this class is in brief for understanding and examination of under graduate students

1. Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.
1

2. 1. Alteration in concentration of drug that reaches the
receptor-age, weight, sex, disease states,
MDR(Multi-Drug Resistance genes)
2. Variation in concentration of an endogenous
receptor ligand-pharmacological antagonists-
propranolol, Saralasin
3. Alteration in number and function of receptor-
thyroid hormone and β receptor, agonist(DR),
antagonist(UR)
4. Changes in the components of response distal to
the receptor-vasodilator drugs

3. 1. Body size
2. Age – pediatric &
geriatric
3. Sex
4. Species and race
5. Genetics –P’genomics
and P’genetics
6. Routes of drug
administration
7. Pregnancy & Lactation
8. Physiological states– GI
diseases,congestive heart
disease, thyroid disease,
kidney & liver disease
9. Diet &Environmental
factors
10. Psychological factors
11. Cumulation
12. Tolerance & resistance

5. Influences the concentration of drug
Attained at the site of action
Average adult dose for – medium built
For ext. Obese or lean individual –
individual dose = bw(kg)/70 χ average
Adult dose

6. Body surface area (BSA) provides a more
Accurate basis for dose calculation
Individual dose = BSA (m2)/1.7 χ av. Adult Dose
BSA(m2) = bw(kg)0.425 χ height(cm)0.725 χ 0.007184
Obtained from chart form or slide
Rule nomograms based on bw and
Height. Avail. For some drugs

7. Solid dosage forms and aerosol inhalation are difficult
to administer to young children .
Many drugs prepared for children are in the form of
elixirs or suspensions.
Elixirs are alcoholic solutions in which the drug
molecules are dissolved and evenly distributedno
shaking is required.
Suspensions contain dissolved particles of drug that
must be distributed throughout the vehicle by shaking

8. Dose calculation
Young’s formula –
child dose = age /age + 12 χ adult dose
Dilling’s formula –
child dose = age/20 χ adult dose
Body surface area

9. Chloramphenicol-gray baby syndrome
Rectal diazepam
Theophylline, phenytoin, carbamazepine- shorter t1/2
Elderly- renal function
slower absorption
Lesser plasma protein binding
Decrease in the volume of distribution

10. Females- lesser body surface area
Digoxin in women
Antihypertensives- clonidine, methyl dopa, beta
blocker and diuretics

11. Pharmacogenetics –the study of genetic basis for
variability in drug response
Human genome project
Pharmacogenomics-it is the use of genetic information
to guide the choice of drug and dose on individual
basis
Specific gene defects
can lead to variation in drug responses ‐
e.g. Atypical pseudo‐cholinesterase ‐ prolonged
succinylcholine induced apnoea

12. G‐6 pd deficiency – Hemolysis with primaquine and
other oxidizing drugs like sulphonamides, Dapsone,
quinine, chloroquine, Nalidixic acid, nitrofurantoin
Acute intermittent porphyria- precipitated by
barbiturates is due to genetic defect in repression of
porphyrin synthesis
Dose of a drug to produce the same effect may vary by
4‐6 fold among different individuals because of ‐
different rate of metabolism‐ due to difference in
the amount and isoform pattern of drug metabolizing
enzymes which is genetically controlled.

13. Differences in target organ sensitivity
The low activity of CYP2C9 variants metabolize
warfarin at a slow rate and are at higher risk of
bleeding
Slow acetylators- polymorphism at NAT2 (N-acetyl
transfrase 2) gene results in rapid and slow acetylator
status

14. GENE PRODUCT DRUGS RESPONSES AFFECTED
N-Acetyl transferase(NAT2) Isoniazid, hydralazine,
sulfonamides,
procainamide, dapsone
Hypersensitivity to
sulfonamides, hydralazine
induced lupus, isoniazid
neurotoxicity
Glutathione
transferases(GSTM1)
Anticancer agents Decreased response in breast
cancer, more toxicity in AML
Thiopurine Methyl
Transferase(TPMT)
Mercaptopurine,
Azathioprine
Thiopurine toxicity
COMT Levodopa Enhanced drug effect
Organic cation transporter
(OCT1, OCT2)
Metformin Pharmacokinetic, renal
clearance
Novel organic cation
tranporter(OCTN1)
Gabapentin Renal clearance
CYP2B6 Cyclophosphamide Ovarian failure

