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Dr. RAGHU PRASADA M S
MBBS,MD
ASSISTANT PROFESSOR
DEPT. OF PHARMACOLOGY
SSIMS & RC.
1
1. Alteration in concentration of drug that reaches the
receptor-age, weight, sex, disease states,
MDR(Multi-Drug Resistan...
1. Body size
2. Age – pediatric &
geriatric
3. Sex
4. Species and race
5. Genetics –P’genomics
and P’genetics
6. Routes of...
Influences the concentration of drug
Attained at the site of action
Average adult dose for – medium built
For ext. Obese o...
Body surface area (BSA) provides a more
Accurate basis for dose calculation
Individual dose = BSA (m2)/1.7 χ av. Adult Dos...
Solid dosage forms and aerosol inhalation are difficult
to administer to young children .
Many drugs prepared for children...
Dose calculation
Young’s formula –
child dose = age /age + 12 χ adult dose
Dilling’s formula –
child dose = age/20 χ adult...
Chloramphenicol-gray baby syndrome
Rectal diazepam
Theophylline, phenytoin, carbamazepine- shorter t1/2
Elderly- renal fun...
Females- lesser body surface area
Digoxin in women
Antihypertensives- clonidine, methyl dopa, beta
blocker and diuretics
Pharmacogenetics –the study of genetic basis for
variability in drug response
Human genome project
Pharmacogenomics-it is ...
G‐6 pd deficiency – Hemolysis with primaquine and
other oxidizing drugs like sulphonamides, Dapsone,
quinine, chloroquine,...
Differences in target organ sensitivity
The low activity of CYP2C9 variants metabolize
warfarin at a slow rate and are at...
GENE PRODUCT DRUGS RESPONSES AFFECTED
N-Acetyl transferase(NAT2) Isoniazid, hydralazine,
sulfonamides,
procainamide, dapso...
GENE RESPNSE DRUGS RESPONSE AFFECTED
Angiotensin converting
enzyme inhibitor(ACE)
Enalapril Renoprotective effect,
hypoten...
Differences in responsiveness to drugs
Among different species ‐
Rabbits are resistant to atropine
Rats & mice to digitali...
Governs the speed and intensity of drug
response.
Use & action may vary with route,
e.g. magnesium sulfate ‐given orally c...
Exposure to insecticides , carcinogens, tobacco smoke ,
charcoal broiled meat induce drug metabolism.
Type of diet can alt...
Most drugs can cross the placenta and
Expose the developing embryo and fetus
to their pharmacologic and teratogenic effect...
Distribution characteristics in different Fetal tissues.
Stage of placental and fetal development at the time of
exposure ...
Drug’s efficacy can be affected by Patient’s
expectations and attitude .
Anxious patient requires more general anesthetic
...
Placebo- this is an inert substance which is given in the
garb of medicine.
MOA-It works by psychodynamic rather than
phar...
GI disease- in coeliac disease the absorption of
amoxicillin is decreased but that of cephalexin and
cotrimoxazole is incr...
Protein binding of acidic drugs-if serum albumin is
reduced then more drug is present in free form
Metabolism and eliminat...
Aminoglycoside, phenobarbitone, digoxin –clearance of
drugs primarily excreted unchanged in urine is reduced
parallel to d...
Decreasing drug absorption from GIT due to mucosal
edema and splanhnic vasoconstriction.
Ex-Procainamide, hydrochlorthiazi...
Hypo thyroid patients are more sensitive to digoxin,
morphine and CNS depressants
Hyperthyroid patients are more sensitive...
Antipyretic drugs can lower body temperature only
when it is raised
Thiazides induce more marked diuresis in edematous
pat...
Head injury patients are prone to go into respiratory
failure with normal doses of morphine
Atropine, imipramine, furosemi...
Any drug can accumulate in the body if the rate of
administration is more than the rate of elimination
A course of emetine...
Requirement of higher dose of a drug to produce a given
response.
Natural ‐ inherently less sensitive to the drug
rabbits ...
Tolerance develops to sedative action of
chlorpromazine but not to its antipsychotic action
Tolerance occurs to the sedati...
Pharmacokinetic/drug disposition- the effective
concentration of the drug at the site of action is
decreased, mostly due t...
Development of tolerance to pharmacologically
related drugs.
Alcoholics to barbiturates.
Closer the drugs, more complete i...
Rapid development of tolerance ‐ doses of a drug
repeated in quick succession result in marked
reduction in response.
Usua...
Therapeutic methods Tachyphylaxis –acute Tolerance -chronic
Clinical practice Rarely seen, as the
drug administration is
n...
Natural-mycobacterium tuberculi are insensitive to
tetracyclines
Acquired-Tolerance of micro‐organisms to
Inhibitory actio...
Class factors modifying drug action
Class factors modifying drug action
Class factors modifying drug action
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Class factors modifying drug action

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Class factors modifying drug action

  1. 1. Dr. RAGHU PRASADA M S MBBS,MD ASSISTANT PROFESSOR DEPT. OF PHARMACOLOGY SSIMS & RC. 1
  2. 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. 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
  4. 4. 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
  5. 5. 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
  6. 6. 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
  7. 7. 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
  8. 8. 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
  9. 9. Females- lesser body surface area Digoxin in women Antihypertensives- clonidine, methyl dopa, beta blocker and diuretics
  10. 10. 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
  11. 11. 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.
  12. 12. 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
  13. 13. 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
  14. 14. 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
  15. 15. 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
  16. 16. 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
  17. 17. 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
  18. 18. 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
  19. 19. 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
  20. 20. 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
  21. 21. 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
  22. 22. 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
  23. 23. 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
  24. 24. 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
  25. 25. 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
  26. 26. 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
  27. 27. 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
  28. 28. 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
  29. 29. 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
  30. 30. 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
  31. 31. 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
  32. 32. 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
  33. 33. 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
  34. 34. 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
  35. 35. 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
  36. 36. 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
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