General Pharmacology

for MD Medicine/ selection exam

Chamila Mettananda; MBBS, MD, FRCP, PhD

Senior Lecturer & Consultant Physician
Faculty of Medicine, University of Kelaniya
30.08.2020
Q1. True or false regarding
Pharmacodynamics?
a. It is the study of the drug action
b. An agonist can provoke biological effect by
binding with receptor
c. Activity of an agonist depend on the number of
receptors occupied
d. A competitive antagonist shifts the drug dose
response curve to the left
e. Noncompetitive antagonist does not alter the
maximum efficacy
 Drugs

• ‘What the drug does to the patient’

Pharmacodynamics

• ‘What the patient does to the drug’

Pharmacokinetics
PHARMACODYNAMICS
• Drug must exert chemical influence on constituent(s) of
cells to produce EFFECT
• Drug must be BOUND to cell constituents

EFFECT

Drug Cell

• Drugs bind to targets - protein molecules

(exceptions – some antitumour drugs/antibiotics)
Drug binding
Protein targets:
• Receptors – atenolol (beta-blocker)
• Carrier molecules – furosemide (diuretic)
• Enzymes – captopril (ACE-inhibitor)
• Ion channels – lignocaine (channel blocker)
Receptors
• Protein macromolecules
• Usually situated on the cell membrane
• Specific for a ligand – e.g. insulin receptor
• Three types of ligands:
- agonists
- antagonists
- partial agonists (e.g. oxprenolol)
Specificity of drug action
• Drugs must act selectively on cells/tissues
• For selective action
- drugs show binding site specificity
- binding targets show ligand specificity
• No drug acts with complete specificity
(higher doses – affect other targets)
• Results in unwanted/adverse effects
Dose-response in drug therapy

• Effect of a drug is related to concentration of the drug

at the site of action
• Higher the concentration – greater the effect
• The relationship between drug concentration and
effect: dose-response curve
 100
Response (%) % Potency Potency

50
%

EC50 Drug concentration

• EC50 – concentration of drug producing 50% of maximum effect

• Most drugs are used at doses close to the top of D-R curve
Q2. Which drugs have a narrow
therapeutic index?
a) Lithium
b) Theophylline
c) Digoxin
d) Azithromycin
e) Dexamethasone
Therapeutic index (TI)
adverse effects
Response

Wide TI (drug A)
e.g.penicillin
Narrow TI (drug B)
B A e.g. digoxin
phenytoin
gentamicin
lithium

TI TI Dose
PHARMACOKINETICS
Pharmacokinetics – study of the time course of
following activities:
• Absorption
• Distribution
• Metabolism
• Excretion
Absorption & bioavailability
• Movement of drug from site of administration into
systemic circulation
• Oral drugs – mainly upper small intestine
• To cross cell barriers (GIT, renal tubule) drugs must
cross lipid membranes
• Drugs cross lipid membranes mainly by:
- passive diffusion
- carrier mediated transfer
Absorption
Factors affecting absorption :
i. Lipid solubility
ii. Molecular weight and state of ionization
iii. Malabsorptive states
iv. Presence of food
Q3. Regarding Bioavailability;
a) The amount of drug dose reaching the systemic
circulation
b) Influenced by gastric motility
c) Plasma concentration is 100% in oral absorption
d) Not influenced by first pass metabolism
e) Peak plasma concentration(Max) is influenced by
the bioavailability
Bioavailability (systemic availability)
Bioavailability defined in terms of:
Indicates the proportion of drug entering systemic
circulation after oral administration

100% bioavailability – only with iv administration

Bioavailability
Factors affecting bioavailability:
• Pharmaceutical factors
• Biological factors
• First pass (pre-systemic) metabolism (e.g. nitrates)

Avoid first pass metabolism - sublingual administration

Speed of availability may be influenced by other
factors (e.g. motility stimulants in migraine)
pH partitioning
• Unionized drug molecules cross membranes better
• Acidic drugs concentrated in body compartments with
alkaline (high) pH: “ion trapping”
• Urinary alkalinisation promotes excretion of weak acids
(e.g. aspirin)
pH partitioning of drugs – ion trapping
Ionisation greatest at high pH

Stomach Plasma Urine

Relative concentration pH 3 pH 7.4 pH 8
Aspirin
(pKa 3.5)

Pethidine
(pKa 8.6)

Ionisation greatest at low pH

Distribution
Distribution between compartments depend on:
• Permeability across barriers (e.g. blood brain barrier:
use of domperidone in nausea)
• Binding within compartments
• pH partition
• Fat:water partition
 Distribution

Interstitial water Intracell. water

16% 35%

Plasma Transcell.
5% water 2%
(e.g. BBB)

