBPs]) located in the bacterial
Wall cytoplasmic membrane;
(2) inhibition of the transpeptidation reaction that cross-links the linear peptidoglycan chain constituents of
Synthesis
the cell wall; and
Inhibitors (3) activation of autolytic enzymes that cause lesions in the bacterial cell wall. Enzymatic hydrolysis of the
beta-lactam ring results in loss of antibacterial activity
The formation of beta-lactamases (penicillinases) by most staphylococci and many gram-negative
organisms is a major mechanism of bacterial resistance. Inhibitors of these bacterial enzymes (eg,
clavulanic acid, sulbactam, tazobactam) are often used in combination with penicillins to prevent their
inactivation.
Identify the prototype drugs in each subclass of penicillins, and describe their
antibacterial activity and clinical uses.
A. Narrow-spectrum penicillinase-susceptible agents—
Penicillin G is the prototype of a subclass of penicillins that have a limited spectrum of antibacterial
activity and are susceptible to beta-lactamases
Clinical uses include therapy of infections caused by common streptococci, meningococci, gram-positive
bacilli, and spirochetes.
penicillin G remains the drug of choice for syphilis.

Penicillin V is an oral drug used mainly in oropharyngeal infections.

Pen V is more acid-stable than Pen G. It is often employed orally in the treatment of infections,where it is
effective against some anaerobic organsims.

B. Very-narrow-spectrum penicillinase-resistant drugs- methicillin (the prototype, but rarely

used owing to its nephrotoxic potential), nafcillin, and oxacillin.
Their primary use is in the treatment of known or suspected staphylococcal infections.

C. Wider-spectrum penicillinase-susceptible drugs

a. Ampicillin and amoxicillin
Ampicillin- the drug of choice for the gram-positive bacillus Listeria monocytogenes. These
agents are also widely used in the treatment of respiratory infections.
Amoxicillin is employed prophylactically by dentists for patients with abnormal heart valves
who are to undergo extensive oral surgery
b.Piperacillin and ticarcillin
•Are called antipseudomonal penicillins because of their activity against P.aeruginosa.
•Piperacillin is the most potent of these antibiotics. They are effective against many gram-
negativebacilli,but not against klebsiella,because of its constitutive penicillinase.
•Formulation of ticarcillin or piperacillin with Clavulanic acid or
tazobactam,respectively,extends the antimicrobial spectrum of these antibioticsto include
penicillinase-producing organism.
Identify the 4 subclasses of cephalosporins, and describe their antibacterial
activities and clinical uses.
4.A. First-generation drugs—
Cefazolin (parenteral) and cephalexin (oral) are examples of this subgroup.
They are active against gram-positive cocci, including staphylococci and common streptococci. They are
resistant to the staphylococcal penicillinase against P roteus mirabilis, E . c oli, and K lebsiella and also
have activity pneumoniae (the acronym PEcK has been suggested).

B. Second generation drugs

The seconddrugs generation cephalosporins display additional gramnegative organisms: H greater activity
against three . influenzae, aerogenes , and some N eisseria species positive organisms is weaker , whereas
(the acronym E nterobacter activity against gram HENPEcKhas been suggested with the second
generation’s increased coverage)

C. Third- generation drugs

Although inferior to first-generation cephalosporins in regard to their activity against ram-positive cocci,the
third-generation cephalosporins have enhanced activity against gram-negative bacilli,including those
mentioned above,a swell as most other enteric organisms plus Serratia marcescens.

Ceftriaxone or cefotaxime have become agents of choice in the treatment of meningitis. •Ceftazidime has
activity against P.aeruginosa

Drugs in this subclass should usually be reserved for treatment of serious infections.

Ceftriaxone (parenteral) and cefixime (oral), currently drugs of choice in gonorrhea, are exceptions.
Likewise, in acute otitis media, a single injection of ceftriaxone is usually as effective as a 10-day course of
treatment with amoxicillin.

D. 4th- generation drugs

Cefepime is classified as a fourth-generation cephalosporins and must be administered parenterally.

Cefepime combines the gram-positive activity of first-generation agents with the wider gram-negative
spectrum of third-generation cephalosporins
List the major adverse effects of the penicillins and the cephalosporins.
PENICILLINS
1. Allergy
 This is the most important adverse effect of the penicillins.
 The major antigenic determinant of penicillin hypersensitivity is its metabolite, penicilloic acid, which reacts with
proteins and serves as a hapten to cause an immune reaction.
 Approximately five percent of patients have some kind of reaction, ranging from maculopapular rash to
angioedema (marked swelling of the lips, tongue, and periorbital area) and anaphylaxis.
 Methicillin causes interstitial nephritis, and nafcillin is associated with neutropenia.
 Complete cross-allergenicity between different penicillins should be assumed.
 Ampicillin frequently causes maculopapular skin rash that does not appear to be an allergic reaction.
2. Gastrointestinal disturbances
Nausea and diarrhea may occur with oral penicillins, especially with ampicillin.
Gastrointestinal upsets may be caused by direct irritation or by overgrowth of gram-positive organisms or yeasts.
Ampicillin has been implicated in pseudomembranous colitis.

CEPHALOSPORINS
1. Allergy
 Patients who have had an anaphylactic response to penicillins should not receive cephalosporins.
 The cephalosporins should be avoided or used with caution in individuals who are allergic to penicillins (about 5-
15 percent show cross-sensitivity).
 In contrast, the incidence of allergic reactions to cephalosporins is one to two percent in patients without a history
of allergy to penicillins.
2. Other adverse effects
 Cephalosporins may cause pain at intramuscular injection sites and phlebitis after intravenous administration.
 They may increase the nephrotoxicity of aminoglycosides when the two are administered together.

Identify the important features of aztreonam, imipenem, and meropenem.

Aztreonam,
 which is the only commercially available monobactam, has antimicrobial activity directed primarily against the
enterobacteriaceae, but it also acts against aerobic gram-negative rods, including P. aeruginosa.
 It LACKS activity against gram-positive organisms and anaerobes.
 This narrow antimicrobial spectrum precludes its use alone in empiric therapy.
 Aztreonam is resistant to the action of beta-lactamases.
 It is administered either IV or IM and is excreted in the urine. It can accumulate in patients with renal failure.
 Aztreonam is relatively nontoxic, but it may cause phlebitis, skin rash, and occasionally, abnormal liver function
tests.
 This drug has a low immunogenic potential, and it shows little cross-reactivity with antibodies induced by other
beta-lactams.
 Thus, this drug may offer a safe alternative for treating patients who are allergic to penicillins and/or
cephalosporins.
Imipenem is compounded with cilastatin to protect it from metabolism by renal dehydropeptidase.
-Imipenem/cilastatin and meropenem are the BROADEST-SPECTRUM beta-lactam antibiotic preparations currently
available.
-Imipenem resists hydrolysis by most beta-lactamases, but not the metallo-beta-lactamases.
-The drug plays a role in empiric therapy because it is active against penicillinase-producing gram-positive and gram-
negative organisms, anaerobes, and P. aeruginosa.
-Meropenem has antibacterial activity similar to that of imipenem.
 Describe the clinical uses and toxicities of vancomycin.
Vancomycin is effective primarily against gram-positive organisms.
-It has been lifesaving in the treatment of MRSA and methicillin-resistant Staphylococcus epidermidis (MRSE) infections
as well as enterococcal infections.
-With the emergence of resistant strains, it is important to curtail the increase in vancomycin-resistant bacteria by
restricting the use of vancomycin to the treatment of serious infections caused by beta-lactam resistant, gram-positive
microorganisms or for patients with gram-positive infections who have a serious allergy to the beta-lactams.
-Oral vancomycin is limited to treatment for potentially life-threatening, antibiotic-associated colitis due to C. difficile
or staphylococci.
-Vancomycin is used in individuals with prosthetic heart valves and in patients undergoing implantation with prosthetic
devices.
-Vancomycin acts synergistically with the aminoglycosides, and this combination can be used in the treatment of
enterococcal endocarditis.
Adverse effects
-Side effects are a serious problem with vancomycin and include fever, chills, and/or phlebitis at the infusion site.
-Flushing (red man syndrome) and shock results from histamine release associated with a rapid infusion.
-If an infusion-related reaction occurs, slow the infusion rate to administer vancomycin over 2 hours, increase the
dilution volume, or pretreat with an antihistamine 1 hour prior to administration.
-Additionally, reactions can be treated with antihistamines and steroids
-Dose-related hearing loss has occurred in patients with renal failure who accumulate the drug.
-Ototoxicity and nephrotoxicity are more common when vancomycin is administered with another drug (for example,
an aminoglycoside) that can also produce these effects.

Chloramphe Explain (per drug class) how these agents inhibit bacterial protein synthesis
nicol
CHLORAMPHENICOL inhibits transpeptidation (catalyzed by peptidyl transferase) by blocking the binding of the
Tetracycline aminoacyl moiety of the charged transfer RNA (tRNA) molecule to the acceptor site on the ribosome-messenger (mRNA)
complex. Thus, the peptide at the donor site cannot be transferred to its amino acid acceptor.
s
• Chloramphenicol is active against a wide range of gram-positive and gram-negative organisms.
Macrolides,
• However, because of its toxicity, its use is restricted to life-threatening infections for which no alternatives exist.
Clindamycin

linezolid
Mechanism of Action •

The drug binds to the bacterial 50S ribosomal subunit and inhibits protein synthesis at the peptidyl transferase reaction.

• Because of the similarity of mammalian mitochondrial ribosomes to those of bacteria, protein synthesis in these
organelles may be inhibited at HIGH circulating chloramphenicol levels, producing BONE MARROW TOXICITY.

TETRACYCLINES

• The tetracyclines are a group of closely related compounds that, as the name implies, consist of four fused rings with
a system of conjugated double bonds.

• Substitutions on these rings are responsible for variation in the drugs' individual pharmacokinetics, which cause small
differences in their clinical efficacy. Mechanism of action
 • Entry of these agents into susceptible organisms is mediated both by passive diffusion and by an energy-dependent
transport protein mechanism unique to the bacterial inner cytoplasmic membrane.

• Nonresistant strains concentrate the tetracyclines intracellularly.

• The drug binds REVERSIBLY to the 30S subunit of the bacterial ribosome, thereby blocking access of the amino acyl-
tRNA to the mRNA-ribosome complex at the acceptor site. By this mechanism, bacterial protein synthesis is inhibited.

MACROLIDES

• The macrolides are a group of antibiotics with a macrocyclic lactone structure to which one or more deoxy sugars are
attached.

• The macrolides bind IRREVERSIBLY to a site on the 50S subunit of the bacterial ribosome, thus inhibiting the
translocation steps of protein synthesis.

