Clinical Pharmacy

(TDM, ADR, Clinical Trial, Clinical Toxicology & Methods of

Isotropic Tagging)
 Therapeutic Drug Monitoring (TDM)
Therapeutic Drug Monitoring refers to the individualization of dosage by using the serum drug
concentrations, pharmacokinetic data and pharmacodynamic data and maintaining the plasma or
blood drug concentration within therapeutic range. It is the application of pharmacokinetic
principles for the rational design of individualized dosage regimen. Its main objective is to
maintain the optimum drug concentration at the receptor site to produce the desired therapeutic
response for a specific period and for the minimization of adverse effect of the drug.

Various criteria to be considered for TDM to have clinical significance:

a. Drug whose therapeutic range (differences between minimum effective concentration and
minimum toxic concentration) is narrow. Ex: Digoxin and Phenytoin
b. Drug which has direct relationship within the plasma drug concentration and therapeutic
response or toxicity. Ex: Theophylline

c. Drug whose therapeutic effect cannot be readily assessed by the clinical observation. Ex:
Phenytoin toxicity can cause an increase rather than decrease in frequency of seizures
d. Drug which has large individual variability at steady state plasma concentration in any given
dose. Ex: Phenobarbitones

e. Drug with steep dose response curve. Ex: Small increase in theophylline dose cause marked
increase in desired and undesired response
f. Drug producing tolerance at receptor site. Ex: Morphine and Codeine

g. Drug whose efficacy is difficult to establish clinically. Ex: Phenytoin

h. Drugs producing active metabolites. Ex: Procainamide gives N-acetyl procainamide which
also has anti-arrhythmic character

Objectives of TDM:
a. TDM helps to maintain optimum drug concentration at the receptor site to produce desired
therapeutic response.
b. TDM helps for prediction of patient response.
b. TDM helps for the maintenance of optimum drug concentration and for the individualization
of drug dose which leads for better patient compliance.
c. TDM helps for the maximizes the efficacy and avoids the toxicity of drugs.

TDM for Digoxin: Digoxin is a cardiac glycoside used in the treatment of Congestive Heart
Failure and Arrhythmia. Digoxin therapy requires monitoring because of its narrow therapeutic
index i.e. 1-2.5 mmol/l. Toxicity of Digoxin increases when its concentration is above 2.6mmol/l.
The most common adverse effects associated with digoxin are Ventricular tachycardia, 2nd or 3rd
degree heart block, SA node arrest, Fatigue, Confusion and Abnormal color vision. TDM result of
digoxin can only be interpreted correctly when serum digoxin concentration is measured for at
least 8 hours. It should be taken attention for the dose regimen of digoxin in renal failure patient,
hypokalemic patient and patient under diuretic therapy.

1 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

TDM for Theophylline: Theophylline is used as a bronchodilator for treatment of moderate to
severe asthma and chronic obstructive pulmonary disease (COPD). TDM is needed for
theophylline because the kinetics of the drug are highly variable. It has a narrow therapeutic
window i.e. 5-20 μ g/ml. It shows steady state plasma concentration after 36 hours of
administration. The drug can be metabolized to caffeine in neonates and in adults where there is
impairment of hepatic drug metabolism. Its overdose can result in elevated heart rate, arrhythmia,
muscle cramps, muscle pain, abdominal pain, blurred vision, confusion, diarrhea, decrease in
urination and numbness or tingling in hands and feet. Clearance of the drug is increased in children,
smokers, persons with cystic fibrosis and persons with hyperthyroidism while elimination of the
drug is slowed in congestive heart failure and in the elderly.

TDM for Vancomycin: Vancomycin is a glycopeptide antibiotic and is used for the first-line
treatment for infections caused by MRSA (Methicillin-resistant Staphylococcus aureus).
Vanocomycin has poor oral absorption and mainly given by IV route. Its therapeutic range is about
10-20 μg/ml. Trough serum vancomycin concentrations should be monitored to ensure efficacy
and renal safety. Trough serum vancomycin concentrations should be maintained at 10–20 mg/L
in adult patients with serious MRSA infections. Initial vancomycin TDM should be started after
48 hour of vancomycin therapy for patients with normal renal function and after 72 hours for the
patients with impaired renal function. Monitoring of vancomycin trough concentration may
decrease the risk of nephrotoxicity and ototoxicity.

TDM for Carbamazepine: Carbamazepine is an antiepileptic drug and chemically related to

Tricyclic Anti- depressant drug. Carbamazepine is the drug of choice or first line drug for partial
seizures and most grand mal seizure. The therapeutic range of Carbamazepine in plasma is about
4 to 12 mg/L. Its half-life is about 20-30 hours. Carbamazepine is primarily metabolized by
Cytochrome P4503A4 in the liver. Its plasma drug concentration is elevated by various drugs such
as Cimetidine, Clarithromycin, Erythromycin, Diltiazem, Fluoxetine, Isoniazid and Verapamil.
Timing of TDM is very important in case of Carbamazepine because there is significant decrease
in plasma drug levels during the first few weeks due to auto-induction. High-performance liquid
chromatography (HPLC), Gas chromatography and Mass spectrometry are few methods to detect
Carbamazepine in plasma. TDM helps to minimize the risk of overdosing due to drug/food
interaction or genetic polymorphism of enzymes and transporters involved in the metabolism of
Carbamazepine.

TDM for Isoniazid: Isoniazid is an anti-tuberculosis agent which inhibits the mycolic acid
synthesis in tuberculi bacilli. The Therapeutic Drug Monitoring of isoniazid is needs to be
performed to monitor the hepatotoxicity symptoms. Isoniazid is generally absorbed quickly from
the GI tract within 1 to 2 hours when given at empty stomach. The unusual maximum concentration
is about 3-6 μg /ml. Hepatic damage and peripheral neuritis is the major adverse effects of
isoniazid. Generally pyridoxine is given to overcome peripheral neuritis. Hence hepatic and renal
parameters should be monitor regularly after administration of Isoniazid. The first sample of
Isoniazid is generally collected at 2 hours and the second sample is collected at 6 hours for provide
information about clearance and half-life.

2 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

TDM for Verapamil: It is Verapamil falls under Class IV of Anti-arrhythmic drug. It is a calcium
channel blocker. It is used for Angina, Hypertension, Migraine and Supraventricular
tachyarrhythmias. Verapamil is metabolized by N-demethylation to Nor-Verapamil. Drug
undergoes first pass metabolism and cleared by kidney. There is no immunoassay for the TDM of
Verapamil but its active metabolite i.e. Nor-Verapamil can be measured by using either gas
chromatography or HPLC. Its maximum oral adult dosage is about 80 to 120 mg in every 8 hours.
Similarly its oral adult dose for the patient with hepatic disease and on geriatric patient is about 40
mg in every 8 hours.

TDM for Valproic acid: Valproic acid is the anticonvulsant drug which increase levels of GABA
in brain. Therapeutic drug monitoring (TDM) is used to optimize seizure control and minimize
toxicity. Peak concentrations are achieved within 0.5–2 hours after oral administration. The
therapeutic range for valproic acid in total is 50-100 µg/mL while its therapeutic range in free state
is 6-22 µg/mL. It is required to take precaution during Hypersensitivity, Liver disease, Urea cycle
disorder, Pancreatitis and Thrombocytopenia.

TDM for Cyclosporine: Cyclosporine is an immunosuppressive drug used in organs and tissues
transplantations to prevent rejection and in different autoimmune or inflammatory diseases. Its
therapeutic range is about 100-300 mcg/L and its half-life is about 19 hours. Its plasma concentration
may be decreased by Rifampicin, Carbamazepine, Phenytoin and Phenobarbitones. The purpose of
monitoring is to prevent graft rejection and to improve nephrotoxicity.