Bound drug
Unbound (free) drug

Fat 20%
Q4. Regarding Volume of distribution
(Vd);
a) Is a measure of how widely a drug is distributed
in body tissues
b) Is not important to determine dosage regimens
c) Vd is not influenced by lipid solubility
d) Amiodarone has a large Vd
e) Vd is small when it is remaining in the plasma
 Volume of distribution (Vd)
• Volume of fluid needed (in litres) to contain the total
amount of drug (Q) in the body at the same concentration
as that in the plasma (Cp)
Vd = Q / Cp
• Measure of how widely a drug distributes in the body
• Fat soluble drugs with low mw – large Vd
(e.g. cyclosporin 100 L)
• H2O soluble drugs with high mw – small Vd
(e.g. heparin 3 L)
Volume of distribution
Vd: relates amount of drug in the body to plasma conc.
Therefore, Vd = amount of drug in body / plasma conc.

Vd = 20/2 = 10 L

Vd = 20/18 = 1.1 L

Plasma Extracell. comp

Factors affecting distribution
• Specific receptors in tissues – Na/K pump
• Disease - obesity & fat soluble drugs
- hyperthyroidism & digoxin
• Regional blood flow – heart, liver, kidneys
• Other drugs – TCA drugs inhibit active transport of
adrenergic neuron blockers
• Plasma protein binding – phenytoin, warfarin
Factors affecting protein binding
• Hypoalbuminaemia (< 25g/L)
• T3 of pregnancy (increase TBG, free drug is less)
• Saturability
• Displacement by other drugs e.g;
• warfarin & phenytoin
• tolbutamide & aspirin)
Volume of distribution
Drug with a large Vd (TCA drugs, haloperidol):
• Likely to be highly lipid soluble
• Likely to reach all compartments
• May accumulate in body fat
• Vd may be beyond total body water
• Haemodialysis unhelpful in overdosage
Q5. First pass metabolism;
a) Does not influence the bioavailability of an orally
administrated drugs
b) Gut lumen is the principle site for first pass
metabolism of drug
c) Of orally administrated Propranolol is usually 70%
d) Of orally administrated drug is 0%
First pass metabolism
• First pass metabolism may occur in the
• liver -propranolol, lidocaine, chloromethiasole
and GTN
• in the gut - benzylpenicillin and insulin
Metabolism
• Occurs mainly in the liver
• Results in two major changes to drug:
- Reduced lipid solubility (for renal elimination)
- Reduced biological activity (inactive compounds)
• Metabolism
- drug to inactive compounds
- drug to active compound (nitrates, spironolactone,
diazepam)
- inactive drug to active (e.g. enalapril): prodrugs
Metabolism
Occurs in two phases: phase I & II
Phase I
• Alters chemical structure of drug: catabolic reactions
such as oxidation or hydroxylation
• Enzymes cytochrome P450 system in hepatic ER
• Phase I products – eliminated directly / further
metabolism in phase II (conjugation)
Metabolism
Phase II
• Reactions are anabolic (synthetic): conjugation of the
parent drug / metabolite of phase I
• After conjugation – excreted in urine (mw<65000)
or in bile (mw≥65000)
• Some deconjugated by gut bacteria – parent drug
reabsorbed (enterohepatic recirculation)
Cytochrome P450 system

• Present in – ER of liver, intestinal wall, lungs, kidneys

• Three families in this system – CYP1, CYP2 & CYP3
• Each P450 enzyme has a unique but overlapping range
of drug substrates
• P450 system - many potential drug interactions
Determinants of drug metabolism
• Genetic factors
• Age & gender – ethanol
• Other drugs – enzyme inducers / inhibitors
Genetic factors
• Acetylation (N-acetyltransferase): fast and slow
acetylators determined by amount of enzyme in the
liver
- susceptible drugs: Isoniazid, hydralazine, dapsone
• G6PD deficiency – haemolysis associated with
anti-malarials in enzyme deficiency
Enzyme induction / inhibition
Inducers: ethanol, carbamazepine, rifampicin,
greseofulvin
• Induce enzymes when given repeatedly
• Increases metabolism of inducing drug / other drugs
(e.g. rifampicin & OCP)
• Increased metabolism – increase drug effect (e.g.
paracetamol toxicity)

Inhibitors: cimetidine, ketoconazole, valproate

• Increases activity of other drugs - toxicity
Enzyme induction / inhibition
-pnemonic
Inhibitors Inducers

SICK FACES Group    CRAP GPS induce me to madness!! 