• They may also interfere at other steps, such as transpeptidation. Generally considered to be bacteriostatic, they may
be bactericidal at higher doses.

CLINDAMYCIN

• Clindamycin has a mechanism of action that is the same as that of erythromycin. Clindamycin is employed primarily
in the treatment of infections caused by anaerobic bacteria, such as Bacteroides fragilis, which often causes abdominal
infections associated with trauma. However, it is also significantly active against nonenterococcal, gram-positive cocci.

• Resistance mechanisms are the same as those for erythromycin, and cross-resistance has been described. [Note:
Clostridium difficile is always RESISTANT to clindamycin.]

• It distributes well into all body fluids except the CSF. Adequate levels of clindamycin are not achieved in the brain,
even when meninges are inflamed.

• Penetration into bone occurs even in the absence of inflammation. • The drug is excreted into the bile or urine by
glomerular filtration.

• Accumulation has been reported in patients with either severely compromised renal function or hepatic failure.

• In addition to skin rashes, the most serious adverse effect is potentially fatal pseudomembranous colitis caused by
overgrowth of C. difficile, which elaborates necrotizing toxins. Oral administration of either metronidazole or
vancomycin is usually effective in controlling this serious problem. [Note: Vancomycin should be reserved for a
condition that does not respond to metronidazole.]

LINEZOLID

• The first of a novel class of antibiotics (oxazolidinones), linezolid is active against drug-resistant gram-positive cocci,
including strains resistant to penicillins (eg, MRSA,) and vancomycin (eg, VRE).

• The drug is also active against L monocytogenes and corynebacteria.

• Linezolid binds to a unique site located on the 23S ribosomal RNA of the 50S ribosomal subunit, and there is currently
no cross-resistance with other protein synthesis inhibitors.

• Resistance (rare to date) involves a decreased affinity of linezolid for its binding site.

• Linezolid is available in both oral and parenteral formulations and should be reserved for treatment of infections
caused by multidrug-resistant gram-positive bacteria.

• The drug is metabolized by the liver and has an elimination half-life of 4–6 h.

Name the most important features of azteonam, imepenem, and meropenem

Azetolam- they are uniqe because the beta lactam ring is not fussed to another ring. It lacts activity against gram positive
and anerobes. It has low immunogenic potential. It shows little cross-reactivity with antibodies induced by other beta
lactam,

Imepenem/Meropenem broadest spectrum beta lactam antibiotic preparations.

Imepenem undergoes cleavage by dehydropeptidase. Thus it is combined with Silastatine that protects the parent drug
and prevents the formation of toxic metabolite.
Recall distinctive pharmacokinetic features of the major drugs

Chloramphenicol

Pharmacokinetics

• Chloramphenicol may be administered either intravenously or orally.

• It is widely distributed throughout the body. It readily enters the normal CSF.

• Excretion of the drug depends on its conversion in the liver to a glucuronide, which is then secreted by the renal
tubule.

• Only about 10 percent of the parent compound is excreted by glomerular filtration.

• Chloramphenicol is also secreted into breast milk.

Tetracyclines

Pharmacokinetics: Absorption

• All tetracyclines are adequately but incompletely absorbed after oral ingestion.

• However, taking these drugs concomitantly with dairy foods in the diet decreases absorption due to the formation of
nonabsorbable chelates of the tetracyclines with calcium ions.

• Nonabsorbable chelates are also formed with other divalent and trivalent cations (for example, those found in
magnesium and aluminum antacids and in iron preparations).

• This presents a problem if a patient self-treats the epigastric upsets caused by tetracycline ingestion with antacids.

• Doxycycline and minocycline are almost totally absorbed on oral administration.

• Currently, doxycycline is the preferred tetracycline for parenteral administration.

Pharmacokinetics: Distribution

• The tetracyclines concentrate in the liver, kidney, spleen, and skin, and they bind to tissues undergoing calcification
(for example, teeth and bones) or to tumors that have a high calcium content (for example, gastric carcinoma).

• Although all tetracyclines enter the cerebrospinal fluid (CSF), levels are insufficient for therapeutic efficacy, except for
minocycline. Minocycline enters the brain in the absence of inflammation and also appears in tears and saliva. Although
useful in eradicating the meningococcal carrier state, minocycline is not effective for central nervous system infections.

• All tetracyclines cross the placental barrier and concentrate in fetal bones and dentition.
Pharmacokinetics: Fate

• All the tetracyclines concentrate in the liver, where they are, in part, metabolized and conjugated to form soluble
glucuronides.

• The parent drug and/or its metabolites are secreted into the bile.

• Most tetracyclines are reabsorbed in the intestine via the enterohepatic circulation and enter the urine by glomerular
filtration.

• Obstruction of the bile duct and hepatic or renal dysfunction can increase their half-lives.

• Unlike other tetracyclines, doxycycline can be employed for treating infections in renally compromised patients,
because it is preferentially excreted via the bile into the feces.

• [Note: Tetracyclines are also excreted in breast milk.]

Macrolides

Pharmacokinetics: Administration

• The erythromycin base is destroyed by gastric acid. Thus, either enteric-coated tablets or esterified forms of the
antibiotic are administered.

• Clarithromycin, azithromycin, and telithromycin are stable to stomach acid and are readily absorbed.

• Food interferes with the absorption of erythromycin and azithromycin but can increase that of clarithromycin.

• Azithromycin is available for intravenous infusion, but intravenous administration of erythromycin is associated with
a high incidence of thrombophlebitis.

Pharmacokinetics

• Erythromycin distributes well to all body fluids except the CSF. It is one of the few antibiotics that diffuses into
prostatic fluid, and it has the unique characteristic of accumulating in macrophages.

• Inflammation allows for greater tissue penetration.

• Serum levels of azithromycin are low; the drug is concentrated in neutrophils, macrophages, and fibroblasts.
Azithromycin has the longest half-life and largest volume of distribution of the four drugs.

• Erythromycin and azithromycin are primarily concentrated and excreted in an active form in the bile. Inactive
metabolites are excreted into the urine.

• In contrast, clarithromycin and its metabolites are eliminated by the kidney as well as the liver, and it is recommended
that the dosage of this drug be adjusted in patients with compromised renal function.

Macrolides
Adverse effects

• Epigastric distress: This side effect is common and can lead to poor patient compliance for erythromycin.
Clarithromycin and azithromycin seem to be better tolerated by the patient, but gastrointestinal problems are their
most common side effects.

• Cholestatic jaundice: This side effect occurs especially with the estolate form of erythromycin, presumably as the
result of a hypersensitivity reaction to the estolate form. It has also been reported for other forms of the drug. •
Ototoxicity: Transient deafness has been associated with erythromycin, especially at high dosages.

• Contraindications: Patients with hepatic dysfunction should be treated cautiously with erythromycin, telithromycin,
or azithromycin, because these drugs accumulate in the liver. Recent cases of SEVERE hepatotoxicity with telithromycin
use have emphasized the caution needed when utilizing this agent. Additionally, telithromycin has the potential to
prolongate the QTc interval in some patients.

Therefore, it should be avoided in patients with proarrhythmic conditions. Similarly, patients who are renally
compromised should be given telithromycin with caution. Telithromycin is CONTRAINDICATED in patients with
myasthenia gravis.

Clindamycin and linizolid ( refer to top)

List the characteristic toxic effects of the major drugs in each class

Chloramphenicol

Adverse effects

• The clinical use of chloramphenicol is limited to life-threatening infections because of the serious adverse effects
associated with its administration.

• In addition to gastrointestinal upsets, overgrowth of Candida albicans may appear on mucous membranes.

• ANEMIAS: Hemolytic anemia occurs in patients with low levels of glucose 6-phosphate dehydrogenase. Other types
of anemia occurring as a side effect of chloramphenicol include reversible anemia, which is apparently dose-related and
occurs concomitantly with therapy, and aplastic anemia, which although rare is idiosyncratic and usually fatal. [Note:
Aplastic anemia is independent of dose and may occur after therapy has ceased.]

• GRAY BABY SYNDROME: This adverse effect occurs in neonates if the dosage regimen of chloramphenicol is not
properly adjusted. Neonates have a low capacity to glucuronylate the antibiotic, and they have underdeveloped renal
function. Therefore, neonates have a decreased ability to excrete the drug, which accumulates to levels that interfere
with the function of mitochondrial ribosomes. This leads to poor feeding, depressed breathing, cardiovascular collapse,
CYANOSIS (hence the term gray baby) and death. Adults who have received very high doses of the drug can also exhibit
this toxicity.

• INTERACTIONS: Able to inhibit some of the hepatic mixed-function oxidases and, thus, blocks the metabolism of such
drugs as warfarin, phenytoin, tolbutamide, and chlorpropamide, thereby elevating their concentrations and
potentiating their effects

TETRACYCLINES

Adverse effects

• Gastric discomfort: Epigastric distress commonly results from irritation of the gastric mucosa and is often responsible
for noncompliance in patients treated with these drugs. The discomfort can be controlled if the drug is taken with foods
other than dairy products.

• Effects on calcified tissues: Deposition in the bone and primary dentition occurs during calcification in growing
children. This causes discoloration and hypoplasia of the teeth and a temporary stunting of growth.

• Fatal hepatotoxicity: This side effect has been known to occur in pregnant women who received high doses of
tetracyclines.

• Phototoxicity: Phototoxicity, such as severe sunburn, occurs when a patient receiving a tetracycline is exposed to sun
or ultraviolet rays. This toxicity is encountered most frequently with tetracycline & doxycycline.

• Vestibular problems: These side effects (for example, dizziness, nausea, and vomiting) occur particularly with
minocycline, which concentrates in the endolymph of the ear and affects function. Doxycycline may also cause
vestibular effects.

• Superinfections: Overgrowths of Candida (for example, in the vagina) or of resistant staphylococci (in the intestine)
may occur. Pseudomembranous colitis due to an overgrowth of Clostridium difficile has also been reported.
• Contraindications: - Renally impaired patients except doxycycline Accumulation of tetracyclines may aggravate
preexisting azotemia by interfering with protein synthesis, thus promoting amino acid degradation. - Pregnant or
breast-feeding women - Children less than 8 years of age
Aminoglyco Describe the mechanism of action of aminoglycosides
sides

Susceptible gram-negative organisms allow aminoglycosides to diffuse through porin channels in their outer
membranes. These organisms also have a oxygen- dependent system that transports the drug across te
cytplasmic membrane.

The antibiotic then binds to the 30s ribosomal subunit prior to ribosome formation. There, it interferes with the
assembly of the functional ribosomal apparatus and/ or can cause the 30s subunit of the completed ribosome to
misread the genetic code.
Iist the major clinical applications of aminoglycosides and identify their main two toxicities

Adverse effects

• The elderly are particularly susceptible to nephrotoxicity and ototoxicity.