Steps involved in the interpretation of TDM data:

a. Availability of drug concentration measurements: Drug concentration measurements are
required to assist the manipulation of a patient's current medication regimen. Drug concentration
level of patient is required only when toxicity is suspected or potential drug interaction due to
change in medication is occur.

b. Collection of biological samples: Biological samples are collected in such a way that they
provide a clinically meaningful measurement. Blood samples should be collected when the drug
concentrations have attained steady-state at the current dosage regimen. Blood or plasma
concentrations change throughout a dosage interval and the time of the blood sample relative to
the time of administration of the dose must be known to enable sensible interpretation. Absorption
is variable after oral administration and blood samples should be collected in the elimination rather
than in the absorption or distribution phases. Usually blood samples are collected at the end of the
dosage interval (trough). Peak concentrations are also measured for antibiotics which are given
intravenously.

c. Availability of information required for interpretation of drug concentration: Various

information’s required for interpretation of drug concentration can be illustrate as:
 Time of blood sample taken
Dosage regimen (Dose, Duration and Dosage form)
 Patient demographics (Age, Sex and Ethnicity)
 Co-medications
 Indication for monitoring
 Pharmacokinetics and therapeutic range of drugs
3 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]
d. Laboratory measurement: Ideally a quality of drug should be assayed within a clinically useful
time frame. Rapid and cost-effective measurement of most drugs for which TDM is indicated can
be achieved by using commercial kits which are used on automatic analyzers by using a number
of different methodologies including fluorescence polarization immunoassay. Similarly it is
necessary to use quality control material from an independent source whenever possible.

e. Communication of results by the laboratory: The laboratory should ensure that the drug
concentration is available for clinical interpretation as quickly as possible after it has been verified
by senior staff. Assays for the same patient performed in different laboratories by using different
antibodies can varied from the metabolites of the drug to the concentration of drug which can be
analyzed clinically.

f. Clinical interpretation: Clinical interpretation can add value and transform a therapeutic drug
measuring service into a TDM service. The concentration measured must always be interpreted in
light of the clinical response, clinical status of the individual patient, dosage regimen, indication
for therapeutic drug monitoring and pharmacokinetic characteristics of the drug. The ideal TDM
team should consist of clinical pharmacologists and clinical pharmacists for clinical interpretation
of TDM data.

g. Therapeutic management: The therapeutic management for a patient can be carried out by the
appropriate modification of a drug dosage regimen.

Timing of specimen collection: The specimen should be collected after the absorption and
distribution phases are complete and steady state has been achieved. Trough level are collected
just prior to the next dose.

Individualization of therapy: Rational drug therapy requires individualization of dosage regimen

to fit a particular patient’s needs. The main objective of individualization is to optimize the dosage
regimen. An inadequate therapeutic response calls for a higher dosage whereas drug related
toxicity calls for a reduction in dosage

Advantages of Individualization:
a. Individualization of dosage regimen help in development of dosage regimen which is specific
for the patient.
b. For decrease in toxicity and side effects and increase in efficacy of pharmacological drug.
c. For decrease in allergic reactions of the patient for the drug.
d. For increase patient compliance.

Steps involved in the individualization of dosage regimen:

a. Estimation of pharmacokinetic parameters in individual patients to evaluate the degree of
variability.
b. Attributing the variability for measurable characteristics such as hepatic or renal diseases, age
and weight.
c. Designing the new dosage regimen from the collected data for adjustment of dosage and
dosing interval.
4 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]
Dosing of Drugs in Neonates, Infants and Children: Neonates, Infants and children require
different dosages than that of adults because of differences in the Body Surface Area, Total Body
Water and Extra Cellular Fluid. The volume of distribution for most water-soluble drugs is larger
in infants while volume of distribution for most lipid soluble drugs is smaller.
(Height ×Weight)1⁄2
Surface area in m2 = → (i)
60

Surface area in m2
Child’s dose = × Adult dose → (ii)
1.73

Since surface area of a child is proportion to the body weight so equation (ii) can be written as:
Weight of child in kg 0.7
Child’s dose = [ ] × Adult dose
70

Dosing of drugs in Elderly: Drug dose should be reduced in elderly patients because of general
decline in body function with age. The volume of distribution of water-soluble drugs may decrease
and that of lipid soluble drugs like diazepam increases with age. Age related changes in renal and
hepatic functions greatly alters the clearance of drugs.

(Weight in Kg)0.7 (140−Age in years)

Elderly dose = × Adult dose
1660

Dosing of drugs in Hepatic diseases: The influence of hepatic disorder on the drug bioavailability
and disposition is unpredictable because of the multiple effects that liver produces. The altered
response to drugs in liver disease could be due to decreased metabolizing capacity of the
hepatocytes, impaired biliary elimination and due to biliary obstruction Impaired hepatic blood
flow increases the bioavailability by a reduction in first pass metabolism. For example
bioavailability of Morphine and Labetalol have been reported to double in patients with Cirrhosis.
Examples of drugs whose drug concentration changes due to hepatic impairment are
Chlorpromazine, Haloperidol, Calcium channel blockers, Morphine, Glyceryl trinitrates,
Levodopa, Propranolol, Non-steroidal anti-inflammatory drugs, Diazepam, Carbamazepine,
Phenytoin and Warfarin.

Dosing of drugs in Renal Disease: The half-life of the drug is increase and its clearance
drastically decreases if it is predominantly eliminated by way of excretion in the patient with renal
failure.

Adjustment of drug dosage in case of renal disease are carried out by mainly two approaches:
a. Dose adjustment based on Total body clearance
i. Dose adjustment in renal insufficiency:
F . X0
Average drug concentration at steady state (Css,av) =
ClT . τ

Where F = Bioavailability X0 = Amount of dose

ClT = Total body clearance τ = Dosing interval

5 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

ii. Dose adjustment in renal failure:
X0 X′0
Average drug concentration at steady state (Css,av) = =
ClT . τ Cl′T . τ′
X′0 Cl′T . X0
Equation in term of dose and dose interval: =
τ′ ClT . τ

b. Dose adjustment based on Elimination rate constant or Half-life

i. Dose adjustment in renal insufficiency:
1.44 F t1/2 X0
Average drug concentration at steady state (Css,av) =
Vd τ

Where Half-life of drug (t1/2) = 0.693/ K E

Volume of distribution (Vd ) = Dose of drug/Concentration of drug at target site

ii. Dose adjustment in renal failure:

t1/2 X0 t′1/2 X′0
Average drug concentration at steady state (Css,av) = =
τ τ′
X′0 t′1/2 . X0
Equation in term of dose and dose interval: =
τ′ t1/2 . τ

[Old is Gold]
1. What is mean by Individualization of therapy? How can it be done in practical set-ups? [2+6]
[IOM 2074]
2. What do you mean by individualization of therapy? Explain how TDM can be helpful in it.
[4+4] [IOM 2069]
3. Define Therapeutic Drug Monitoring. Describe the importance of sampling time and patient
education in the interpretation and utilization of TDM. [2+6] [IOM 2073]
4. Explain the valid TDM criteria. How the TDM data should be interpreted? [10] [IOM 2068,
2072 Back Paper]
5. Sample taking is an important aspect of TDM. Justify [8] [IOM 2071]
6. Describe the criteria for TDM with suitable examples. [10] [IOM 2070]
7. What is the importance of TDM? Justify the TDM for Theophylline and Carbamazepine.
[4+4+4] [IOM 2068, 2066]
8. Write down the criteria for valid TDM. What are the essentials for effective TDM? [4+4]
[IOM 2065]
9. Define TDM. Give four examples of drugs for which TDM is essential with justification.
[2+8] [IOM 2064]
10. What is TDM? What are the important criteria to be considered for TDM to have clinical
significance? List the commonly monitored drugs in Nepal. [8] [IOM 2062, 2061]
11. Decide whether TDM is necessary for the following drugs. Justify with suitable reasons. [16]
[IOM 2072 Regular Paper]
a) Verapamil b) Vancomycin c) Digoxin d) Isoniazid

6 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

 Adverse Drug Reaction (ADR)

WHO defines ADR as any response to a drug which is noxious, unintended and occurs at doses
used in for prophylaxis, diagnosis or therapy of disease or for the modification of physiological
function.

Side effect are unintended effects of a pharmaceutical product occurring at doses used in man
which is related to the pharmacological properties of the product and in which there is no deliberate
overdose.

Classification of ADR according to Type of reaction:

a. Type A: It is dose-dependent type of ADR and do not usually cause serious illness. This type
of ADRs are generally predicted from the pharmacology of prescribed drug. Examples of Type A
ADRs are Myelosuppression by anticancer drug, Gastric ulcer by Aspirin and Tachycardia by
Digoxin.

b. Type B: It is dose-independent type of ADR and cause serious illness. This type of ADRs are
unpredictable from the pharmacology of prescribed drug. This type of ADRs are generally occurs
by hypersensitivity and idiosyncratic mechanism.

