This document discusses how various factors can modify the effects of drugs in patients. It describes how genetics, race, diet, environment, psychological factors, and concurrent diseases or medications can influence pharmacokinetic and pharmacodynamic processes. Specific examples are given of genetic polymorphisms that affect drug metabolism by enzymes like CYP2C9 and CYP2D6. It also explains concepts like tolerance, drug-drug interactions, receptor antagonism, and how conditions like liver or kidney disease can impact drug handling in the body. The lecturer concludes that considering these modifying factors is important for selecting appropriate drugs and doses for each individual patient.

1. Pharmacodynamics-
IV
Dr. Pravin Prasad
M.B.B.S., MD Clinical Pharmacology
Lecturer, Lumbini Medical College & TH
18 December, 2018 (3 Poush, 2075), Tuesday

2. Question from last class
A 60 years female presented to General
Practice OPD with swelling of legs for last two
weeks, easy fatiguability for last one month.
After examination and investigations, she was
diagnosed as congestive cardiac failure and
was prescribed Tablet Digoxin 2 mg, orally,
once daily.
What are the special considerations in this
clinical situation?

3. By the end of the class, MBBS
Ist year students will be able
to:
List the factors that can modify the action of a
drug
Describe the basis of modification of drug
action by various factors
Apply the information to modify the drug
prescription in clinical setting

4. Drug effects and race
Atropine/ephedrine to dilate pupil
Black population: higher concentration
Mongols: lower concentration
β blockers as antihypertensive
Afro-caribbeans: less effective
Chloramphenicol induced aplastic anaemia
Subacute myelo-optic neuropathy

5. Drug effects and genetics
All components of PK and PD are influenced
by genetic composition
Pharmacogenetics:
Study of genetic basis for variability in drug
response
Pharmacogenomics:
Use of genetic information to guide the
choice of drug and dose on an individual
basis

6. Drug effects and genetics
Genetic defects Drugs
implicated
Effects
Atypical
pseudocholinestera
se
Succinylcholine Prolonged
apnoea
G-6PD deficiency Primaquine,
chloroquine,
dapsone
Haemolysis
Low activity of
CYP2C9
Warfarin Increased
bleeding

7. Drug effects and genetics
Genetic
defects
Drugs
implicated
Effects
N-acetyl
transferase 2
polymorphism
Isoniazid,
hydralazine
Isoniazid
neuropathy,
Drug induced
lupus
CYP2D6
deficient
Codeine No analgesia
by codeine
Ryanodine
Receptor
Halothane Malignant
hyperthermia

8. Drug effects and
environment/time
Exposure to insecticides, tobacco smoke,
carcinogens  induce drug metabolism
Type of diet (fatty, non-fatty)
Time:
Drug ingestion and meals
Morning dosing: corticosteroids
Evening: statins
Night: hypnotics

9. Drug effects and psychological
factors
Efficacy of drug affected by patient’s
psychological state
More applicable for centrally acting drugs
Nervous and anxious patient: more general
anesthetics
Anxious state (fear of punishment):
performance may improve by alcohol

10. Drug effects and psychological
factors
Placebo:
Inert substance which is given as a medicine
Acts by psychodynamic means
Individuals who easily respond to placebo:
placebo reactors
Prescribed in two situations:
In clinical trials as dummy medicine
In clinical practice

11. Drug effects and psychological
factors
Placebo:
Lactose tablets/capsules, water injection
• Multivitamins – misused as placebo
Placebo effects highly variable
Nocebo:
Negative psychodynamic effect evoked by
the pessimistic attitude of the patient, or by
loss of faith in the medication and/or

12. Pathological states and Drug
effect
Gastro-intestinal tract affections:
Gastric stasis(migraine): Retards
absorption of ingested drugs.
Achlorhydria: decrease aspirin
absorption
Effects of gastro-intestinal disease can
be complex, e.g. in Coeliac disease:
Amoxicillin absorption decreased

13. Pathological states and Drug
effect
Liver disease:
Altered metabolism:
Prodrugs- less
effective
Increased
bioavailability of drugs
with high first pass
metabolism
Decreased metabolism
and elimination of

14. Pathological states and Drug
effect
Liver disease:
Decreased protein synthesis:
Altered serum albumin:
• Increased unbound fraction of acidic drugs
Decreased clotting factors:
• Increased activity of anti-coagulants

15. Pathological states and Drug
effect
Liver disease:
Pharmacodynamic alterations:
Sensitivity of brain to depressant action of
morphine and barbiturates in cirrhotics
Brisk diuresis by diuretics:
• Mental changes in patients with impending
hepatic encephalopathy

16. Pathological states and Drug
effect
Kidney disease:
Nephrotoxic drugs
Clearance of drug
decreases parallel to
creatinine clearance
Maintenance dose needs
to be modified
Decreased/low plasma
proteins