• Ototoxicity: Ototoxicity (vestibular and cochlear) is directly related to high peak plasma levels and the
duration of treatment. The antibiotic accumulates in the endolymph and perilymph of the inner ear, and
toxicity correlates with the number of destroyed hair cells in the organ of Corti. Deafness may be
irreversible and has been known to affect fetuses in utero. Vertigo and loss of balance (especially in
patients receiving streptomycin) may also occur, because these drugs affect the vestibular apparatus.

Nephrotoxicity: Retention of the aminoglycosides by the proximal tubular cells disrupts calcium mediated
transport processes, and this results in kidney damage ranging from mild, reversible renal impairment to
severe, acute tubular necrosis, which can be irreversible.

• Neuromuscular paralysis: This side effect most often occurs after direct intraperitoneal or intrapleural
application of large doses of aminoglycosides. The mechanism responsible is a decrease in both the
release of acetylcholine from prejunctional nerve endings and the sensitivity of the postsynaptic site.
Patients with myasthenia gravis are particularly at risk. Prompt administration of calcium gluconate or
neostigmine can reverse the block.

• Allergic reactions: Contact dermatitis is a common reaction to topically applied neomycin.

Describe amonoglycoside pharmacokinetic characteristics with reference to their renal clearance
and potential toxicity

Pharmacokinetics

• All aminoglycosides (except neomycin) must be given parenterally to achieve adequate serum levels.

• Note: The severe nephrotoxicity associated with neomycin precludes parenteral administration, and its current
use is limited to topical application for skin infections or oral administration to prepare the bowel prior to
surgery.

• Have a post-antibiotic effect once-daily dosing with the aminoglycosides can be employed results in
fewer toxicities and is less expensive to administer.

• The exceptions are pregnancy, neonatal infections, and bacterial endocarditis, in which these agents are
administered in divided doses every 8 hours.

• High concentrations accumulate in the renal cortex and in the endolymph and perilymph of the inner ear,
which may account for their nephrotoxic and ototoxic potential.

• All aminoglycosides cross the placental barrier and may accumulate in fetal plasma and amniotic fluid.

• All are rapidly excreted into the urine, predominantly by glomerular filtration.

• Accumulation occurs in patients with renal failure and requires dose modification.
 Sulfonamides, Describe how sulfonamides and trimethoprim affect bacterial folic acid
Trimethoprim, synthesis.
&
Fluoroquinolones
Sulfonamides currently in clinical use are synthetic analogs of p-
aminobenzoic acid( PABA) compete with this substrate for the bacterial
enzyme, dihydropteroate synthetase. They thus inhibit the synthesis of
bacterial dihydrofolic acid and, thereby, the formation of its essential
cofactor forms.

Trimethoprim, a potent inhibitor of bacterial dihydrofolate reductase

The active form of folate is the tetrahydro-derivative that is formed

through reduction of dihydrofolic acid by dihydrofolate reductase. This
enzymatic reaction is inhibitedby trimethoprim, leading to a decreased
availability of the tetrahydrofolate coenzymes required for purine,
pyrimidine, and amino acid synthesis.

Identify major clinical uses of sulfonamides and trimethoprim, singly and

in combination, and describe their characteristic pharmacokinetic
properties and toxic effects.

I. Clinical Uses
SULFONAMIDES

Sulfa drugs are active against selected enterobacteria in the urinary

tract and nocardia.

sulfadiazine, in combination with the dihydrofolate reductase

inhibitor pyrimethamine, is the preferred form of treatment
for toxoplasmosis and chloroquine-resistant malaria.

TRIMETHOPRIM

Used alone for treatment of acute UTIs, baterial prostatis (fluoroquinolones

preferred) and vaginitis.

COTRIMOXAZOLE (trimethoprim w/ sulfamethoxazole)

Treatment of UTIs and respiratory tract, Pneumocystis jiroveci pneumonia

and ampicillin- or chloramphenicol- resistant systemic salmonella
infections.
 II. Pharmacokinetic properties
SULFONAMIDES

Administration

Oral administration- most well absorbed vi small intestine except for

Sulfasalazine reserved for treatment of chronic inflammatory bowel disease
( Crohn’s or ulcerative colitis). Split into sulfapyridine ( toxicity pt. who are
slow acetylators) and 5 aminosalicylate (anti inflammatory effect).

Not usually applied topically beacause of risk of sensitisation. However,

creams of silver sulfadiazine ( preferred) or mafenide acetate ( pain on
application and increase risk of acid-base imbalance) are effective in
reducing burn-associated sepsis by preventing colonisation of bacteria.

Distribution

Throughout the body’s water, penetrate well into CSF even w/o
inflammation and can pass the placental barrier- enter fetal tissues.

Metabolism

Acetylated- primarily in the liver

Product devoid of anti microbial activity but retains the toxic potential to
precipitate at neural or aidic pH- crystalluria( stone formation)- potential
damage to kidney.

Excretion

Eliminated via glomerular filtration. Depressed kidney- accumulation

Also eliminated in breast milk.

TRIMETHOPRIM

Similar halflife w/ sulfamethoxazole

Weak base- higher concentration in acidic prostatic and vaginal fluids

Penetrates the CSF

Excreted unchanged through the kidney.

COTRIMOXAZOLE (trimethoprim w/ sulfamethoxazole)

Trimethoprim more lipid soluble, greater volume distribution

1 part of trimethoprim to 5 parts of sulfamethoxazole- administration

25 parts of sulfamethoxazole to 1 part of trimethoprim- plasma

Generally Administered Orally

IV- severe pneumonia by P. jiroveci/ pts who cannot take drug by mouth

Both distribute throughout the body and excreted in the urine.

III. Adverse Effects

SULFONAMIDES

Crystalluria- Nephrotoxicity

Sulfisoxazole and sulfamethoxazole less liable to cause

crystalluria.

Hypersensitivity- rashes, angioedema, and Stevens- Johnson syndrome

( frequently w/ long-acting agents) FAIRLY COMMON

Hemopoietic disturbances- Hemolytic anemia(w/ G6PD deficiency),

Granulocytopenia and thrombocytopenia

Drug potentiation- hypoglycaemic effect of tolbutaline/ anticoagulant

effect of warfarin- results from their displacement from bining sites

on serum albumin.

Contraindication- Kernicterus

Avoided in newborn and infants below 2months and pregnant

women.

TRIMETHOPRIM

Effects of FOLIC ACID DEFICIENCY- Megaloblastic anemia, leukopenia and

granulocytopenia, esp. pregnant patients and having very poor diets.

Reverse by administration of Folinic acid.

COTRIMOXAZOLE (trimethoprim w/ sulfamethoxazole)

Dermatologic- very common, severe in elderly

Gastrointestinal- N/V, glossitis and stomatitis not usual

Hematologic- Megaloblastic anemia, leukopenia and thrombocytopenia.

Reverse by administration of folinic acid. Haemolytic anemia (G6PD

deficiency due to sulfamethoxazole )

Pts infected w/ HIV- immuno compromised w/ P. Jiroveci pneumonia

frequently show drug induced fever, rashes, diarrhea and or

pancytopenia

Drug interactions- warfarin- prolonged prothrombin times

Phenytoin- plasma half-life increased

Methotrexate- rise by sulfamethoxazole

Describe how fluoroquinolones inhibit nucleic acid synthesis.

Inhibit the replication of bacteria by interfering with the action of DNA gyrase
(topoisomerase II) and topoisomerase IV during baterial growth and
production.

Forms ternary complex that inhibits the resealing step and cause cell death
by inducing cleavage of DNA

Second site blocked by fluoroquinolones topoisomerase IV, is required by

bacteria for cell division

List the major clinical uses of fluoroquinolones and describe their

characteristic pharmacokinetic properties and toxic effects

Ciprofloxacin- effective against systemic infections except caused by

MRSA, enterococci, and pneumococi.

Tx infections caused by Enterobacteriaceae and other gram negative

bacilli (travelers diarrhea caused by E.coli)

Drug of choice prophylaxis

Tx of anthrax, most potent pseudomonas aeroginosa infections

 associated w/ cystic fibrosis

W/ betalactams benefit tx of tuberculosis

Nirfloxacin- tx complicated and uncomplicated UTIs and prostatitis.

Levofloxacin- tx of prostatitis due to E.coli, tx of sexually transmitted

diseases except syphilis

Moxifloxacin- enhanced activity against gram positive but also excellent

against ANAEROBES, very poor against P. Aeruginosa.

Antimycobacter Identify the first-line agents used to treat tuberculosis and their mechanisms
ial Drugs of action.

Isoniazid- inhibits enzymes essential fo the synthesis of mycolic acid

Rifampin (or Rifabutin/ Rifapentine)- blocks transription by interating w/

betasubunit of bacterial DNA- dependent RNA polymerase. Inhibits

mRNA synthesis by supressing the initiation step.

Pyrazinamide- unknown

Ethambutol- inhibits arabinosyl transferase, an enzyme that is important

for the synthesis of mycobacterial arabinogalactan cell wall.

Describe the strategy in treating tuberculosis and in addressing the problem

of resistance.

Strains of M. tuberculosis that are RESISTANT to a particular agent emerge

during treatment w/ a single drug-> Multidrug therapy is employed to delay
or prevent the mergence of resistant strains-> multidrug-resistant organisms
has risen-> minimum of two drugs, preferably with both being bactericidal
to prevent the emergence of resistant strains-> multidrug regimen is
continued well beyond the disappearance of clinical disease to eradicate any
persistent organism ex. Initial short-course isoniazid, rifampin, ethambutol,
and pyrazinamide for 2 months then isoniazid and rifampin for next 4 months(
continuation phase)-> If previously had tuberculosis/ multidrug resistant
tuberculosis suspected, ADDED DRUGS include an aminoglycoside(
streptomycin, kanamycin, or amikacin) or capreomycin( injectable agents),
fluoroquinolone, and second-line anti tuberculosis agent( cycloserine,
ethionamide, or para-aminosalicylic acid) Drug regimen can be tailored to
patient once susceptibility data are available-> patient compliance is often
low when multidrug schedules last for 6months/ longer-> DIRECTLY
OBSERVED THERAPY (DOT) achieve better treatment completion rates.
Shown to decrease resistance as well as relapse and mortality rates; and
improve cure rates.

Identify important pharmacokinetic features and major toxicity associated

with first-line agents.

I. Pharmacokinetic properties
ISONIAZID

Bacteriostatic for bacilli in stationary phase

Bactericidal for rapidly dividing organisms

Resistant organisms rapidly emergen if used alone

Cross-resistance does not occur between isoniazid and other antitubercular

drugs.