⇒ Allergic Type B ADRs: Type I, II, III and IV hypersensitive reaction

⇒ Non- Allergic Type B ADRs: Myelosuppression, Aplastic anemia, Agranulocytosis
⇒ Idiosyncratic toxicity: Lymphoid tumor, Vaginal adenocarcinoma and Uterine cancer by the
long-term use of Cyclophosphamide, Stilbistirol and Oestrogen respectively.

c. Type C (Chronic): Type C ADR is related to the cumulative dose. Example of Type C ADR
is Hypothalamic-pituitary-adrenal axis suppression by corticosteroids.

d. Type D (Delayed): Type D ADR occurs after sometimes the use of the drug. Examples of Type
D ADR are Teratogenesis and Carcinogenesis.

e. Type E (End of use): Type E ADR occurs soon after withdrawal of the drug. Examples of Type
E ADR are Opiate withdrawal syndrome & Myocardial ischaemia (Beta-blocker withdrawal
syndrome).

Classification of ADR according to Severity:

a. Mild ADRs: Mild ADRs are minor types of ADRs. These ADRs do not required an antidote,
therapy or prolongation of hospitalization for the treatment. Ex: Drowsiness by the intake of
Antihistamines and Constipation by the intake of Opioids

b. Moderate ADRs: A change in treatment is required and the hospitalization may be prolonged
or specific treatment may be required. Ex: Venous thrombosis by the intake of Hormonal
Contraceptives and the Hypertension and edema by the intake of NSAIDs

7 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

c. Severe ADRs: Severe ADRs are potentially life threatening and requires discontinuation of -
the drug and specific treatment of the ADR. Ex: Angioedema by the intake of ACE inhibitors
and Abnormal heart rhythm by the intake of Phenothiazines

d. Lethal ADRs: Lethal ADRs directly or indirectly causes the death of patient. Ex: Liver failure
due to the intake of Acetaminophen and Hemorrhage due to the intake of Anticoagulants in
higher dose

Classification of ADR according to onset of event:

a. Acute: Appearance of ADRs within 60 minutes. Ex: Thrombocytopenia by Digitoxin
b. Sub-acute: Appearance of ADRs within 1 to 24 hours. Ex: Sedation and drowsiness due to
the overdose of Phenobarbital
c. Latent: Appearance of ADRs after more than two days. Ex: Hair loss due to the overdose of
anticancer drugs

ADR Risk Factors:

a. Age e. Altered physiology
b. Multiple medications f. Dose and duration of medicine
c. Inappropriate prescribed medication g. Genetic predisposition
d. Organ dysfunction h. Multiple co-morbid condition

Predisposing Factors to ADRs:

a. Age: The incidence of adverse drug reaction appears to be highest in the children and very old
people because of the poorly developed and altered physiological function in children and very
old people respectively. Therefore the metabolism and elimination of certain drugs also become
delayed

b. Pathophysiological conditions: Underlying diseases may alter the pharmacokinetic parameters

such as drug absorption, metabolism, elimination and the body’s response to drugs.

c. Sex: Several studies have shown that women are more likely to suffer from ADRs than men due
to the pharmacokinetic and pharmacodynamic sex-related factors. Females have 1.5 to 1.7 -fold
greater risk of developing ADR. Women are more prone to blood dycrasias with Phenylbutazone
and chloramphenicol.

d. Genetic Polymorphism: Genetic disorders that affect the drug’s pharmacokinetic and
pharmacodynamics are responsible for the risk of ADR. Genetic variations in genes for drug-
metabolizing enzymes and drug receptors have been associated with individual variability in the
efficacy and toxicity of drugs. The final goal of pharmacogenetics is to individualize drug therapy
where the medicines are chosen by the genetic status of the patient.

e. Route of administration: IV administration may be associated with more serious side effects
to the site of injection such as Phlebitis and Extravasation. Digoxin has great risk of causing
Cardiac Arrhythmia. Oral administration may be associated with mild type of adverse events.

8 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

f. Duration of therapy: Prolonged duration of therapy on sixty year of old age person with NSAID
may leads to the GI toxicity.

g. Multiple drug therapy: The probability of adverse drug reactions and drug interactions has
been shown to increase sharply with the practice of polypharmacy. That means various number of
drugs taken are generally considered for incidence of ADR. It has been seen that effects of multiple
drugs used are not always additive. There may be synergistic or antagonistic effect.

h. External factors: The various external factors such as Alcohol consumption, Smoking and
Environmental pollution are responsible for ADR.

Criteria for distinguishing allergic reactions from other adverse reactions:

a. Allergic reactions occur in a minority of the patients receiving the drug.
b. Observed manifestations do not resemble with the pharmacologic actions of the drug.
c. The reactions may be manifested by a variety of skin rashes, anaphylaxis, pulmonary reactions,
hepatitis, fever, interstitial nephritis and connective tissue disorders.
d. Eosinophilia may be present.
e. Specific antibodies may be detectable occasionally.
f. The reaction resolves spontaneously if the medication is quickly discontinued.

Types of Allergic Reactions

Type Mechanism Examples
I Anaphylactic (IgE Mediated) Acute anaphylaxis, Urticaria
II Complement dependent Hemolytic anemias, Thrombocytopenias,
cytolysis (IgG/IgM) Interstitial nephritis
III Immune complex damage Serum sickness, Fever, Vasculitis
IV Cellular Hypersensitivity Contact dermatitis

Adverse Drug Reaction of Immune-suppressants: Immunosuppressants are drugs which inhibit

cellular or humoral or both types of immune responses and are commonly use in organ
transplantation and autoimmune diseases. Cyclosporine, Azathioprine, Methotrexate,
Cyclophosphamide, Chlorambucil, Prednisolone, Anti-thymocyte globulin and Rho (D)
immunoglobulin are major immune-suppressants drugs.

Drugs Adverse Drug Reaction

Cyclosporine Nephrotoxicity, Hepatotoxicity, Hypertrophy of gums, Hypertension,
Hyperglycaemia and Hyperlipidaemia
Prednisolone Cushing’s syndrome, Peptic ulcer, Glaucoma, Osteoporosis
Anti-cancer drugs Hemorrhagic cystitis (Cyclophosphamide), Dysuria, Haematuria,
Megaloblastic anemia (Methotrexate), Hepatic fibrosis, Bone marrow
suppression, Thrombocytopenia, Alopecia, Gout, oligozoospermia in males
and amenorrhoea in females

9 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

Monitoring of ADR: Pre-marketing studies and Post-marketing surveillance are responsible for
monitoring the ADR. The safety of new medicines is tested in animal models on pre-marketing
studies. Similarly the various methods adopted for Post-marketing surveillance are Case Reports,
Cohort studies, Case-control studies and Spontaneous reporting schemes.

⇒ Case Reports: Case Reports is applicable for detection of Type B ADR. It involves publication
of case reports or case series of ADR on medical literature.

⇒ Cohort studies: Cohort studies involves the study of large groups of patients by taking
particular drugs. Cohort studies comprises ADR in group of patients taking drug of intent with
comparative groups. In cohort studies a group of individuals that is exposed to a risk factor (study
group) is compared with the group of individuals not exposed to a risk factors (control group).

⇒ Case-control studies: Case-control studies involves the comparison of drug usage between a
group of patients with a particular disease and control group who are similar in confounding factors
but do not have the disease. Case-control studies is a useful retrospective method which can
provide valuable information on the incidence of type B reactions and the association between
drugs and disease. E.g. Reye’s syndrome and aspirin

⇒ Spontaneous reporting schemes: Spontaneous reporting schemes helps for the reporting of
ADR of new product. Many countries established a scheme for ADR reporting which is called as
Committee on Safety of Medicines (CSM). CSM introduced Yellow card scheme for reporting
rare and common reactions.