15. GENE RESPNSE DRUGS RESPONSE AFFECTED
Angiotensin converting
enzyme inhibitor(ACE)
Enalapril Renoprotective effect,
hypotension, cough
Β2adrenergic
receptor(ADBR1)
B2 antogonists-albuterol,
terbutaline
Bronchodilation,
peripheral vasodilation
5-lipoxygenase(ALOX5) Leukotreine receptor
antogonists
Asthma response
Dopamine
receptors(D1,D2,D3)
Antipsychotics-
haloperidol, clozapine
Antipsychotic response,
tardive dyskinesia
Vitamin K oxidoreductase
(VKORC1)
Warfarin Anticoagulant effect,
bleeding risk
Corticotropin releasing
hormone receptor(CRHR1)
Glucocorticoids Bronchodilation, ostepenia
Vitamin D receptor Estrogen Bone mineral density

16. Differences in responsiveness to drugs
Among different species ‐
Rabbits are resistant to atropine
Rats & mice to digitalis
Imp. to know while extrapolating results from
experimental animals to man
Racial differences in human beings ‐
Blacks require higher and
Mongols require lower conc. of atropine & Ephedrine
to dilate the pupil

17. Governs the speed and intensity of drug
response.
Use & action may vary with route,
e.g. magnesium sulfate ‐given orally causes purgation
Applied on inflamed areas - ↓ses swelling
I.V. – produces CNS depression and hypotension

18. Exposure to insecticides , carcinogens, tobacco smoke ,
charcoal broiled meat induce drug metabolism.
Type of diet can alter drug absorption set up in which
drug is taken – hypnotics work better when taken at
night in quiet surroundings

19. Most drugs can cross the placenta and
Expose the developing embryo and fetus
to their pharmacologic and teratogenic effects .
As a rule we try to avoid drugs during pregnancy, if
possible. Factors affecting placental drug transfer and
drug effects on fetus
The physicochemical properties of drug.
Rate at which drug crosses the placenta
And amount of drug reaching the fetus.
Duration of exposure to drug

20. Distribution characteristics in different Fetal tissues.
Stage of placental and fetal development at the time of
exposure to drug.
Drug passage across the placenta is dependent on
Lipid solubility and Degree of drug ionization .
Lipophilic drugs diffuse readily across
The placenta and enter the fetal circulation
For example‐ thiopental , drug used for
Cesarean Section (CS) crosses the placenta almost
immediately and can produce sedation or apnea in
newborn

21. Drug’s efficacy can be affected by Patient’s
expectations and attitude .
Anxious patient requires more general anesthetic
PLACEBO “I will please”- relieves symptoms of illness
by creating expectations for the good
NOCEBO “I will harm” harms by creating a panic or
fear for nothing, nocebo reactors are usually
pessimistic persons whose symptoms of illness do not
respond to medications

22. Placebo- this is an inert substance which is given in the
garb of medicine.
MOA-It works by psychodynamic rather than
pharmacodynamic means and produces response
equal to active drug
USES-As a control device in clinical trial of drugs
To treat a patient who, in the opinion of physician does
not require active drug

23. GI disease- in coeliac disease the absorption of
amoxicillin is decreased but that of cephalexin and
cotrimoxazole is increased
Aclorohydria decreases aspirin absorption by favoring
its ionization
NSAIDs can aggravate peptic ulcer disease
Liver disease-liver disease can influence drug
disposition in several ways-
Bioavailability of drugs having high first pass
metabolism is increased due to loss of hepatocellular
function and portocaval shunting

24. Protein binding of acidic drugs-if serum albumin is
reduced then more drug is present in free form
Metabolism and elimination of some drugs- morphine,
lidocaine and propranolol
Prodrugs needing hepatic metabolism for activation –
bacampicillin are less effective
Cirrhotics –sensitivity of brain to depressant action of
morphine and barbiturates is markedly increased
Low clotting factors- increased prothrombin time