Orally administered readily absorbed.

Absorption impaired if taken w/ food, particularly carbohydrates, or w/

aluminum containing antacids.

Difusses into all body fluids, cells, and caseous material( necrotic tissue
resembling cheese that produce in tubercles).

RIFAMPIN

Broader antimicrobial activity than isoniazid

Never giver given as single agent in tx of tuberculosis- resistant strains

rapidly emerge.
Bactericidal for both intracellular and extracellular mycobacteria( M.
tuberculosis) and atypical mycobacteria( M. kansasii)

Usually given in combination w/ other drugs to delay the emergence of

resistant strains in tx of antileprosy.

Well tolerated

RIFABUTIN

Less potent inducer of cytochrome P450 enzymes

RIFAPENTINE

Longer halflife than rifampin and rifabutine, w/c permits weekly dosing.

For intensive phase(initial 2months) of short-course therapy for

tuberculosis, it is given twice weekly.

In subsequent phase, it is given once per week for 4months.

PYRAZINAMIDE

Bactericidal for dividing organism

ETHAMBUTOL

Bacteriostatic

Can be used in combination w/ pyrazinamide, isoniazid and rifampin for tx

of tuberculosis.

Absorbed an oral administration

Penetration into CNS is therapeutically adequate in tuberculosis meningitis.

II. Adverse Effects

ISONIAZID

Fairly low
Peripheral neuritis( paresthesias of hands and feet), most common adverse
effect- pyridoxine deficiency- corrected by supplementation of

25 to 50mg per day of pyridoxine( vitamin B6). Note: It can achieve

levels in breast milk that are high enough to cause pyridoxine
deficiency in infants.

Hepatitis and idiosyncratic hepatotoxicity: Potentially fatal hepatitis,

most common severe side effect, increases w/ increasing age, pts

who take rifampin/ who drink alcohol daily.

Drug interactions: Phenytoin- inhibits metabolism of phenytoin->

(nystagmus and ataxia)

RIFAMPIN

N/V and rash- most common adverse reactions.

Hepatitis and death due to liver failure- rare. However, should be used
judiciously in pts who are alcoholic, elderly, or have chronic liver disease due
to increase of severe hepatic dysfunction w/ rifampin alone or
concomitantly w/ isoniazid.

Flu-like Syndrome associated w/ fever- often w/ intermittent dose/ daily

dose of 1.2g or greater w/ rifampin.

Drug interactions: rifampin can induce cytochrome P450 enzymes, it can

decrease the halflives of other drugs -> higher dosage requirements for
these drugs.

PYRAZINAMIDE

May experience liver dysfunction about 1- 5% of pts taking isoniazid,

rifampin and pyrazinamide.

May precipitate a gouty attack- urate retention

ETHAMBUTOL
TABLE A.E.

Identify the second-line agents for tuberculosis and why they were classified
as such.

Classified as second- line agents:

No more effective than the firstline agents and their toxicities are often
serious or because they are particularly active against atypical strains of
mycobacteria.

Streptomycin- first antibiotic effective in tx of tuberculosis, directed against

extracellular organisms

Capreomycin- parenteral, reserved for tx of multidrug resistant tuberculosis-

> Nephrotoxicity and ototoxicity

Cycloserine- oral, tuberculostatic agent, accumulation w/ renal insufficiency,

A.E. CNS disturbances, epileptic seizure activity may be exacerbated;
Peripheral neuropathies- may respond to pyridoxine.

Ethionamide- structural analog of isoniazid but is not believed to act by the

same mechanism, oral, A.E. gastric irritation, hepatotoxicity, peripheral
neuropathies, optic neuritis- supplementation w/ Vit B6( pyridoxine), may
lessen severity of neurologic side effects.

Fluoroquinolones- moxifloxacin and levofloxacin tx of multidrug resistant

tuberculosis, some atypical strains of mycobacteria are susceptible.

Macrolides- azithromycin and clarithromycin, are part of regimen that

includes ethambutol and rifabutin tx of iinfections by M. avium- intracellular
complex. Azithromycin preferred for HIV infected pts- least likely to interfere
w/ metabolism of antiretroviral drugs.
 TOPICS POINTERS
BASIC
PRINCIPLES OF
PHARMACOLOG
Y
Differentiate pharmacokinetics from pharmacodynamics
Pharmacokinetics - describes the effect of the body on drugs
example : absorption , excretion
Pharmacodynamics : -denotes the actions of the drug on the body
example : mechanism of action . toxic effects
List and discuss the common routes of drug administration and
excretion.
Oral (swallowed) PO- convenient, slower absorption, subject to first-
pass effect
The next routes avoid the first-pass metabolism:
Buccal & sublingual (not swallowed) SL- direct absorption into the
systemic venous circulation
Intravenous (IV)- instant & complete absorption; more dangerous
Intramuscular (IM)- often faster and more complete than with oral
Subcutaneous (SC)- slower absorption than IM
Rectal (suppository)- partial avoidance of the first-pass effect; drugs
with unpleasant taste
Inhalation - offers delivery closest to respiratory tissues(eg, for
asthma)
usually very rapid absorption (eg, for anesthetic gases)

Describe how drugs are metabolized.

Phase I reaction
include:
1.Oxidation
- especially by the cytochrome P450 group of enzymes, a.k.a. mixed-
function oxidases
2.Reduction
3.Deamination
4.Hydrolysis
-These enzymes are found in high concentrations in the smooth
endoplasmic reticulum of the liver.
-They are not highly selective in their substrates, so a relatively small
number of P450 isoforms are able to metabolize thousands of drugs.
-Of the drugs metabolized by phase I cytochrome P450s, approximately
75% are metabolized by just two:
CYP3A4
CYP2D6
PHASE II reaction
-Synthetic reactions that involve addition (conjugation) of subgroups to
—OH, —NH2, and —SH functions on the drug molecule.
-Most of these groups are relatively polar and make the product less
lipid-soluble than the original drug molecule.
-Like phase I enzymes, phase II enzymes are not very selective.
Drugs that are metabolized by both routes may undergo phase II
metabolism before or after phase I.

Differentiate first-order elimination from zero-order elimination.

FIRST-ORDER ELIMINATION
Implies that the rate of elimination is proportional to the
concentration (ie, the higher the concentration, the greater the
amount of drug eliminated per unit time).
 The result is that the drug’s concentration in plasma decreases
exponentially
 with time.
 Have a characteristic half-life of elimination that is constant
regardless of the amount of drug in the body.
 The concentration of such a drug in the blood will decrease by 50%
for every half-life.
 Most drugs in clinical use demonstrate first-order kinetics.

ZERO-ORDER ELIMINATION
Implies that the rate of elimination is constant regardless of
concentration.
 Occurs with drugs that saturate their elimination
mechaniscentrations of these drugs in plasma decrease in a linear
fasms
 the conhion over time
Examples:
Ethanol
Phenytoin at high therapeutic or toxic concentrations
Aspirin
BLOOD & GOUT 5
DRUGS
Name the 2 most common types of nutritional anemia, and, for each,
describe the most likely biochemical causes.
Iron deficiency and vitamin deficiency anemia
Microcytic hypochromic anemia
-Caused by iron deficiency
-Most common type of anemia
Pernicious anemia
-The most common type of vitamin B12 deficiency anemia
-Caused by a defect in the synthesis of intrinsic factor, a protein
required for efficient absorption of dietary vitamin B12, or by surgical
removal of that part of the stomach that secretes intrinsic factor.

Identify the iron and folic acid requirements for pregnant women.
30 mg to 60 mg of elemental iron and
400 µg (0.4 mg) folic acid
Explain how folic acid and B12 deficiency affects the body and how
they can be treated.
folic acid is required for normal DNA synthesis, and its deficiency
usually presents as megaloblastic anemia.
In addition, deficiency of folic acid during pregnancy increases the risk
of neural tube defects in the fetus
Anemia resulting from folic acid deficiency is readily treated by oral
folic acid supplementation.
Because maternal folic acid deficiency is associated with increased risk
of neural tube defects in the fetus, folic acid supplementation is
recommended before and during pregnancy.
Vitamin B12 (cobalamin),
a cobalt-containing molecule, is, along with folic acid, a cofactor in the
transfer of 1-carbon units, a step necessary for the synthesis of DNA.
Administration of folic acid to patients with vitamin B12 deficiency
helps refill the tetrahydrofolate pool and partially or fully corrects the
anemia.
However, the exogenous folic acid does not correct the neurologic
defects of vitamin B12 deficiency.
The 2 available forms of vitamin B12—hydroxocobalamin and
cyanocobalamin—have equivalent effects.
The major application is in the treatment of naturally occurring
pernicious anemia and anemia caused by gastric resection.
 Because vitamin B12 deficiency anemia is almost always caused by
inadequate absorption, therapy should be by replacement of vitamin
B12, using parenteral therapy.
Name 3 types of anticoagulants and describe their mechanisms of
action.
Heparin acts by binding to endogenous antithrombin III; the resulting
complex irreversibly inactivates thrombin and factor Xa

Direct Thrombin Inhibitors

-The protein analogs of lepirudin bind simultaneously to the active site
of thrombin and to thrombin substrates.
-Argatroban binds solely to the thrombin-active site.
-Unlike the heparins, these drugs inhibit both soluble thrombin and the
thrombin enmeshed within developing clots.
-Bivalirudin also inhibits platelet activation.
These small molecules directly bind to and inhibit both free factor Xa
and factor Xa bound in the clotting complex.
Warfarin acts by interfering with the normal post-translational
modification of clotting factors in the liver
Compare the pharmacokinetics, clinical uses, and toxicities of the major
antiplatelet drugs.

CARDIOVAS
CULAR
DRUGS
Drugs Used in
Hypertension
List the 4 major groups of antihypertensive drugs, and give examples of drugs in each
group. (Renin inhibitors are not considered an independent major group; can you
name the drug that acts by this mechanism?) Drugs Used in Hypertension

Renin inhibitors

Aliskiren(newest drug) – does not cause cough

Captopril (old drugs) – cause cough

Losartan – lower cough incidence

List the 4 mechanisms of action of vasodilator drugs.

 release of nitric oxide

 opening of potassium channels (which leads to hyperpolarization)
 blockade of calcium channels
 activation of D1 dopamine receptors(causing vasodilation)
List the major antihypertensive vasodilator drugs and describe their effects.

Hydralazine and Minoxidil

Hydrolazine – realease of nitric oxide and dilate arterioles.

High dose causes induced Lupus erythematosis

Minoxidil – opening potassium channel opener that hyperpolarizes and relax smooth
muscles. Can cause hirsusm and can treat baldness

Calcium Channel-Blocking Agents – Nifedipine, Verapamil, Diltiazem

Moderate vasodilators.