17. Pathological states and Drug
effect
Kidney disease:
Increased permeability of blood-
brain barrier
Increased activity of opioids,
barbiturates, benzodiazepines
Accumulation of
drugs/metabolite:
Pethidine  nor-pethidine 
seizure

18. Pathological states and Drug
effect
Congestive heart disease:
Decreased absorption from gastro-intestinal
tract
Procainamide, hydrochlorothiazide
Altered volume of distribution
(increase/decrease)
Lidocaine, procainamide
Slower drug elimination

19. Pathological states and Drug
effect
Thyroid disease:
Hypothyroidism:
More sensitive to digoxin,
morphine and CNS depressants
Hyperthyroidism:
Relative resistant to inotropic
action of digoxin, but more prone to
its arrhythmogenic action

20. Pharmacological variables and
Drug effect
Cumulation
Occurs when rate of
administration is more than
rate of elimination
Slowly eliminated drug
more likely to cause
cumulative toxicity
• Chloroquine  retinal
toxicity

21. Pharmacological variables and
Drug effect
Tolerance
Adaptive biological phenomenon
Can be:
• Natural: inherently less sensitive
• Acquired: occurs by repeated use of a
drug in an individual who was initially
responsive
More easily seen with CNS depressants

22. Pharmacological variables and
Drug effect
Tolerance
Tolerance for different effects of a drug can
vary
• Chlorpromazine: tolerance to sedative
action but not antipsychotic action
• Phenobarbitone: tolerance to sedative
action but less to antiepileptic actions
• Morphine: tolerance to constipation, miotic
action more

23. Pharmacological variables and
Drug effect
Tolerance
Cross tolerance
• Tolerance to pharmacologically related
substance
• Closer the drugs, more complete is the
tolerance
• Morphine-barbiturates vs morphine-
pethidine

24. Pharmacological variables and
Drug effect
Tachyphylaxis
Rapid development of tolerance when doses
of a drug repeated in quick succession result
in marked reduction in response
Seen with ephedrine, tyramine, nicotine

25. Pharmacological variables and
Drug effect
Drug resistance
Tolerance of micro-organisms to inhibitory
action of antimicrobials
Can be natural or acquired
• Natural: Cell wall of gram negative
bacteria
• Acquired: Mutation and Gene transfer

26. Pharmacological variable and
drug effects: Drug-Drug
Interaction
Synergism: Action of one drug is increased by
other drug
Can be:
Additive: Effect of two drug in the same
direction and simply adds up
Eg; Effect of drug A + Effect of drug B = Effect
of drug A + B
• Aspirin + Paracetamol = Analgesic/antipyretic
effect

27. Pharmacological variable and
drug effects: Drug-Drug
Interaction
Synergism: Action of one drug is increased by
other drug
Can be:
Supra-additive (potentiation): Effect of
combination of two drug is greater than the
individual effect of drugs
Effect of drug A + Effect of drug B < Effect of
drug A + B
• Sulfonamide + Trimethoprim effective against
wider range of bacteria

28. Pharmacological variable and
drug effects: Drug-Drug
Interaction
Antagonism:
Action of one drug is abolished by other
drug
 Effect of drug A + Effect of drug B > Effect of
drug A + B

29. Pharmacological variable and
drug effects: Drug-Drug
Interaction
Antagonism: Types
Physical antagonism
• Charcoal and alkaloids
Chemical antagonism
• Chelating agents, Nitrites
Physiological antagonism
• Glucagon and insulin on blood sugar level
Receptor antagonism

30. Pharmacological variable and
drug effects: Drug-Drug
Interaction
Antagonism: Types
Receptor antagonism
• One drug (antagonist) blocks the receptor
action of the other drug (agonist)
• Is selective
• Can be competitive or non-competitive

31. Pharmacological variable and
drug effects: Drug-Drug
Interaction
 Competitive equilibrium: Acetylcholine & Atropine
 Non-equilibrium: Phenoxybenzamine + adrenaline
(α receptors)

32. Pharmacological variable and
drug effects: Drug-Drug
Interaction
 Non-competitive antagonism (allosteric
antagonism):
 Diazepam & Bicuculline

33. Post-Test
A 40-year female patient was diagnosed as a
case of tuberculosis and was started on first
line antitubercular drugs.
Later she presented to follow-up OPD
complaining about tingling sensation over her
hands and feet. This could have been due to:
What could be the reason for this complain?

34. Conclusion
Modification of drug action can occur due to
multitude of reasons affecting each step from
the drug being prescribed to the effects of
drugs on the patient
Factors can be physiological, psychological,
genetic, pathological, environmental,
pharmacological
Choice of drug and the dose of drug needs to
be modified if any of these factors are present
in an individual

35. Next class…
Tuesday, 19 December (11am -12 pm)
Topics:
Adverse Drug Reaction
Any queries?
Thank you!