Information required in Yellow Card:

a. Patient detail
b. Identity of physician reporting
c. Other medicine history
d. Allergic condition

Reporting of ADRs in Nepal: Government of Nepal nominated Department of Drug

Administration (DDA) in October 2004 as the National Pharmacovigilance centre for liaison with
WHO collaborating centre for International Drug Monitoring, Sweden and started collecting
adverse drug reactions. Nepal became a WHO program member in July 2006. The DDA has
established various regional centers for reporting of ADRs to DDA.

Various regional centers for reporting of ADRs to DDA:

a. Tribhuvan University Teaching Hospital, Maharajgunj
b. Civil Service Hospital, Minbhawan
c. Manipal Teaching Hospital, Pokhara
d. Nepal Medical College Teaching Hospital, Jorpati
e. Norvic International Hospital, Thapathali
f. Nepal Cancer Hospital and Research Center, Harisiddhi
g. Patan Hospital, Lalitpur

10 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

h. Dhulikhel Hospital, Banepa
i. KIST Medical College, Imadol
j. Shree Birendra Hospital, Chhauni
k. B.P. Koirala Institute of Health Science, Dharan

The regional centers report ADRs to the National center (DDA) through Vigiflow (an online
program) which are then forwarded to the Uppsala Monitoring Center (UMC) by the National
Centre.

Roles of pharmacist for minimize ADR:

a. Identification and documentation of ADRs: Pharmacist in hospital can check and identify the
ADRs after receiving prescription by monitoring above parameters.
 Appropriateness of prescribed drug
 Reasons of patients for receiving particular medicines
 Indications of Drug interactions
 Indications of abnormal lab values
 Prevalence of polypharmacy

b. Monitoring and Reporting of ADRs: Pharmacists are often involved in Monitoring and
Reporting of ADRs in hospital and helps for physicians for filling the yellow cards towards the
ADRs. Pharmacists are also involved in the preparation of information on most common ADR
problems and also for the analysis of each reported ADRs. They also help for the development of
policies and procedures for ADR monitoring and also support for the monitoring the safety of drug
use in high risk patients.

c. Prevention of ADRs: Pharmacist can use various preventive methods for minimize the ADRs
which are illustrates below in systemic way.
 Identifying potential side effect of prescribed drug
 Avoiding unnecessary polypharmacy by reviewing the prescription
 Choosing of most effective and least toxic drugs
 Checking the history of drug allergies and drug interactions
 Educating the patients towards the drug regimen
 Encouraging the patient to complete the course of medication
 Preparation of formularies and scientific protocols to ensure appropriate selection of drugs
 Advising the best regimens towards the medication to improve patient compliance

Pharmacovigilance: Pharmacovigilance is a science relating to the detection, assessment,

understanding and prevention of risks involved with medicines. It has become an important
process in pharmaceutical industry and hospital. Various industrial companies and hospitals use
various pharmacovigilance parameters to ensure drug safety and to assess the quality of drugs.
Pharmacovigilance is regarded as the quality control system of medicines.

11 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

Pharmacovigilance help in minimizing health costs by ensuring the safety ad rationale use of
medicines when they released for general use in society. Pharmacovigilance helps for the
prevention of adverse reaction involved with medicines due to which the health economic loss will
be minimized. Pharmacovigilance is concerns with various drug related problems such as drug
interactions, drug resistance, drug abuse, counterfeiting of drug, quality problems of drug,
poisoning and medication error. The ultimate aim of pharmacovigilance is to minimize the health
costs by ensuring the safety ad rationale use of medicines once they released for general use in
society.

Factors necessary for establishing pharmacovigilance are as follows:

a. Use of alternative medicines is very common in Nepal
b. There are different races of population in Nepal having different genetic makeup.
c. Self-medication is one of the common cause of ADRs in Nepal.
d. There are no mandatory requirements for clinical trial data to be submitted to the drug regulatory
authority in Nepal. Thus the exact risk of occurrence of ADRs is unknown.
e. There are very less safety data on the drugs. Therefore it is important to monitor the safety of
the medicines in Nepalese population.

[Old is Gold]
1. Define adverse drug reactions. List the major ADRs of immune-suppressants. [2+6] [IOM 2074]
2. Define Pharmacovigilance. How does it help in minimizing health costs? [2+6] [IOM 2073]
3. Write in detail about ADRs, its classification, monitoring and reporting of ADRs. [10] [IOM
2072 Back Paper]
4. Classify ADRs with examples. Describe the role of pharmacist in reducing ADRs? [6+4]
[IOM 2070]
5. How can adverse drug events be reported in Nepalese context? How can evaluation be made
whether a drug was responsible for alleged reactions? [3+5] [IOM 2069]
6. Classify ADRs in terms of time of onset and severity with examples. [10] [IOM 2064, 2068]
7. Explain the preventable adverse drug reactions. What roles can hospital pharmacist play in
minimizing such reactions? [8] [IOM 2067]
8. Classify the ADRs with examples. What are the risks factors involved with the ADRs? [8+4]
[IOM 2066]
9. Define ADRs. Classify ADRs with two examples of each. [8] [IOM 2065]
10. What do you mean by ADRs? Describe briefly about the predisposing factors of ADRs. [8]
[IOM 2062]

12 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

 Clinical Toxicology

Toxicity is the degree to which a chemical substance or a particular mixture of substances can
damage an organism. Poison can define as the toxicant that causes immediate death or illness when
experienced in very small amount. Toxicant is a substance that produces any kind of adverse
biological effects while Toxin is the protein produced by living organism.

Classification of Toxicity:
i. Acute Toxicity: Acute Toxicity describes the adverse effects of a substance that result either
from a single exposure or from multiple exposures within 24 hours. Death can be a major concern
in cases of acute exposures. For example many people die each year from inhaling carbon dioxide
from faulty heaters.

ii. Sub chronic Toxicity: Sub chronic Toxicity results from the repeated exposure for several
weeks or months. It is more common on the individuals which are generally exposed to
pharmaceutical agents. Ingestion of Coumadin Tablets for several weeks as treatment of venous
thrombosis can cause internal bleeding. Similarly exposure to lead over a period of several weeks
can result in anemia.

iii. Chronic Toxicity: Chronic toxicity represents the cumulative damage of specific organ system
and takes many months or years to become a recognizable clinical disease. Within the repeated or
long-term exposures there will be cumulative damage of specific organ due to which organ can’t
function normally for long period and a variety of chronic toxic effects may result.

Examples of Chronic toxic effects:

 Cirrhosis in alcoholics who have ingested ethanol for several years.
 Chronic kidney disease in workmen with several years of exposure to lead.
 Chronic bronchitis in long-term cigarette smokers.
 Pulmonary fibrosis in coal miners.

Initial management approach of the poisoned patient:

i. Stabilization: Initially the airway should be cleared and endotracheal tube should be inserted if
needed. Similarly breathing should also observe and patients with respiratory insufficiency should
be mechanically ventilated. The circulation should be assessed by continuous monitoring of pulse
rate, blood pressure, urinary output and evaluation of peripheral perfusion. An intravenous line
should be placed and blood drawn for serum glucose should also be determined.
Adults are given 25 gm dextrose solution intravenously. Alcoholic or malnourished
patients should also receive 100 mg of thiamine in the intravenous infusion. The opioid antagonist
naloxone may be given in a dose of 0.4–2 mg intravenously because it reverses respiratory and
CNS depression due to various varieties of opioid drugs. The benzodiazepine antagonist
flumazenil is essential in patients with suspected benzodiazepine overdose.

ii. History and Physical Examination: History provides critical information in the assessment of
the patient with suspected overdose. Physical examination gives important clauses in both the
severity and the cause of poisoning. Vital sign and mental status abnormalities are important signs
of severity of toxicity. A brief examination should be performed towards Vital signs, Eyes, Mouth,
Skin, Abdomen and Nervous system.

13 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

 Vital signs: Vital signs include Blood pressure, Pulse, Respirations and Temperature.
Hypertension and tachycardia are typical with amphetamines, cocaine and anti-muscarinic
(anticholinergic) drugs. Similarly Hypotension and bradycardia are characteristic features of
overdose with calcium channel blockers, beta blockers, clonidine and sedative hypnotics.