Treat chronic HTN.

More commonly used than Hydrolazine and Minoxidil

Nitroprusside, Diazoxide and Fenoldopam

Parenteral; for hepertensive emergency

Nitroprusside – release nitric and cause vasodilation in both artery and veins smooth muscle

Diazoxide – a thiazide but has no diuretic effect

opens potassium channel

reduces insulin and can also treat hypoglysemia caused by insulin inducing tumors.

Fenoldopam – activate dopamine recetor and causes arteriolar dilation

Parenteral only

Use in emergencies

Can cause excessive hypotention

Describe the differences between the 2 types of angiotensin antagonists.
1)Angiotensin Converting Enzyme (ACE) Inhibitors – Captopril (benazepril, enalapril)
Decrease Angiotensin II and increase bradykinin = vasodilation

Reduce peripheral resistance w/o increasing cardiac output

TOXICITY; Cough

Renal damage in renal disease patient and Fetus

Fetal renal toxicity - Contraindicated in pregnancy

2)Angiotensin II Receptor Blockers (ARB) – Losartan (valsartan,irbesartan)

Inhibit Ang II and block aldosterone secretion

Lower salt and water retention and blood pressure

TOXICITY; Fetal renal toxicity – contraindicated in pregnancy

List the major toxicities of the prototype antihypertensive agents.

Thiazide – hypokalemia, hypovolemia, hyperuricemia and hyperglycemia

Furosemide – hypokalemia, hypovolemia and ototoxicity

Prazosin (alpha blocker) – orthostatic hypotension

Propernolol(beta blocker) – bronchospasm in asthma patients, cardiac depression and

sexual dysfunction

Clonidine and methyldopa (CNS agonist) – rebound hypertension, drowsiness

Captopril – feto renal toxicity

 Drugs Used
in the
Treatment of Contrast the therapeutic and adverse effects of nitrates, beta-blockers, and calcium
Angina channel blockers when used for angina.
Pectoris

Nitrate (Nitroglycerin)

10 – 20min Short duration of action (sublingual administration; for Acute angina)

8 – 10 hours Long duration of action(transdermal; for prophylaxis of angina)

Intermediate duration of action (oral; for prophylaxis of angina)

Nitrate also treats acute coronary syndrome

MOA: stimulate Guanylyl cyclase and then increase cGMP(secondary messenger)

cGMP induce smooth muscle relaxation.

Toxicities: tachycardia,

orthostatic hypotension

flushing, headache

Beta blockers

Prophylactic use

Ineffective in acute attack and vasospastic angina

Combination with Nitrate inhibits nitrate’s toxicities

Calcium blockers

All are arteriolar vasodilators

Reduce blood pressure

Verapamil – affects myocardium(Decrease BP, heart rate, contractility and oxygen demand)

Nifedipine – affects peripheral vasculature (minimal effect on cardiac conduction and heart
rate)

Diltiazepine – is intermediate in its action

Relieve coronary artery spasm (variant angina)

Antiarrhythmic Enumerate the 4 major types of antiarrhythmic drugs and list 2-3 important drugs under each
Drugs group.
Group 1 (local anesthetics)
 Group 1A
Procainamide- slows conduction, prolong the action potential and increase the
ventricular effective refractory period. It is used in atrial and ventricular
arrhythmias
Toxicities- hypotension and a reversible syndrome similar to lupus
erythematosus.
Quinidine- toxicities: cinchonism( headache, vertigo, tinnitus), cardiac
depression and autoimmune reaction.
: Torsades de pointes
 Group 1B (shorten the AP)
- Lidocaine and Mexiletine
- Selectively affect ischemic or depolarized purkinje and ventricular
tissue and have little effect on atrial tissue
- Lidociane- useful after MI
- Toxicities: convulsion, cardiovscular depression and allergy
- Hyperkalemia increases cardiac toxicity
 Group 1C ( no effect on AP)
Flecainamide- Powerful depressants of sodium current
-increases QRS duration
-approved only for refractory ventricular tachycardias and for
certain intractable
Supraventriculararrhythmias
Toxicities: cause greater mortality, exacerbate or precipitate arrhythmias

Group 2 (beta blockers)

Propranolol and esmolol
- Mechanism, cardiac b- adrenoceptor blockade and reduction in cAMP which
results in reduction of both sodium and calcium currents and suppression of
abnormal pacemakers
- PR interval is prolonged
- Used for atrial flutter and fibrillation and av nodal reentrant tachycardia
Esmolol-very short acting, used for acute arrhythmias
Propranolol, metoprolol and timolol- Prophylactic drugs in pts who have had a myocardial
infarction

Group 3 ( Potassium channel blockers)

- Prolong AP duration, increase in effective refractory period and reduce the ability
of the heart to respond to rapid tachycardias
Amiodarone- It has complex effects showing class I,II,III and IV actions
- Effective in the treatment of severe refractory supraventricular and ventricular
tachyarrhythmias
- Used mainly in arrhythmias that are resistant to other drugs
- Toxicities: interstitial pulmonary fibrosis, hyper-hypothyroidism, blue skin and
corneal discoloration, liver toxicity, photosensitivity, neuropathy, muscle
weakness
 Group 4( calcium L type channel blockers)
Verapamil and diltiazem
- Decrease the inward current carried by calcium, resulting in a decreased rate of
phase 4 spontaneous depolarization.
- Major effect is on vascular smooth muscle and heart
- AV conduction velocity is decreased and effective refractory period and PR
interval are increased
- Toxicities: excessive depression of cardiac contractility, AV conduction and blood
pressure
- Should be avoided in ventricular tachycardias

List the major toxicities of those drugs

Drugs Used in Describe the strategies and list the major drug groups used in the treatment of acute heart
Heart Failure failure and chronic failure.
Therapeutic strategies:
 Removal of retained salt and water with diuretics
 Reduction of afterload and salt and water retention by means of ACE inhibitors
 Reduction of excessive sympathetic stimulation by means of B blockers
 Reduction of preload or afterload with vasodilators
 Systolic failure: direct augmentation of depressed cardiac contractility with
positive inotropic drugs such as digitalis glycosides
Therapeutic strategies: acute heart failure
 Loop diuretics
 Very severe HF: a prompt acting positive inotropic agent such as B agonist or
phosphodiesterase inhibitor, and vasodilators should be used as required to
optimize filling pressures and blood pressure.
 Nesiritide- recombinant form of brian natriuretic peptide
Has vasodilating and diuretic properties
Therapeutic strategies: chronic heart failure
 Best treated with diuretics( often a loop agent plus spironolactone) plus an ACE
inhibitor and if tolerated, a B blocker
 Digitalis may be helpful id systolic dysfunction is prominent.

Cardiac glycosides
Digitalis- inhibition of na/k ATPase of the cell membrane
Increases force of contraction of the heart
Increase in contractility results in:
- Inc. ventricular ejection
- Dec. end-systolic and end- diastolic size
- Inc. cardiac output
- Inc. renal perfusion
ECG effects:
- Increases PR interval
 - Flattening of the T wave

Toxiciy:
- Increased automacity caused by intracellular calcium overload
- Extrasystoles, tachycardia, fibrillation
- Extrasystoles aare recognized as premature ventricular beats
- Chronic: abnormal automaticity and arrhythmias
- Severe,acute: cardiac depression leading to cardic arrest

Diuretics
- First line therapy for both systolic and diastolic failure
- Furosemide- immediate reduction of the pulmonary congestion
For Acute heart failure and Moderate or severe chronic failure
- Hydrochlorothiazide- Mild chronic failure
- Spironolactone and Eplerenone- can reduce mortality in chronic failure

Angiotensin Antagonists
- Reduce morbidity and mortality in chronic heart failure
- Reduce aldosterone secretion, salt and water retention and vascular resistance.
- Considered along with diuretics to be the first line drugs for Chronic heart failure

Beta1 adrenoceptor agonists

- Dobutamine, Dopamine
- Useful in Acute heart failure
- Not appropriate for chronic failure

Beta adrenoceptor antagonists

- Carvedilol, labetalol, metoprolol
- Reduce progression of Chronic heart failure
- Not of value in acute failure

Phosphodiesterase inhibitors
- Inamrinone, Milrinone
- Increases cAMP, increase in caardiac intracellular calcium
- Also cause vasodilation
- Should not be used in Chronic failure

Vasodilators
- Nitroprusside, Nitroglycerin
- For Acute severe failure with congestion
- Nesiritide- IV infusion for Acute failure only. Has significant renal toxicity

Describe the mechanism of action of digitalis and its major effects. Indicate why digitalis is no
longer considered a first-line therapy for chronic heart failure.
TOPICS POINTERS
CNS
DRUGS
Sedati Identify major drugs in each sedative-hypnotic subgroup
ve-
Hypno
tics
Drugs

Describe the proposed mechanisms of action of benzodiazepines, barbiturates, and zolpidem.

Benzodiazepines
• The targets for benzodiazepine actions are the GABAA receptors.
• Binding of GABA to its receptor triggers an opening of a chloride channel, which leads to an increase in chloride
conductance.
• Benzodiazepines increase the frequency of channel openings produced by GABA.
• The influx of chloride ions causes a small hyperpolarization that moves the postsynaptic potential away from its
firing threshold  inhibits the formation of action potentials.
Barbiturates
• Interaction with GABAA receptors  enhances GABAergic transmission
• The binding site is distinct from that of the benzodiazepines.
• Potentiate GABA action on chloride entry into the neuron by prolonging the duration of the chloride channel
openings.
• Can block excitatory glutamate receptors
• Anesthetic concentrations of pentobarbital also block high-frequency sodium channels.
• All of these molecular actions lead to decreased neuronal activity
Zolpidem

• The hypnotic zolpidem is not a benzodiazepine in structure, but it acts on a subset of the benzodiazepine receptor
family, BZ1.
• Zolpidem has no anticonvulsant or muscle-relaxing properties.
List the pharmacodynamic actions of major sedative-hypnotics in terms of their clinical uses
and their adverse effects.
Benzodiazepines
Therapeutic uses
Anxiety disorders
• Benzodiazepines are effective for the treatment of the anxiety symptoms secondary to panic disorder,
generalized anxiety disorder, social anxiety disorder, performance anxiety, posttraumatic stress disorder,
obsessive-compulsive disorder, and the extreme anxiety sometimes encountered with specific phobias, such as
fear of flying.
• The benzodiazepines are also useful in treating the anxiety that accompanies some forms of depression and
schizophrenia.
• These drugs should not be used to alleviate the normal stress of everyday life.
• They should be reserved for continued severe anxiety, and then should only be used for short periods of time
because of their addiction potential.
• The longer-acting agents, such as clonazepam, lorazepam and diazepam, are often preferred in those patients
with anxiety that may require treatment for prolonged periods of time.
• The antianxiety effects of the benzodiazepines are less subject to tolerance than the sedative and hypnotic
effects.
• Tolerance occurs when used for more than one to two weeks.
• Cross-tolerance exists among this group of agents with ethanol.
• For panic disorders, alprazolam is effective for short- and long-term treatment, although it may cause
withdrawal reactions in about 30 percent of sufferers.
Muscular disorders
• Diazepam is useful in the treatment of skeletal muscle spasms, such as occur in muscle strain, and in treating
spasticity from degenerative disorders, such as multiple sclerosis and cerebral palsy.
Amnesia
• The shorter-acting agents are often employed as premedication for anxiety-provoking and unpleasant
procedures, such as endoscopic, bronchoscopic, and certain dental procedures as well as angioplasty.
• Cause a form of conscious sedation, allowing the person to be receptive to instructions during these
procedures.
• Midazolam is an injectable-only benzodiazepine also used for the induction of anesthesia.