25. Aminoglycoside, phenobarbitone, digoxin –clearance of
drugs primarily excreted unchanged in urine is reduced
parallel to decrease in creatinine clearance
Permeability of blood brain barrier is increased in renal
failure-opiates, barbirturates, phenothiazines,
benzodiazepines, produce more CNS depression
Tetracyclines have an anti-anabolic effect and accentuate
uraemia
NSAIDs cause more fluid retention
Neprotoxic drugs-aminoglycosides, tetracyclines,
sulfonamides, vancomycin, nitrofurantoin, cyclosporine,
amphotericin-B- should be avoided

26. Decreasing drug absorption from GIT due to mucosal
edema and splanhnic vasoconstriction.
Ex-Procainamide, hydrochlorthiazide
Volume of distribution is altered –loading dose of
lignocaine should be reduced
Retarding drug elimination as a result of decreased
perfusion and congestion of liver-dosing of drugs
should be reduced in lignocaine, theophylline

27. Hypo thyroid patients are more sensitive to digoxin,
morphine and CNS depressants
Hyperthyroid patients are more sensitive to arrhythmic
action of digoxin and less sensitive to inotropic action

28. Antipyretic drugs can lower body temperature only
when it is raised
Thiazides induce more marked diuresis in edematous
patients
Myocardial infarction patients are more sensitive to
adrenaline and digitalis induced cardiac arrhythmias
Myasthenics are very sensitive to curare, and in them
weakness is aggravated by quinine
Schizophrenics tolerate large doses of phenothizines

29. Head injury patients are prone to go into respiratory
failure with normal doses of morphine
Atropine, imipramine, furosemide, can cause urinary
retention in individuals with prostatic hypertrophy
Hypnotics given to a patient in severe pain may cause
mental confusion and delirium
Cotrimoxazole produces a higher incidence of adverse
reactions in AIDS patients

30. Any drug can accumulate in the body if the rate of
administration is more than the rate of elimination
A course of emetine should not be repeated within 6
weeks
Loading dose of digoxin is not needed with in one
week

31. Requirement of higher dose of a drug to produce a given
response.
Natural ‐ inherently less sensitive to the drug
rabbits are tolerant to atropine
black races are tolerant to mydriatics
Acquired – by repeated use of a drug in an individual
who was initially responsive. A continuous presence of
drug in the body leads to tolerance
Exceptions –atropine, cocaine, sodium nitroprusside

32. Tolerance develops to sedative action of
chlorpromazine but not to its antipsychotic action
Tolerance occurs to the sedative action of
phenobarbitone but not as much to antiepileptic
action
Tolerance occurs to analgesic and euphoric action of
morphine, but not to constipating and miotic actions

33. Pharmacokinetic/drug disposition- the effective
concentration of the drug at the site of action is
decreased, mostly due to enhancement of drug
elimination on chronic use- barbiturates and
carbamazepine induce their own metabolism, while
renal excretion of amphetamine is accelerated after
regular intake
Pharmacodynamic/cellular tolerance- drug action is
lessened, cell of target organ become less responsive
Eg- morphine, barbiturates, nitrates—desensitization/
down regulation of receptors

34. Development of tolerance to pharmacologically
related drugs.
Alcoholics to barbiturates.
Closer the drugs, more complete is the tolerance
Partial tolerance between morphine and barbiturates
But complete tolerance between morphine and
pethidine

35. Rapid development of tolerance ‐ doses of a drug
repeated in quick succession result in marked
reduction in response.
Usually seen with indirectly acting
drugs e.g. Ephedrine , tyramine -which act
by releasing catecholamines in the body ,
Synthesis can’t match release when doses given in
quick succession, stores get depleted

37. Therapeutic methods Tachyphylaxis –acute Tolerance -chronic
Clinical practice Rarely seen, as the
drug administration is
never done in quick
succession
Can be seen
Tolerance develops
slowly and is seen with
intermittent dosing
schedule
Original effect of is not
possible as there is
exhaustion of
mediators or due to
faster desensitization
of the receptors
Effect can still be
obtained by increasing
the dose

38. Natural-mycobacterium tuberculi are insensitive to
tetracyclines
Acquired-Tolerance of micro‐organisms to
Inhibitory action of antimicrobials.
E.g. Staphylococcus to penicillin G
Cross tolerance- sulfonamides