 Eyes: The eyes are a valuable source of toxicologic information. Constriction of the pupils
(miosis) is typical effect of opioids, clonidine, phenothiazines and cholinesterase inhibitors
(Organophosphate insecticides). Similarly dilation of the pupils (mydriasis) is common with
amphetamines, cocaine, LSD and atropine. Generally Horizontal nystagmus is observed with the
poisoning with phenytoin, alcohol and barbiturates. However both vertical and horizontal
nystagmus is seen with phencyclidine poisoning.

 Mouth: The mouth may show signs of burns due to corrosive substances or soot from smoke
inhalation. Hypersalivation is generally seen with cholinesterase inhibitors (Organophosphates,
Carbamates and Physostigmne) and iodides. Similarly dry mouth is generally seen due to
anticholinergic or opioid poisoning.

Skin: The skin often appears flushed, hot and dry in poisoning with atropine. Excessive sweating
occurs with organophosphates, nicotine and sympathomimetic drugs. Cyanosis may be caused by
hypoxemia or by methemoglobinemia. Cyanosis is a dark blue or purple discoloration of the skin
and mucous membrane. Similarly Methemoglobulin is abnormal hemoglobin in which the iron
molecule is in the oxidized ferric state.

Abdomen: Hyperactive bowel sounds, abdominal cramping and diarrhea are common in
poisoning with organophosphates, iron, arsenic and theophylline. Similarly constipation is
common with anticholinergic agents, calcium channel blocker and opioids.

 Nervous system: A careful neurologic examination is essential. Nystagmus, dysarthria, and

ataxia are common with phenytoin and carbamazepine. Twitching and muscular hyperactivity are
common with atropine and cocaine. Muscular rigidity can be caused by haloperidol and other
antipsychotic agents. Seizures are often caused by overdose with tricyclic antidepressants, cocaine,
amphetamines, theophylline, isoniazid and diphenhydramine.

iii. Decontamination: Decontamination procedures should be undertaken simultaneously with

initial stabilization, diagnostic assessment and laboratory evaluation. Decontamination involves
removing toxins from the skin or gastrointestinal tract. Generally contaminated clothing should
be completely removed and the contaminated skin should be washed with soap and water.

Emesis: Emesis can be induced with ipecac syrup. Ipecac should not be used if the suspected
intoxicant is a corrosive agent, a petroleum distillate or a rapid-acting convulsant.

Emesis is contraindicated in the above situations:

a. If patient ingested corrosive poison, emesis can increase gastric perforation and causes further
necrosis of the esophagus.
b. If patient is in a state of delirium, emesis may cause aspiration of the gastric contents.
c. If patient has ingested CNS stimulant, emesis may precipitate convulsions.
d. If the patient has ingested petroleum, hydrocarbon can be aspirated readily and can cause
chemical pneumonia.
14 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]
 Gastric lavage: Gastric lavage is the procedure of inserting a tube into the stomach and washing
the stomach with water and normal saline for the removal the unabsorbed poison from the stomach.
It should be performed as soon as possible but only if vital organs are working properly. Lavage
solutions (usually 0.9% saline) should be at body temperature to prevent hypothermia. Gastric
lavage should not use routinely in the management of poisoned patient but should be reserved for
the patient who have ingested a life-threatening amount of poison and when the procedure can be
undertaken within 60 minutes of ingestion.

 Activated charcoal: Activated charcoal can adsorb many drugs and poisons because of its large
surface area. It is most effective if charcoal-drug ratio is 10:1. Charcoal does not bind iron, lithium
or potassium and it binds alcohols and cyanide only poorly. It does not appear to be useful in
poisoning due to corrosive mineral acids and alkali.

 Cathartics: Administration of a cathartic agent reduces the absorption of toxins by hastening

passage of toxins from the gastrointestinal tract. Sorbitol is most effective but sodium sulfate and
magnesium sulfate are also used.

iv. Specific Antidotes:

Antidote Poison Antidote Poison

Acetylcysteine Acetaminophen Ethanol Methanol
Atropine Organophosphate Flumazenil Benzodiazepines
Naloxone Narcotic drugs Oxygen Carbon monoxide
Pralidoxime Organophosphate Hydroxocobalamin Cyanide

Types of Poisoning:
A. Barbiturates poisoning: Barbiturates are a leading cause of acute poisoning because of their
ready availability. Most of the cases are suicidal but some of them are occur due to the accidental
poisoning in children and on drug abusers. Barbiturates generally bind to specific site on
GABAA Cl− channel complex. Then there is increase in the frequency of opening of chloride
channels which leads to increase in GABA mediated chloride conductance. Then there will be
membrane hyperpolarization which ultimately leads to CNS depressant.

The lethal dose of barbiturates is varied as:

 3-4gm for long acting barbiturate such as Phenobarbitone
 2-3gm for medium acting barbiturate such as Pentobarbitone
 1-2gm for short acting barbiturate such as Hexobarbitone

Signs and symptoms of Barbiturates poisoning:

i. CNS: Restlessness, Insomnia, Delirium, Hallucinations, Confusion, Ataxia, Convulsions,
Hypothermia and coma
ii. CVS: Hypotension, Hypovolemic shock and Cardiovascular collapse
iii. Skin: Corneal oedema which alter vision.
iv. Eye: Nystagmus, Miosis (on early stage) and Mydriasis (on prolong exposure)
v. Miscellaneous symptoms: Inflammatory bowel syndrome and Impairment of renal function

15 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

Management of Barbiturates poisoning:
i. Airway should be maintained and endotracheal tube should be inserted if needed.
ii. Breathing should be observed and patients with respiratory insufficiency should be
mechanically ventilated.

iii. The circulation should be then assessed by continuous monitoring of pulse rate, blood
pressure, urinary output and evaluation of peripheral perfusion.
iv. Gastric lavage is then performed for 1-2 hours and 1mg of activated charcoal is administer to
enhance the elimination of phenobarbiturates.

v. There is no specific antidote for barbiturates poisoning so alkaline diuresis is a specific

curative management for barbiturates poisoning. In alkaline diuresis, intravenous sodium
bicarbonate is administered which generally alkalizes the urine. In alkaline urine bicarbonates
exists on ionized form so they will not reabsorbed while passing through renal tubules and
ultimately excreted in urine.

vi. Haemodialysis and Haemoperfusion are now being used extensively in treatment of barbiturate
intoxication to increase rate of removal of barbiturates. Single six-hour haemodialysis can remove
an amount of barbiturate which is comparable to that removed during 24 hours of sustained
diuresis.

B. Organophosphate poisoning: Organophosphate poisoning is a poisoning due to organo-

phosphates compound such as Malathion and Parathion. Organophosphates are used as
insecticides, medications and nerve agents. OPs are one of the most common causes for chronic
poisoning. The organophosphates compounds generally inhibit cholinesterase enzyme and prevent
breakdown of ACh due to which ACh level will raise in synapse and shows various nicotic and
muscarinic effects.

Signs and symptoms:

 Nicotinic Effects: Diarrhea, Urination, Miosis, Broncospasm, Emesis, Lacrimation,
Hypotension, Bradycardia
 Muscarinic Effects: Tachycardia, Hypertension, Sweating, Paralysis, Muscle weakness
 CNS Effects: Agitation, Confusion, Seizures and Coma due to respiratory failure

Management:
General measures:
i. Remove the contaminated clothes and wash skin with soap and water.
ii. Gastric lavage should be generally done within 4 hours.
iii. Airway should be maintained.
iv. Artificial respiration is given if necessary.
V. Diazepam should be continuously by slow IV injection to control convulsions.

Specific measures:
a. Atropine: Atropine is first drug choice to be given in organo-phosphorus poisoning. It
competitively counteracts muscarinic effects. It should be given 2mg through IV route repeatedly
on every 10 minutes until patient is fully atropinized [Fully dilated pupil, dry mouth, flushed skin
and tachycardia]. It should be continued for 7-10 days.

16 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

b. Pralidoxime: Atropine is not effective for reversal of neuromuscular paralysis. Neuromuscular
transmission can be improved by giving cholinesterase reactivators such as Pralidoxime. Generally
Acetylcholinesterase has two binding sites as Esteratic and Anionic sites. Organophosphates bind
to esteratic site irreversibly and prevent breakdown of ACh. While oximes like Pralidoxime
occupy anionic site and forms bond with OP. Then derived complex is hydrolyzed by forming
esteratic sites available for breaking of ACh and ACh can be reactivated. Generally 1-2gm of
Pralidoxime is administered intravenously and dose may be repeated after 1 hour if necessary and
then for every 6-12 hours.