Seizures
• Clonazepam is occasionally used in the treatment of certain types of epilepsy
• Diazepam and lorazepam are the drugs of choice in terminating grand mal epileptic seizures and status
epilepticus.
• Due to cross-tolerance, chlordiazepoxide, clorazepate, diazepam, and oxazepam are useful in the acute
treatment of alcohol withdrawal and reducing the risk of withdrawal-related seizures.
Sleep disorders
• Not all benzodiazepines are useful as hypnotic agents, although all have sedative or calming effects.
• They tend to decrease the latency to sleep onset and increase Stage II of non-rapid eye movement sleep (light
sleep).
• Both REM sleep and slow-wave sleep (deep sleep) are decreased.
• In the treatment of insomnia, it is important to balance the sedative effect needed at bedtime with the residual
sedation (hangover) upon awakening.
• Commonly prescribed benzodiazepines for sleep disorders include:
• long-acting flurazepam
• intermediate-acting temazepam
• short-acting triazolam
Adverse effects

• Drowsiness and confusion

– The two most common side effects of the benzodiazepines.
Ataxia occurs at high doses and precludes activities that require fine motor coordination, such as driving an
automobile
• Cognitive impairment (decreased long-term recall and acquisition of new knowledge) can occur with use of
benzodiazepines.
• Triazolam, one of the most potent oral benzodiazepines with the most rapid elimination, often shows a rapid
development of tolerance, early morning insomnia, and daytime anxiety, along with amnesia and confusion.
Precautions:
• Use cautiously in treating patients with liver disease.
 • Avoid in patients with acute narrow-angle glaucoma
• Alcohol and other CNS depressants enhance the sedative-hypnotic effects of the benzodiazepines.
• Benzodiazepines are, however, considerably less dangerous than the older anxiolytic and hypnotic drugs  drug
overdose is seldom lethal unless other central depressants, such as alcohol, are taken concurrently.
Barbiturates
Therapeutic uses
• Anesthesia:
– the ultrashort-acting barbiturates, such as thiopental, are used intravenously to induce anesthesia.
• Anxiety:
– barbiturates have been used as mild sedatives to relieve anxiety, nervous tension, and insomnia.
– when used as hypnotics, they suppress REM sleep more than other stages. However, most have been
replaced by the benzodiazepines.
• Anticonvulsant:
– Phenobarbital is used in long-term management of tonic-clonic seizures, status epilepticus, and
eclampsia.
– Phenobarbital has been regarded as the drug of choice for treatment of young children with recurrent
febrile seizures. However, phenobarbital can depress cognitive performance in children, and the drug
should be used cautiously.
Pharmacokinetics
• Barbiturates are absorbed orally and distributed widely throughout the body.
• All barbiturates redistribute in the body from the brain  splanchnic areas,  skeletal muscle  finally, to
adipose tissue. This movement is important in causing the short duration of action of thiopental and similar
short-acting derivatives.
• They readily cross the placenta and can depress the fetus.
• Metabolized in the liver, and excreted in the urine
Adverse effects
• CNS:
– drowsiness, impaired concentration, and mental and physical sluggishness
– the CNS depressant effects of barbiturates synergize with those of ethanol
• Drug hangover:
– hypnotic doses of barbiturates produce a feeling of tiredness well after the patient wakes
– this drug hangover may lead to impaired ability to function normally for many hours after waking
– occasionally, nausea and dizziness occur
• Precautions:
– barbiturates induce the P450 system and, therefore, may decrease the duration of action of drugs
that are metabolized by these hepatic enzymes.
– increase porphyrin synthesis  contraindicated in patients with acute intermittent porphyria.
• Physical dependence:
– Abrupt withdrawal from barbiturates may cause tremors, anxiety, weakness, restlessness, nausea
and vomiting, seizures, delirium, and cardiac arrest.
– Withdrawal is much more severe than that associated with opiates and can result in death.
• Poisoning:
– Barbiturate poisoning has been a leading cause of death resulting from drug overdoses for many
decades.
– Severe depression of respiration is coupled with central cardiovascular depression, and results in a
shock-like condition with shallow, infrequent breathing.
– Treatment includes artificial respiration and purging the stomach of its contents if the drug has been
recently taken.
– No specific barbiturate antagonist is available
– Hemodialysis may be necessary if large quantities have been taken.
– Alkalinization of the urine often aids in the elimination of phenobarbital
 Describe the symptoms and management of overdose of sedative-hypnotics and withdrawal from
physiologic dependence.
Dependence
• Psychological and physical dependence on benzodiazepines can develop if high doses of the drugs are given over
a prolonged period.
• Abrupt discontinuation of the benzodiazepines results in withdrawal symptoms, including:
Confusion
Anxiety
Agitation
Restlessness

• Benzodiazepines w/ long half-lives  withdrawal symptoms may occur slowly and last a number of days after
discontinuation of therapy
• Benzodiazepines w/ short half-lives, such as triazolam  induce more abrupt and severe withdrawal reactions
than those seen with drugs that are slowly eliminated, such as flurazepam.

Alcoho Relate blood alcohol levels in a nontolerant person to CNS depressant effects of acute alcohol ingestion.
ls CNS depressant effect
• The major acute effects of ethanol on the CNS are sedation, loss of inhibition, impaired judgment, slurred
speech, and ataxia.
• In nontolerant persons, impairment of driving ability is thought to occur at ethanol blood levels between 60 and
80 mg/dL.
• Blood levels of 120 to 160 mg/dL are usually associated with gross drunkenness.
• Levels greater than 300 mg/dL may lead to loss of consciousness, anesthesia, and coma sometimes with fatal
respiratory and cardiovascular depression.
• Blood levels higher than 500 mg/dL are usually lethal.
• Individuals with alcohol dependence who are tolerant to the effects of ethanol can function almost normally at
much higher blood concentrations than occasional drinkers.
• Additive CNS depression occurs with concomitant ingestion of ethanol and a wide variety of CNS depressants,
including sedative-hypnotics, opioid agonists, and many drugs that block muscarinic and H1 histamine receptors.
• It facilitates the action of GABA at GABAA receptors
• Inhibits the ability of glutamate to activate NMDA (N-methyl-D-aspartate) receptors
• Modifies the activities of adenylyl cyclase, phospholipase C, and ion channels.

Identify the toxic effects of chronic ethanol ingestion.

Chronic Effects
1. Tolerance and dependence
• Tolerance occurs mainly as a result of CNS adaptation and to a lesser extent by an increased rate of ethanol
metabolism.
• There is cross-tolerance to sedative-hypnotic drugs that facilitate GABA activity (eg, benzodiazepines and
barbiturates).
• Both psychological and physical dependence are marked.
2. Liver
• Liver disease is the most common medical complication of chronic alcohol abuse.
• Progressive loss of liver function occurs with reversible fatty liver progressing to irreversible hepatitis, cirrhosis,
and liver failure.
• Hepatic dysfunction is often more severe in women than in men and in both men and women infected with
hepatitis B or C virus.
3. Gastrointestinal system
 • Irritation, inflammation, bleeding, and scarring of the gut wall occur after chronic heavy use of ethanol and may
cause absorption defects and exacerbate nutritional deficiencies.
• Chronic alcohol abuse greatly increases the risk of pancreatitis.
4. CNS
• Peripheral neuropathy is the most common neurologic abnormality in chronic alcohol abuse.
• More rarely, thiamine deficiency, along with alcohol abuse, leads to Wernicke-Korsakoff syndrome, which is
characterized by ataxia, confusion, and paralysis of the extraocular muscles.
• Prompt treatment with parenteral thiamine is essential to prevent a permanent memory disorder known as
Korsakoff’s psychosis.
5. Endocrine system
• Gynecomastia, testicular atrophy, and salt retention can occur, partly because of altered steroid metabolism in
the cirrhotic liver.
6. Cardiovascular system
• Excessive chronic ethanol use is associated with an increased incidence of hypertension, anemia, and dilated
cardiomyopathy.
• Acute drinking for several days (“binge” drinking) can cause arrhythmias.
• However, the ingestion of modest quantities of ethanol (10–15 g/day) raises serum levels of high-density
lipoprotein (HDL) cholesterol and may protect against coronary heart disease.

Describe the treatment of ethanol overdosage.

Treatment of acute and Chronic Alcoholism
1. Excessive CNS depression
• Acute ethanol intoxication is managed by maintenance of vital signs and prevention of aspiration after vomiting.
Intravenous dextrose is standard.
• Thiamine administration is used to protect against Wernicke- Korsakoff syndrome, and correction of electrolyte
imbalance may be required.
2. Alcohol withdrawal syndrome
• In individuals physically dependent on ethanol, discontinuance can lead to a withdrawal syndrome characterized
by insomnia, tremor, anxiety, and, in severe cases, life-threatening seizures and delirium tremens (DTs).
• Peripheral effects include nausea, vomiting, diarrhea, and arrhythmias.
• The withdrawal syndrome is managed by correction of electrolyte imbalance, and administration of thiamine
and a sedative-hypnotic.
• A long-acting benzodiazepine (eg, diazepam, chlordiazepoxide) is preferred unless the patient has compromised
liver function, in which case a short-acting benzodiazepine with less complex metabolism (eg, lorazepam) is
preferred.
3. Treatment of alcoholism
• Alcoholism is a complex sociomedical problem, characterized by a high relapse rate.
• Several CNS neurotransmitter systems appear to be targets for drugs that reduce the craving for alcohol.
• The opioid receptor antagonist naltrexone has proved to be useful in some patients, presumably through its
ability to decrease the effects of endogenous opioid peptides in the brain.
• Acamprosate, an NMDA glutamate receptor antagonist, the aldehyde dehydrogenase inhibitor disulfiram is used
adjunctively in some treatment programs.
• If ethanol is consumed by a patient who has taken disulfiram, acetaldehyde accumulation leads to nausea,
headache, flushing, and hypotension.
•

Describe fetal alcohol syndrome.