Sodium valproate 
Isoniazid  Carbemazepines
Cimetidine  Rifampicin
Ketoconazole  Alcohol (chronic)
Fluconazole  Phenytoin
Alcohol binge drinking 
Chloramphenicol  Griseofulvin
Erythromycin  Phenobarbitone
Sulfonamides  Sulphonylureas
Ciprofloxacin 
Omeprazole 
Metronidazole
Grapefruit juice
Excretion / clearance (CL)
• Kidney is the main route
- glomerular filtration: most drugs
- tubular secretion: usually carrier mediated (e.g.
penicillin blocked by probenicid)
- tubular reabsorption
• Other routes: bile, lungs, sweat, tears
Plasma elimination half-life (t½)
Time taken for plasma conc of a drug to reduce by half (50%)
Plasma conc
10

5
2.5

1.25

4 8 12 Time (hrs)
Time taken for plasma conc to fall from any value by half is
constant – 4 hrs. Half-life of the drug is 4 hrs
Q6. Regarding Half- Life;
a) Depend on clearance and independent of volume
of distribution
b) Help in loading dose
c) Drug eliminate approximately in 5 half-life
d) Decrease in renal impairment
e) Helps in determine interval between dose
Half-life (t½)

Half-life = Volume of dist (Vd) / Clearance (CL)

• t½ is directly proportional to Vd
• t½ is inversely proportional to CL
(e.g. drugs with large Vd will have long t½)
Half-life indicates …
• Duration of action after a single dose
• Rate at which drug conc falls after stopping drug
• Dosing frequency (along with TI)
- drug with t½ & TI: regular dosing
- drug with t½ & TI: infusion
- drug with t½: accumulate if given repeatedly
However, many drugs have pharmacol action > than t½
e.g. glibenclamide, omeprazole
Half-life indicates …
• Time taken to reach steady state (3-5 t½)
• Need for a loading / bolus dose
- digoxin t½ = 36 hrs
- lignocaine t½ = 1 hr
Size of the loading dose is determined by TI and is a
function of Vd of the drug
Drug with extremely short t½ - needs to be infused
and activity stops when drug is withdrawn (e.g.
nitroprusside in emergency therapy of hypertension)
A TI
Plasma conc

TI
Steady state conc (Css)
B

Dosing Time
Steady state concentration
• For sustained therapeutic effect conc of drug must be
maintained within the TI
• Plasma level must not fluctuate too much
• A single dose will not usually achieve this
• Rate of absorption = rate of elimination plasma conc
will be steady: steady state (Css)
• Time to Css = 3-5 half-lives of the drug
 Multiple dosing
Concentration

Css

Time
Discrete dosing Intravenous infusion

• Objective: reach Css with minimal toxicity (within TI)

• Maintain Css for minutes, hours, or days
 Peak trough ratio
BP at peak conc.

Blood pressure

BP at trough conc.

Time

• BP at peak conc : BP at trough conc – peak : trough

• Antihypertensives should have peak : trough close to ONE
Q7. True/ False regarding clearance?
a) Measure efficacy of drug elimination from the
body
b) At steady state determine the plasma
concentration
c) Is used to determine the initial dose of drugs
d) If clearance of a drug is decrease half-life of drug
increase
e) Usually the total sum of clearance is renal
clearance plus the hepatic clearance
Clearance (CL)
• Volume of plasma cleared of drug per unit time
• Clearance (unlike t½) is independent of Vd

• Therefore, CL is the best measure of the rate at

which a drug is eliminated from the body
t½ = Vd / CL
Kinetic order
Describes the rate at which kinetic processes take place
• First order kinetics - most common
• Zero-order (saturation kinetics)
• Mixed order

Conc Zero-order kinetics

First-order kinetics

Time
First-order kinetics
• Kinetic processes proceed proportionate to the
amount of drug
• Most drugs have first order kinetics
• Toxicity and drug interactions less
Q8. Regarding drugs with zero-order
kinetics;
a) The rate of elimination is dependent of the
plasma concentration
b) The duration of action is independent of dose
c) Steady state concentration is inversely
proportional to the dose
d) Small increase in dose may results in a
disproportionately a large plasma concentration
e) Phenytoin is an example of a drug with zero-order
kinetics
Zero-order kinetics
• Kinetic processes proceed at a constant rate
• Rate is independent of the amount of drug
Examples:
• Absorption of depot preparations: drug is released
from formulation at a uniform rate
(e.g. oestrogen pellets, fluphenazine in oil)
• Saturable metabolism: when metabolizing enzymes
are saturated rate becomes uniform
(e.g. alcohol, phenytoin, aspirin)
 1st order Zero order
20
30
Plasma conc.