C. Paracetamol toxicity: A clinical condition on which patient suffers from hepatotoxicity and
nephrotoxicity due to the excessive use of paracetamol is known as paracetamol toxicity. It occurs
especially in small children who have low glucuronide conjugating ability. Acute ingestion of
more than 150-200 mg of paracetamol in children or 7 gm in adults is considered as potentially
toxic. Heavy alcohol consumption mainly increases the susceptibility towards hepatic injury.
Generally Paracetamol is conjugated in the liver to form inactive glucuronidated and
sulfated metabolites. Paracetamol also undergoes hydroxylation to form NAPQI [N acetyl
P-benzoquinone imine] which is potentially toxic metabolite. At normal dose NAPQI reacts with
sulfhydryl group of metabolites and produce non-toxic substance such as Mercapturic acid.
However on high dose the available glutathione in the liver becomes depleted and NAPQI binds
covalently sulfhydryl groups of hepatic proteins and results on hepatic necrosis.

Sign and symptoms:

i. Nausea, Vomiting and Abdominal pain within first 24 hours.
ii. Pain on the right upper side of abdomen within 24-48 hours.
iii. Jaundice, Vomiting, Tachycardia, Confusion and Unconsciousness within 2-6 days.
iv. Pathological change showed potential hemorrhage, gastrointestinal bleeding, hepatic necrosis,
renal tubular necrosis and cerebral edema.
v. Severe liver damage occurs when plasma concentration exceeds 200mg/litre of blood.

Management:
General Management:
i. Airway should be maintained and endotracheal tube should be inserted if needed.
ii. Breathing should be observed and patients with respiratory insufficiency should be
mechanically ventilated.
iii. The circulation should be then assessed by continuous monitoring of pulse rate, blood
pressure, urinary output and evaluation of peripheral perfusion.
iv. Gastric lavage is then performed for 4 hours and 1mg of activated charcoal is administered to
enhance the elimination of paracetamol toxicities.
v. Hemodialysis may be required in cases of acute renal failure.

Specific Management: N-acetylcysteine of 150 mg/kg should be infused intravenously over 15

minutes followed by the same dose intravenously over the next 20 hours. N-acetylcysteine
generally fulfills the required amount of glutathione in liver and prevents binding of the toxic
metabolite to other cellular constituents. It is practically ineffective if started after 16 hours of
manifestation of symptoms.

17 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

D. Atropine Poisoning: Atropine generally blocks all cholinergic activity on the eye resulting in
persistent mydriasis and cycloplegia [inability to focus for near vision]. At low doses atropine
generally decreased cardiac rate [bradycardia] by activation of M1 receptors and at higher doses
M2 receptors on the Sino atrial node are blocked and the cardiac rate increases moderately.
Atropine also blocks the salivary glands by producing a drying effect on the oral mucous
membranes [xerostomia]. It also reduces gastric motility, saliva secretion, ocular accommodation
and micturition [urination].

Sign and symptoms:

i. Mild Anticholinergic Toxicities: Dry mouth, Mydriasis, Blurred vision, Elevated body
temperature, Tachycardia
ii. Moderate Anticholinergic Toxicities: Hypertension, Hyperthermia, Decreased gastric motility,
Urinary retention, Headache
iii. Severe Anticholinergic Toxicities: Seizures, Hypotension, Postural hypotension, Circulatory
collapse, ECG abnormalities

Management:
i. Airway should be maintained and endotracheal tube should be inserted if needed.
ii. Breathing should be observed and patients with respiratory insufficiency should be
mechanically ventilated.
iii. The circulation should be than assessed by continuous monitoring of pulse rate, blood
pressure, urinary output and evaluation of peripheral perfusion.
iv. Gastric lavage is then performed if delayed and 1mg of activated charcoal is administered to
enhance the elimination of Atropine toxicities.
v. Diazepam is then used to control convulsion.
vi. Finally Intravenously 1-4 mg of Physostgmine is used as antidote for atropine poisoning.

E. Opoid Poisoning: Over dose of Morphine, Heroin, Fentanyl, Tramadol and Methadone
generally causes opoid Poisoning. Morphine generally exerts its action by interacting with Mu
receptor of opioids.

Sign and symptoms: The overdose of opoids produces significant CNS and respiratory depression
which is mediated predominately by Mu receptors. The common symptoms seen during opoid
poisoning are Pinpoint pupils, Nausea, Vomiting, Constipation, Hypotension, Shock, Convulsions
and Urinary retention. On chronic stage respiratory depression and cyanosis may be occur.

General treatments:
i. Airway should be maintained and endotracheal tube should be inserted if needed.
ii. Breathing should be observed and patients with respiratory insufficiency should be
mechanically ventilated.
iii. The circulation should be then assessed by continuous monitoring of pulse rate, blood
pressure, urinary output and evaluation of peripheral perfusion.
iv. Gastric lavage is then performed with potassium permanganate for 4 hours and 1mg of
activated charcoal is administered to enhance the elimination of opoid toxicities.

18 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

Specific antidote: Naloxone of 0.4mg to 0.8 mg should be given intravenously and repeated for
every 2-3 minute until respiration is normal. It is the specific antagonist choice for acute morphine
poisoning because it acts rapidly, does not have any agonistic action and does not depress
respiration. Due to short duration of action, naloxone should be repeated every 1–4 hours
according to the response.

F. Arsenic poisoning: Arsenic is a naturally occurring element in the earth’s crust. Large numbers
of people are exposed towards high concentrations of arsenic in their well water used for drinking.
Generally humans are exposed to arsenic through Microelectronics industries, wood preservatives,
pesticides, herbicide, fungicide and coal. The lethal dose for arsenic is about 120-200mg on adults
and 2mg on children.

Signs and symptoms:

i. General toxicities of arsenic poisoning causes burning of lips, difficulty in swallowing, gastric
pain, vomiting and severe diarrhea.
ii. Acute arsenic poisoning generally causes necrosis of intestinal mucosa with hemorrhagic
gastroenteritis, hypotension, delayed cardiomyopathy, acute tubular necrosis and hemolysis.
iii. Similarly chronic arsenic poisoning generally causes necrosis of intestinal mucosa with
hemorrhagic gastroenteritis, hypotension, delayed cardiomyopathy, acute tubular necrosis and
hemolysis.

Management:
Airway should be maintained and endotracheal tube should be inserted if needed.
 Breathing should be observed and patients with respiratory insufficiency should be
mechanically ventilated.
The circulation should be than assessed by continuous monitoring of pulse rate, blood pressure
and evaluation of peripheral perfusion. Similarly fluid and electrolyte balances should be
maintained.
 Gastric lavage is then performed and 1mg of activated charcoal is administered with cathartic.
 Chelation therapy is then start with Dimercaprol (3 to 4mg/kg intramuscularly for every 4 to
12 hours) until the abdominal symptoms are relief. Similarly Penicillamine (2gm/day in four
divided dose) can be given orally in the substituents of Dimercaprol.

G. Carbon monoxide poisoning: Carbon monoxide is a colorless, odorless, tasteless gas produced
by burning gasoline, wood, propane, charcoal or other fuel. A smoker is exposed to 400 to 500
ppm of CO while actively smoking. People who work with methylene chloride as paint stripper
can be poisoned because the fumes are readily absorbed and converted to CO in the liver. Generally
Carbon monoxide quickly binds with hemoglobin with a greater affinity than that of oxygen to
form Carboxyhemoglobin (COHb) then results impairment on the transport of oxygen and its
utilization. CO also interferes with peripheral oxygen utilization by inactivating cytochrome
oxidase enzyme. Exposure at 100ppm or greater can be dangerous to human health.

19 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

 COHb Concentration Clinical manifestations
15-20 % Mild headache
20-30 % Pounding headache, Blurring of vision, Irritability
30-40 % Muscle weakness, Nausea, Vomiting, Mental confusion or Delirium
40-50 % Tachycardia, Cardiac irritability
50-60 % Seizures, Respiratory insufficiency
> 60-70 % Coma, Respiratory failure, Death

Management:
 The tightly fitting mask with an inflated face seal is necessary for admission of 100% oxygen.
The circulation should be than assessed by continuous monitoring of pulse rate, blood pressure
and evaluation of peripheral perfusion. Similarly fluid and electrolyte balances should be
maintained.
 Refer to the hyperbaric oxygen therapy if there is loss of consciousness, neurological sigh of
toxicity and if patient is pregnant.