Fetal alcohol syndrome
• Ethanol use in pregnancy is associated with teratogenic effects that include mental retardation (most common),
growth deficiencies, microcephaly, and a characteristic underdevelopment of the midface region.

Antiseizure List the drugs of choice for partial seizures, generalized tonic-clonic seizures, absence and
Drugs myoclonic seizures, and status epilepticus.
 Anti Seizure drugs and Drugs of abuse
Drugs of choice for partial seizures: First choice,
Carbamazepine(oxcarbamazepine) or lamotrigine or
phenytoin

Drugs of choice for generalized tonic-clonic seizures

Valproic acid, carbamazepine, phenytoin

Drugs of choice for absence and myoclonic seizures

Valproic acid, lamotrigine is for adjunctive use

Absence seizures
Ethosuximide or valproic acid

Drugs of choice for status epilepticus

IV diazepam, or Lorazepam, IV phenytoin (for prolonged
therapy), Phenobarbital (for children)
Very severe status epilepticus use general anesthesia
Describe the main pharmacokinetic features, and list the adverse effects of carbamazepine,
phenytoin, and valproic acid.

Drugs of Identify the major drugs that are commonly abused.

Abuse
Cocaine
Phencyclidine
 Marijuana
Amphetamines
Caffeine
Heroin
Describe the signs and symptoms of overdose with, and withdrawal from, CNS stimulants,
opioid analgesics, and sedative-hypnotics, including ethanol.

Describe the general principles of the management of overdose of commonly abused

drugs.
 Stabilization
 Evaluation
 Decontamination
 Poison elimination
 Antidote administration
 Nursing and psychiatric care
Identify the most likely causes of death from commonly abused drugs.

DERMATOLO 5
GICAL
PHARMACOL
OGY
Explain the use of glucocorticoids in dermatologic diseases and their toxicity.
Enumerate important retinoids used in dermatological diseases.
Describe their (retinoid) mechanism of actions, clinical use, and toxicities.
Describe the types of UV radiation and their effects.
Explain the clinical use of azoles.
Explain how tinea capitis and tinea pedis are treated.

TOPICS POINTERS
ENDOCRINE
DRUGS
Thyroid & Explain how thyroid hormones are synthesized and released and indicate in which part of the pathway
Antithyroid antithyroid drugs act.
Drugs
List the principal drugs for the treatment of hypothyroidism.
List the principal drugs for the treatment of hyperthyroidism and compare the
onset and duration of their action.
Describe the major toxicities of thyroxine and the antithyroid drugs.
Corticosteroids Describe the effects of glucocorticoids in the body and relate with the side effects
of glucocorticoid therapy.
Glucocorticoids

Corticosteroids enter the cell and bind to cytosolic receptors that transport the steroid into the
nucleus The steroid-receptor complex alters gene expression

A. Metabolic effects
Glucocorticoids stimulate gluconeogenesis.
A. blood glucose rises
b. muscle protein is catabolized
c. insulin secretion is stimulated d. Both lipolysis and lipogenesis are stimulated, with a net
increase of fat deposition in certain areas (eg, the face and the shoulders and back).

B. Catabolic effects
a. Glucocorticoids cause muscle protein catabolism
. b. Lymphoid and connective tissue, fat, and skin undergo wasting under the influence of high
concentrations of these steroids.

C. Catabolic effects on bone can lead to osteoporosis. ➢In children, growth is inhibited

C. Immunosupressive effects
a. Glucocorticoids inhibit cell-mediated immunologic functions, especially those dependent on
lymphocytes.
b. These agents are actively lymphotoxic and, as such, are important in the treatment of
hematologic cancers
c.The drugs do not interfere with the development of normal acquired immunity but delay
rejection reactions in patients with organ transplants.

D. Anti-inflammatory effects
a. These drugs ↑ neutrophils and ↓ lymphocytes, eosinophils, basophils, and monocytes
. b. The migration of leukocytes is also inhibited.
C. Induced synthesis of an inhibitor of phospholipase A2
d. Decreased mRNA for cyclooxygenase 2 (COX-2)
e. Decreases in interleukin-2 (IL-2) and IL-3 f. Decreases in platelet activating factor (PAF), an
inflammatory cytokine.
 E. Other effects
a. Glucocorticoids such as cortisol are required for normal renal excretion of water loads.
b. The glucocorticoids also have effects on the CNS.
c. When given in large doses, these drugs may cause profound behavioral changes.
D. Large doses also stimulate gastric acid secretion and decrease resistance to ulcer formation.

Cortisol

a. The cortisol molecule also has a small but significant salt-retaining (mineralocorticoid) effect.
b. This is an important cause of hypertension in patients with a cortisol-secreting adrenal tumor
or a pituitary ACTH-secreting tumor (Cushing’s syndrome).

Synthetic Glucocorticoids

a. Prednisone and its active metabolite, prednisolone, dexamethasone, and triamcinolone are
representative.
B. Special glucocorticoids have been developed for use in asthma and other conditions in which
good surface activity on mucous membranes or skin is needed and systemic effects are to be
avoided.
C. Beclomethasone and budesonide readily penetrate the airway mucosa but have very short half-
lives after they enter the blood, so that systemic effects and toxicity are greatly reduced.

F. Toxicity
a. Most of the toxic effects of the glucocorticoids are predictable from the effects already
described.
b. Some are life threatening and include metabolic effects (growth inhibition, diabetes, muscle
wasting, osteoporosis), salt retention, and psychosis.

G. Clinical Uses Adrenal disorders

a. Chronic adrenal cortical insufficiency (Addison’s disease)
b. Acute adrenal insufficiency associated with life-threatening shock, infection, or trauma.
c. Certain types of congenital adrenal hyperplasia, in which synthesis of abnormal forms of
corticosteroids are stimulated by ACTH.

Non-adrenal disorders
a. Asthma, organ transplant rejection, rheumatic disorders
b. Hematopoietic cancers, neurologic disorders, chemotherapy-induced vomiting
c. Betamethasone, a glucocorticoid with a low degree of protein binding, is given to pregnant
women in premature labor to hasten
Pancreatic Describe the effects of insulin on hepatocytes, muscle, and adipose tissue.
Hormones & INSULIN EFFECTS
Antidiabetic
Agents, and A. Liver
Glucagon
a. Insulin increases the storage of glucose as glycogen in the liver.
b. Insulin also decreases protein catabolism.

B. Skeletal muscle

a. Insulin stimulates glycogen synthesis and protein synthesis.

b. Glucose transport into muscle cells is facilitated by insertion of GLUT4 transporters into cell
plasma membranes.
C. Adipose tissues

a. Insulin facilitates triglyceride storage by: •Activating plasma lipoprotein lipase

b. Increasing glucose transport into cells via GLUT4 transporters
c. Reducing intracellular lipolysis
List the types of insulin preparations and their durations of action.
Insulin Preparations:

Rapid-Acting

Three insulin analogs have rapid onsets and early peaks of activity:
Insulin lispro
Insulin aspart I
nsulin glulisine

The 3 rapid-acting insulins have small alterations in their primary amino acid sequences that
speed their entry into the circulation without affecting their interaction with the insulin receptor.

A.Insulin Preparations:
Rapid-Acting Onset: 5 to 15 min
Peak: 1 to 2 h
Duration: 4 to 6 h
Injected immediately before a meal
a. Are the preferred insulin for continuous subcutaneous infusion devices.
B. They also can be used for emergency treatment of uncomplicated diabetic ketoacidosis.

B. Insulin Preparations: Short-Acting/Regular Insulin

Onset: 30 to 60 min
Peak: 2 to 4 h
Duration: 6 to 8 h
a. Used intravenously in emergencies or administered subcutaneously in ordinary maintenance
regimens, alone or mixed with intermediate- or long-acting preparations
b. Before the development of rapid-acting insulins, it was the primary form of insulin used for
controlling postprandial glucose concentrations, but it requires administration 1 h or more
before a meal

C. Inulin Preparations: Intermediate-Acting

Onset: 1 to 2 h
Peak: 4 to 6 h Duration: > 12

a. Neutral Protamine Hagedorn insulin (NPH insulin) is a combination of regular insulin and
protamine (a highly basic protein also used to reverse the action of unfractionated heparin that
exhibits a delayed onset and peak of action).

b. NPH insulin is often combined with regular and rapid-acting insulins.

D. Insulin Preparations: Long-Acting

Onset: 1.5 to 2 h
Peak: Flat, max effect in 5 h
Duration: 12 to 24 h (G), 24 h (D)
a. Insulin glargine and Insulin detemir
b. Modified forms of human insulin that provide a peak-less basal insulin level which helps
control basal glucose levels without producing hypoglycemia.
Describe the major hazards of insulin therapy.
Hazards of Insulin Use

a. The most common complication is hypoglycemia, resulting from excessive insulin effect.
b. To prevent the brain damage that may result from hypoglycemia, prompt administration of
glucose (sugar or candy by mouth, glucose by vein) or of glucagon (by intramuscular injection)
is essential
c. Patients with advanced renal disease, the elderly, and children younger than 7 years are most
susceptible to the detrimental effects of hypoglycemia
d.The most common form of insulin-induced immunologic complication is the formation of
antibodies to insulin or noninsulin protein contaminants, which results in resistance to the action
of the drug or allergic reactions.
E. With the current use of highly purified human insulins, immunologic complications are
uncommon.