20 15

10 10

Time

With zero order / saturation kinetics

• Small increase in dose – large effect on plasma
• No steady state is reached with higher doses
Q9. Phenytoin;

a) In the metabolism changes from first order

kinetics to Zero-order kinetics
b) When oral contraceptives are given increase
their plasma level
c) Used in febrile convulsion
d) Not protein bound
e) Cause congenital malformation in fetus
Q10. A drug which is well absorbed when given orally
has extensive 1st pass metabolism to an inactive
metabolite. Is 20% bound to plasma proteins, has a
large volume of distribution and is excreted by
kidney. T/F regarding above drug?
a) The IV dose would be more than the oral dose
b) Renal failure would require a decrease in the
dose
c) Other drugs that bind to the same plasma
proteins would markedly increase the effect of
the drug
d) The drug should be prescribed with caution in the
cirrhosis
e) The drug is more likely to have a long rather than
a short plasma elimination half-life
Clinical trials phases
Phase Primary goal

Preclinical Testing of drug in non-human subjects, to gather efficacy, 

toxicity and pharmacokinetic information
Pharmacokinetics; particularly, oral bioavailability and half-life
Phase 0 of the drug

Phase I Testing of drug on healthy volunteers for safety; involves

testing multiple doses (dose-ranging)

Phase II Testing of drug on patients to assess efficacy and side effects

Phase III Testing of drug on patients to assess efficacy, effectiveness and

safety

Phase IV Post marketing surveillance – watching drug use in public

11.Monitoring plasma drug concentrations of the
following drugs is recognized as a valuable
supplement to clinical monitoring:
a) Carbimazole
b) Warfarin
c) Gentamycin
d) Lithium
e) Cyclosporine
12.Bio availability of a drug following oral
administration is:
a) defined as the amount of drug which is absorbed from
the stomach.
b) affected by the composition of excipients in a product.
c) Expressed as the ratio of the area under the plasma
concentration time curve(AUC) following oral
administration divided by that following intravenous
administration
d) Reduced by hepatic CYP450 inhibition
e) Not affected by peak concentrations (Cmax)
13.Drugs which are subjected to extensive first pass
metabolism are:
a) Morphine
b) Gentamicin
c) Aspirin
d) Lidocaine
e) Benzyl penicillin
14.The following drugs exert their principle effects
by enzyme inhibition:
a) Pyridostigmine
b) Atropine
c) Amlodipine
d) Digoxin
e) Selegiline
15.The following statements concerning renal drug
handling are correct:
a) The kidneys receive Approximately 20% of the cardiac
output.
b) Non-protein-bound drugs of molecular weight <65000
passes in to the filtrate.
c) Alkalization of urine promotes excretion of weakly acidic
drugs.
d) Low lipid solubility favors tubular reabsorption.
e) Penicillin group of drugs are mainly excreted by filtration.
16. For each drug reaction given below match a
likely causative drug from the below list
a) Gynecomastia
b) Osteoporosis
c) Myositis
d) SLE-Like Syndrome
e) Tardive dyskinesia
• ADVERSE DRUG
REACTIONS:
• Gentamicin • Spironolactone
• Amoxicillin • Clarithromycin
• Simvastatin • Fluoxetine
• Prednisolone • Flupentixol
• Salbutamol  
• Isoniazid
17.The following are type ‘A ’adverse reactions:
a) Propranolol & fatigue
b) Atorvastatin & hepatotoxicity
c) Naproxen & GI hemorrhage
d) Cyclophosphamide & neutropenia
e) Diazepam & sedation
18.Regarding clinical trials:
a) Marketing authorization is given after Phase 2 studies.
b) Ethics review committee is ultimately responsible for
protocol integrity.
c) Proxy consent is required for subjects under the age of 18
years.
d) When a drug is registered, data on efficacy and safety are
available.
e) For anti-cancer medicines, patients are recruited for Phase
1 study.
Clinical trials phases
Phase Primary goal

Preclinical Testing of drug in non-human subjects, to gather efficacy, 

toxicity and pharmacokinetic information
Pharmacokinetics; particularly, oral bioavailability and half-life
Phase 0 of the drug

Phase I Testing of drug on healthy volunteers for safety; involves

testing multiple doses (dose-ranging)

Phase II Testing of drug on patients to assess efficacy and side effects

Phase III Testing of drug on patients to assess efficacy, effectiveness and

safety

Phase IV Post marketing surveillance – watching drug use in public

19.Regarding clinical usefulness of the following
pharmacokinetic parameters?
a) Plasma elimination half-life is useful in deciding the dose
b) Bioavailability is useful in selecting the route of
administration
c) Clearance is useful in deciding the frequency of
administration
d) Therapeutic index is useful in selecting the drug
e) Volume of distribution is useful in deciding the
effectiveness
20. Which of the following precautions/advice to
patients are correctly paired with its
pharmacokinetic/pharmacodynamics explanation?
a) Statins are advised to be taken in the night because they
are known to cause a photosensitive rash
b) Co-administration of Warfarin and erythromycin is
contraindicated because erythromycin inhibits the
metabolism of Warfarin
c) Alcohol should be avoided when a patient is taking
metronidazole because alcohol induce the metabolism of
metronidazole
d) Penicillin has a high therapeutic index because human
cells do not possess cell wall
e) Patients should rinse the throat after inhaling
corticosteroids to remove the bitter taste