H. Methanol poisoning: Methanol or wood alcohol is a colorless and volatile liquid with burning
taste. It is present in certain homemade beverages, antifreeze, paint removers and varnish. Its fatal
dose is about 60-200 ml.

Clinical Manifestation:
 Urine is strongly acid with acetone and trace of albumin
 Acidosis by inhibiting effect on oxidative enzyme
 Pupils are diluted and fixed
 Visual disturbances followed by complete blindness
 Convulsion

Management:
Airway and circulation should be assured by continuous monitoring of pulse rate, respiratory
rate and blood pressure
 Gastric lavage by using 5% bicarbonate solution
 Administration of activated charcoal
 Administration of 1ml/kg of 50% ethyl alcohol through IV route for every 2 hour for 1 week
 Hemodialysis if severe
 Administration of sodium bicarbonate by IV route to correct metabolic acidosis

I. Mushroom Poisoning: Mushroom poisoning refers to harmful effects from ingestion of toxic
substances present in a mushroom. Majority of fatal poisoning are are caused by Amanita
Phalloides mushroom. The lethal dose of Amatoxin is about 10mg.

20 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

Symptoms:
 Within 6-24 hours: Abdominal cramping, Nausea, Vomiting and Severe watery diarrhea and
even circulatory collapse
 Within 1-3 days: Hepatic failure and Renal failure
 Within 3-7 days: Death

Management:
Airway and circulation should be assured by continuous monitoring of pulse rate, respiratory
rate and blood pressure.
 Lavage should be attempted within 1 hour of ingestion.
 Repeated doses of activated charcoal may be given orally for ingestion of an unidentified or
potentially toxic mushroom.
 Gastroduodenal aspiration may be done to remove the toxins eliminated in bile.
 Electrolytes may be given to correct and maintain adequate hydration and urinary output as
well as intensive supportive care for hepatic failure.

Poison information Centre (PIC): The poison information centre is a specialized unit providing
information on prevention, diagnosis, management and treatment of poisoning. The most
fundamental function of Poison information Centre is to reduce morbidity and mortality from toxic
exposure and to prevent poisoning.

Functions of PIC:
1. Information services: Poison centres provide information and guidance to the public and health
care professionals towards the acute and chronic poisoning due to various kind of chemicals, drugs,
animal bites and toxins. Information is provided by telephone in emergency but there should be
email, written response to enquires and publication.

2. Laboratory services: Poison information centres may also provide analytical laboratory service
for taxological analysis and biomedical investigations which are essential for the diagnosis and
treatment of various types of poisoning.

3. Toxicovigilance: Toxicovigilance is an active process of identification and evaluation of toxic

risks in the community. All enquires addressed to a PIC are regularly analyzed to determine the
possible toxic agents and circumstance of poisoning.

4. Chemical Disasters: Poison centres make an important contribution in the prevention and
handling of chemical disasters by providing the appropriate information at the time of an accident.

5. Prevention of poisoning by public education and awareness: Safe use of pesticides can be
prevented by public education and awareness.

6. Antidote bank: PIC serves as antidote banks for those antidotes which are not easily available
in the region and country.

7. Research: Poison centre can support for the research on clinical toxicology.
21 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]
Suggestions used for avoid unintentional poisoning:
 Use of child resistant containers
 Proper labelling and storage of drugs
 Guardian should keep phone number of local poison control centre
 Awareness for basic first aid poisoning

[Old is Gold]
1. Describe symptoms & management of organophosphate poisoning. [3+7] [IOM 2070, 73, 75]
2. Write down the symptoms and management of Mushroom Poisoning. [3+5] [IOM 2074]
3. Write down the ways to minimize non-intentional poisonings related with occupation,
environment and health care. [8] [IOM 2073]
4. Write down the management of Methanol poisoning. [5] [IOM 2072 Regular Paper]
5. What suggestions would you give to the patient party so as to minimize the risks of drug
overdose poisoning in future as a pharmacist working in a poison management center? [8] [IOM
2069]
6. Explain in brief poisoning situation in Nepal. How can you get information related to poisoning
management? [8] [IOM 2068]
7. Write a critical note on, ‘Every drug is a potential poison’. [5] [IOM 2067]
8. Write down the management of carbon monoxide poisoning. Mention the logic behind it. [5]
[IOM 2067]
9. Write the main functions of poison information centre. What are resources needed for poison
information to its services? [8] [IOM 2061]

22 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

 Clinical Trial and New Drug Development Process

Development and testing of new drug is expensive and lengthy process and require
6-12 years. It is estimated that every 5000 compound undergoes clinical trial per year but only one
compound can pass the test and emerge as new product. Generally testing procedures are standard
so that newly released drug might be safe and effective. Although it can’t guarantee the safety
because adverse effect may be detected during testing.

Steps involved in new drug development process:

1. Preclinical testing: Preclinical testing is required before a new drug tested in human. During
pre-clinical testing drugs are evaluated for toxicities, pharmacokinetic and biological effect
through in vitro and in vivo laboratory animal testing.

For short term study on animal: Two weeks to 3 months

For long term study on animal: Few weeks to Several years

2. Clinical testing: When sufficient preclinical data have been obtained then drug developer may
apply to regulatory authority for permission to begin tests in human. If application is approved the
drug is awarded as Investigational New Drug Status and start the clinical trial.

Clinical trial: Clinical Trial means the act of testing of a new drug by administering it to any
patient or a person with his consent in hospital as specified in the letter of permission for the
purpose of ascertain whether it is proper to bring any new drug into use or not. Clinical trial occurs
in four phases.

a. Phase I: Phase I trial is generally conducted within 20-80 healthy volunteers for several months
to one year. This phase is usually performed in research center by specially trained clinical
pharmacologist. This phase helps to address the absorption, distribution, metabolism and
elimination of drug.

Objectives of Phase I:
i. To assess tolerability as well as safety of gradually increasing dose.
ii. To obtain pharmacokinetic and pharmacodynamics information.
iii. To evaluate Pharmacokinetic parameters such as Peak plasma concentration, AUC, Half-life
and Side effects of drug.
iv. To assess dosing range.

b. Phase II: Phase II trial is generally conducted within 100-200 volunteers for few months to
several year. This phase is generally perform on specialized clinical center such as hospital. This
phase helps to address the minimum effective dose, maximum tolerated effective dose and
effectiveness of drug in mild, moderate and severe cases. If a new drug is found to be safety and
effective in phase II trial then it goes to phase III trial.

23 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

Objectives of Phase II:
i. To determine the efficacy of new drug in treating the disease against which it is being tested.
ii. To detect side effects and toxicity symptoms which are not manifested in animal studies i.e.
dose evaluation and safety profile of drug

c. Phase III: Phase III trial is generally conducted within 300-3000 targeted patients for 1-4 years.
This phase helps to address Risk Benefit Ratio, Adverse Reactions and Ideal Dosage Regimen.
Phase III is difficult to conduct and is usually expensive because larger volunteer is needed for
survey and more data must be collected and analyzed. Many Phase III trials are randomized and
blinded.

Objectives of Phase III:

i. To determine the therapeutic effects
ii. To verify effectiveness
iii. To monitor adverse reactions from long-term use

Regulatory authority i.e. FDA will provide approval for New Drug Application (NDA) after
successful completion of Phase III trials. The NDA must contain all the scientific information that
the company has gathered.

d. Phase IV [Post Marketing Surveillance]: Phase IV is regarded as Pre-approval but Post-

launch Phase. It involves safety surveillance and technical support for safety of the drug. This
Phase is conducted within more than 10000 patients. Post surveillance may be continue as long as
useful information is gathered towards the safety and effectiveness of the product. This phase helps
to address Safety, Additional side effects and Risks on prolonged used of drug. It also helps to
address the effective of drug after widely used in clinical trials.