List the prototypes and describe the mechanisms of action, key pharmacokinetic
features, and toxicities of the major classes of agents used to treat type 2 diabetes

.TYPE 2 DIABETES THERAPY

a. Because type 2 diabetes is usually a progressive disease, therapy for an individual patient
generally escalates over time

b. It begins with weight reduction and dietary control

c. Initial drug therapy usually is oral monotherapy with metformin.

d. Although initial responses to monotherapy usually are good, secondary failure within 5 years
is common

e. Increasingly, noninsulin antidiabetic agents are being used in combination with each other or
with insulin to achieve better glycemic control and minimize toxicity

f. Because type 2 diabetes involves both insulin resistance and inadequate insulin production, it
makes sense to combine an agent that augments insulin’s action (metformin, a thiazolidinedione,
or an α-glucosidase inhibitor) with one that augments the insulin supplies (insulin secretagogue
or insulin

g. Long-acting drugs (sulfonylureas, metformin, thiazolidinediones, exenatide, sitagliptin, some

insulin formulations) help control both fasting and postprandial blood glucose levels, whereas
short-acting drugs (α-glucosidase inhibitors, repaglinide, pramlintide, rapid-acting insulins)
primarily target postprandial levels.

h. As is the case for type 1 diabetes, clinical trials have shown that tight control of blood glucose
in patients with type 2 diabetes reduces the risk of vascular complications
Describe the clinical uses of glucagon

Glucagon

a. Glucagon is a protein hormone secreted by the A cells of the endocrine pancreas

b. Acting through G protein-coupled receptors in heart, smooth muscle, and liver, glucagon
increases heart rate and force of contraction, increases hepatic glycogenolysis and
gluconeogenesis, and relaxes smooth muscle. The smooth muscle effect is particularly marked
in the gut.
 c. Glucagon is used to treat severe hypoglycemia in diabetics, but its hyperglycemic action
requires intact hepatic glycogen stores.

d. The drug is given intramuscularly or intravenously

e. In the management of severe β-blocker overdose, glucagon may be the most effective method
for stimulating the depressed heart because it increases cardiac cAMP without requiring access
to β receptors.

GI DRUGS
Identify 5 different groups of drugs used in peptic ulcer disease.

Drugs used in PUD

A. Antacids
Commonly used antacids are salts of aluminum and magnesium a. Aluminum hydroxide
(Al[OH]3)
b. Magnesium hydroxide [Mg(OH)2]
c. Calcium carbonate [CaCO3] reacts with HCl to form CO2 and CaCl2 -Has systemic effect
;less popular

Systemic absorption of sodium bicarbonate [NaHCO3] can produce transient metabolic

alkalosis; therefore, this antacid is not recommended for long-term use

B. H2-receptor antagonists

The four drugs used commonly are: cimetidine, ranitidine, famotidine, and nizatidine —potently
inhibit (greater than 90 percent) basal, food-stimulated, and nocturnal secretion of gastric acid
after a single dose.

a. Cimetidine -the prototype histamine H2-receptor antagonist -its utility however is limited by
its adverse effect profile and drug interactions C. Proton pump inhibitors

a. Omeprazole and other proton pump inhibitors (esomeprazole, lansoprazole, pantoprazole, and
rabeprazole)
are lipophilic weak bases that diffuse into the parietal cell canaliculi, where they become
protonated and concentrated more than 1000-fold.

B. MOA: There they undergo conversion to compounds that IRREVERSIBLY INACTIVATE

the parietal cell H+/K+ ATPase, the transporter that is primarily responsible for producing
stomach acid.

c. It takes about 18 hours for the enzyme to be resynthesized.

d. At standard doses, all PPIs inhibit both basal and stimulated gastric acid secretion by more
than 90 percent.

D. Sucralfate

aluminum sucrose sulfate, sucralfate is a small, poorly soluble molecule that polymerizes in the
acid environment of the stomach

E. Misoprostol
An analog of PGE1, misoprostol increases mucosal protection and inhibits acid secretion
 F. Colloidal Bismuth

G. Antibiotics
The agents used with the greatest frequency include amoxicillin, metronidazole, tetracycline,
clarithromycin, and bismuth compounds.

Describe the mechanism of action of omeprazole and related drugs.

Describe the mechanism of action, clinical uses, and adverse effects of metoclopramide.

Metoclopramide
a. The D2 receptor-blocking action of these drugs in the area postrema is also of value in
preventing emesis after surgical anesthesia and emesis induced by cancer chemotherapeutic
drugs.

B. When used chronically, METOCLOPRAMIDE can cause symptoms of parkinsonism, other

extrapyramidal effects, and hyperprolactinemia.
C. Because it does not cross the blood-brain barrier,
DOMPERIDONE is less likely to cause CNS toxicity

Identify 2 drugs commonly used as antidiarrheal agents and 4 drugs with different
mechanisms that are used as laxatives.

Antidiarrheal agents
a. Antimotility agents -Two drugs that are widely used to control diarrhea are diphenoxylate and
loperamide
-Both are analogs of meperidine and have opioid-like actions on the gut, activating presynaptic
opioid receptors in the enteric nervous system to inhibit acetylcholine release and decrease
peristalsis

b. Adsorbents -Bismuth subsalicylate, methylcellulose, and aluminum hydroxide c. Agents that

modify fluid and electrolyte transport -Bismuth subsalicylate

LAXATIVES

A. Irritants and stimulants -Senna, Bisacodyl, Castor Oil

B. Bulk laxatives -hydrophilic colloids -methylcellulose, psyllium seeds, bran

C. Saline and Osmotic laxatives -Saline cathartics (magnesium citrate, magnesium sulfate,
sodium phosphate, and magnesium hydroxide) -Lactulose

D. Stool softeners/emollient laxatives -docusate sodium, docusate calcium, and docusate

potassium.

E. Lubricant laxatives -mineral oil and glycerin suppositories

REPRODUCTI
VE DRUGS
Describe the pharmacologic effects, clinical uses, and toxicity of estrogens and
progestins.
 Effects
 ESTROGEN
-for normal female reproductive enlargement
-for the growth of the genital structures during childhood and for the
appearance of secondary sexual characteristics and growth spurt
associated with puberty
-metabolic effects: modifies serum protein levels and reduces bone
resorption
-enhances coagulability of blood and increases plasma triglyceride levels
while reducing LDL cholesterol and increasing HDL cholesterol
-its continuous administration, in combination with progestin, it inhibits
the secretion of gonadotropin from the anterior pituitary
PROGESTINS
-Progesterone induces secondary changes in the endometrium (also other
progestins) and is required for the maintenance of pregnancy
-affect carbohydrate metabolism and stimulate deposition of fat
-high doses suppress gonadotropin secretion and often cause anovulation
in pregnancy
 Clinical Uses
ESTROGEN
-treatment of HYPOGONADISM in young females
-HORMONE REPLACEMENT THERAPY (ameliorates hot flushes and
atrophic changes in the urogenital tract)--- in women with estrogen
deficiency resulting from premature ovarian failure, menopause, or
surgical removal of the ovaries
-prevents bone loss and osteoporosis
-components of HORMONAL CONTRACEPTIVES
PROGESTINS
-used as CONTRACEPTIVES (alone or in combination with an estrogen)
-HORMONE REPLACEMENT THERAPY (in combination w/ estrogen)
---prevent estrogen- induced Endometrial CA
-promote and maintain pregnancy
 Toxicity
ESTROGENS
-In hypogonadal girls, dosage must be adjusted carefully to prevent
premature closure of the epiphyses of the long bones and short stature
-When used as HRT, increases risk of endometrial CA (prevented by
combining estrogen w/ a progestin)
-when used by postmenopausal women, it is associated with a small
increase in the risk of breast CA and cardiovascular events (myocardial
infarction, stroke)
-dose-dependent toxicities: nausea, breast tenderness, increased risk of
migraine headache, thromboembolic events (e.g. deep vein thrombosis) ,
gallbladder disease, hypertriglyceridemia and hypertension
PROGESTINS
-low toxicity
-may increase blood pressure and decrease HDL
-long term use of high doses by postmenopausal women- reversible
decrease in bone density (secondary effect of ovarian suppression and
 decreased ovarian production of estrogen) and delayed resumption of
ovulation after termination of therapy

List the benefits and hazards of hormonal contraceptives.

 BENEFITS
-combination contraceptives used in young women with PRIMARY
HYPOGONADISM to prevent estrogen deficiency
-combination contraceptives and progestin alone- treatment of acne,
hirsutism, dysmenorrhea and endometriosis
-combination contraceptives- users seen to have reduced risks of ovarian
cysts, ovarian and endometrial CA, benign breast disease and PID as well
as a lower incidence of ectopic pregnancy, iron deficiency anemia, and
rheumatoid arthritis
 HAZARDS
-THROMBOEMBOLISM
- major complication; relates to action of estrogen component in blood
coagulation
-MI, stroke, DVT, pulmonary hypertension
-increased risk in older women, smokers, women with personal or
family history of
such problems, and women with genetic defects that affect production
or function of
clotting factors
-risk incurred is usually less than that imposed by pregnancy
-BREAST CANCER
-Low-dose combined and progestin only preparations cause significant
breakthrough
Bleeding especially during first few months of therapy
-Nausea, Breast tenderness, Headache, Skin pigmentation, Depression
-Weight loss, acne, hirsutism- Preparations with older, more androgenic
progestins
-Significant nausea when high dose of estrogen

List the benefits and hazards of postmenopausal estrogen therapy.

 BENEFITS
-HRT ameliorates hot flushes and atrophic changes in the urogenital tract
 HAZARDS
-increase risk of endometrial CA
-associated with small increase in risk of breast CA and cardiovascular
event (MI, stroke)

Describe the use of gonadal hormones and their antagonists in the treatment of cancer in women and men.

 Gonadal Hormones: steroids of ovary (estrogen and progestins), and testis

(testosterone)
 ESTROGENS (Ethinyl estradiol)
 -Combination Contraceptives (Estrogen and Progestins)- reduced risk of
ovarian and endometrial CA
 ANTIESTROGEN
-TAMOXIFEN (SERM)-treatment of Hormone- responsive breast CA
-prophylactic use reduces incidence of breast CA in
high risk women
-RALOXIFENE (SERM)- antagonist effects in breast tissue and reduces
incidence of breast
CA
-FULVESTRANT(Pure Estrogen Receptor Antagonist)- treatment of
women with breast CA that has developed resistance to tamoxifen
 ANTIANDROGENS
-FLUTAMIDE(Receptor Inhibitor)- decrease action of endogenous
androgens in patients with prostate CA
-Leuprolide (GnRH Agonist)- used in prostatic CA
-Abarelix and Degarelix (GnRH antagonists)- approved for advanced
prostate CA
-Ketoconazole (Inhibitor of Steroid Synthesis)- suppress adrenal steroid
synthesis in patients with steroid-responsive metastatic prostate CA

List or describe the toxic effects of anabolic steroids used to build muscle mass.
- Feminization
- Cholestatic Jaundice
- Elevation of Liver Enzyme Levels
- Hepatocellular CA

RESPIRATOR
Y DRUGS
Describe the strategies of drug treatment of asthma and COPD.
-Acute Bronchospasm: bronchodilators (Beta2 agonists, muscarinic antagonists,
theophylline
-Long-term preventive treatment: control of inflammatory process in the airways/
“Controller Drugs” (manly Corticosteroids, Long-acting B-agonists to improve
response to corticosteroids, Anti-IgE antibodies)
List the major classes of drugs used in asthma and COPD.

Describe the mechanisms of action of these drug groups.

List the major adverse effects of the prototype drugs used in airways disease.