Objectives of Phase IV:

i. To determine drug efficacy in prolong use.
ii. To identify the adverse reactions which may only occur with long term use or which rarely
occurs.
iii. For the evaluation of different formulations, dosages, durations of treatment and medicine
interactions.

Investigational Drugs: Investigational or experimental drugs are a new drugs which have not yet
been approved by the FDA and those drugs are in the process of being tested for safety and
effectiveness.

Importance of Clinical trial:

i. Clinical trials helps to determine suitable treatments mechanism such as a development of new
drugs, new surgical procedure or new radiation technique for particular patient.

ii. Clinical trials provide information about the natural history of a disease and evaluate the
medication therapy.

24 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

iii. Clinical trial allow for testing of biological hypothesis and provide scientific methods for
solving clinical problem.

iv. Clinical trial reduces the risk of developing disease.

v. Clinical trials helps to identify the disease in earlier stage as on cancer diagnosis.
vi. Clinical trials are an essential link between lab and clinic and identify whether the use of lab
findings in the treatments of patient is justify or not.

Ethical Issue related with the clinical trials:

i. The voluntary consent for the human subject should be absolutely essential.
ii. Research subject should be suited so as to exercise free power of choice.
iii. Researcher should have sufficient knowledge towards the elements of the subject matter to
make an understanding and enlightened decision.

iv. Research should never include serious risks of harm towards to the participants.
v. Experiments should be performed to avoid unnecessary pains and injury.
vi. Qualified persons must conduct the research.
vii. Subject should be at liberty to withdraw at any time.
viii. The integrity and confidentiality of study subjects should be protected.

25 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

Pharmacist’s role in clinical trials: Pharmacist play the vital role in clinical trial and can ensure
the Investigational Medicinal Products (IMP) are appropriate for use and IMP’s can procured,
stored and use safely and correctly. The pharmacist can use his or her expertise towards the
indications, dosage, administration, contraindications, adverse effects and interactions of
investigational drugs. Pharmacist can help to ensure the safety of human subjects and their rights
which are mainly protected by local Institutional Review Board. Currently, pharmacists are at the
forefront of patient care and provide significant impact on patient management.

Pharmacists have vital role in various parts of clinical trial:

i. Reviewing of study protocol (Protocol is a written plan for how the drug is to be studied and
the procedures to be followed by each investigator)
ii. Writing and approving of dispensing procedures
iii. Staff training
iv. Randomization of products
v. Safely order, receipt, storage and destruction of IMP used in clinical trial
vi. Accurate record keeping
vii. Audit and monitoring of clinical trial activity

[Old is Gold]
1. Define investigational drugs. Write down how a chemical molecule can become a marketable
medicine. [3+7] [IOM 2076]
2. Define clinical trials. Write down the ethical issues related with the clinical trials. Write down
the importance of Phase III trials. [2+3+3] [IOM 2075]
3. Define new drug. How can its efficacy and safety established? [2+6] [IOM 2075]
4. Write down the different phases of clinical trials. Who are the participants in each of them?
What is the sample size? What are the aims of each of these phases? [1+2+2+3] [IOM 2074]
5. Describe the phases of clinical trials and their purposes and pharmacist’s role in clinical trials.
Write its precautions in reading the clinical trial reports. [10] [IOM 2072 Back Paper]
6. What is a clinical trial? Explain different phases of clinical trials. [2+10] [IOM 2064, 65, 71]
7. Define clinical trials. Mention its phases with short descriptions. [2+8] [IOM 2070]
8. Define clinical trials. Describe in brief what is surrounded by post- marketing surveillance.
[3+5] [IOM 2069]
9. What are the investigational drugs? List the phases of clinical trials and their purposes. What
precautions should be taken while reading clinical trial reports? [2+4+6] [IOM 2068]
10. List and discuss the different stages of clinical trials. Write down the importance of
preclinical tests. [8] [IOM 2067]
11. Write down the different phases of clinical trials. What are the major differences among
them? [2+4] [IOM 2066]

26 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]

Methods of Radiolabeling or Methods of Isotropic Tagging: The use of compounds labeled
with radionuclides has grown considerably in medical, biochemical and other related fields. In
the medical field compounds labeled with β-emitting radionuclides are mainly restricted to in-
vitro experiments and therapeutic treatment whereas compounds labeled with gama-emitting
radionuclides have much wider applications. Nowadays Gama-emitting radionuclides are
particularly useful for in vivo imaging of different organs.

In a radiolabeled compound atoms or groups of atoms of a molecule are substituted by similar or

different radioactive atoms or group of atoms. In labelling process variety of physiochemical
conditions can be employed to achieve specific kind of labelling. There are the six methods of
Isotropic Tagging.

1. Isotope Exchange Reactions: One or more atoms in a molecule are replaced by isotopes of the
same element having different mass numbers in isotope exchange reactions. Since the radiolabeled
and parent molecules are identical except for the isotope effect, they are expected to have the same
biologic and chemical properties. Examples are 125I – Tri-iodothyronine (T3 ) and 125I - Thyroxine
(T4 ) labeled compounds. These labeling reactions are reversible and are useful for labeling iodine-
containing material with iodine radioisotopes and for labeling many compounds with tritium.

2. Introduction of a Foreign Label: A radionuclide is incorporated into a molecule that has a

known biologic role by the formation of covalent or coordinate covalent bonds in this type of
labeling. The tagging radionuclide is foreign to the molecule and does not label it by the exchange
of one of its isotopes. Certain examples are 99mTc-labeled albumin, 51Cr-labeled red blood cells
and many iodinated proteins and enzymes. In this type of labeling the chemical bond is formed by
chelation i.e. more than one atom donates a pair of electrons to the foreign acceptor atom. Most of
the 99mTc-labeled compounds used in nuclear medicine are formed by chelation.

3. Labeling with Bifunctional Chelating Agents: A bifunctional chelating agent is conjugated to

a macromolecule such as Protein and antibody on one side and further conjugate to a metal ion
such Tc by chelation on the other side in this type of labeling. Examples of bifunctional chelating
agents are DTPA, Metallothionein, Diamide dimercaptide ( N2 S2 ), Hydrazinonicotinamide
(HYNIC) and Dithiosemicarbazone.

The two methods applied for Labeling with Bifunctional Chelating Agents are Preformed 99mTc
chelate method and Indirect chelator-antibody method. In Preformed 99mTc chelate method, 99mTc
chelates are initially pre-formed by using chelating agents such as diamidodithiol and cyclam
which are then used to label macromolecules by forming bonds between the chelating agent and
the protein. Similarly in the indirect method the bifunctional chelating agent is initially conjugated
with a macromolecule which is then allowed to react with a metal ion to form a metal-chelate-
macromolecule complex.

4. Biosynthesis: In biosynthesis a living organism is grown in a culture medium containing the

radioactive tracer and the tracer is incorporated into metabolites produced by the metabolic
processes of the organism and the metabolites are then chemically separated. For example vitamin
B 12 is labeled with 60Co or 57Co by adding the tracer to a culture medium in which the organism
Streptomyces griseus is grown. Similarly the examples of biosynthesis also include 14C-labeled
carbohydrates, proteins and fats.
27 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]
5. Recoil Labeling: Recoil labeling is of limited interest because it is not used on a large scale for
labeling. In a nuclear reaction when particles are emitted from a nucleus then the recoil atoms or
ions are produced which can form a bond with other molecules present in the target material. The
high energy of the recoil atoms results in poor yield and shows a low specific activity of the labeled
product. Several tritiated compounds can be prepared in the reactor by the 6Li(n,α)3 reaction. The
compound to be labeled is mixed with a lithium salt and irradiated in the reactor. Tritium produced
in the above reaction labels the compound primarily by the isotope exchange mechanism and then
the labeled compound is separated.

6. Excitation Labeling: Excitation labeling illustrate the utilization of radioactive and highly
reactive daughter ions in a nuclear decay process. During β decay or electron capture energetic
charged ions are produced which are capable of labeling various compounds. 77Kr decays to 77Br
and energetic 77Br ions label the compound to form the brominated compound. Similarly various
proteins have been iodinated with 123I by exposing them to 123Xe and 123Xe further decays to 123I.
The yield is considerably low with this method

28 | Hospital and Clinical Pharmacy [Sanjeev Khanal, B. Pharma, IOM]