Transcript factors modifying drug action

FACTORS MODIFYING DRUG
ACTION
DR NARENDRA KUMAR
FACTORS MODIFYING DRUG ACTION
I.
II.
III.
IV.
V.
Physiological Factors.
Pathological Factors (Diseases).
Genetic Factors.
Environmental Factors.
Interaction with other drugs.
I. Physiological Factors
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Age
Sex
Pregnancy
Body weight
Lactation
Food
Physiological Factors
1. AGE
Newborn
– ↓ gastric acid secretion.
– ↓ liver microsomal enzymes (glucuronyl
transferase).
– ↓ Plasma protein binding.
– ↓ GFR & tubular secretion.
– Immaturity of BBB in neonates.
• GIT absorption of ampicillin and
amoxicillin is greater in neonates due to
decreased gastric acidity.
• Chloramphenicol ----- Grey baby syndrome
Inadequate glucouronidation of
chloramphenicol with drug accumulation.
• Sulfonamides ------ Hyperbilirubinemia
Kernicterus
&
CHILDREN
• Tetracyclines
Permanent teeth staining
• Corticosteroids
Growth & development retardation
• Antihistaminics
Hyperactivity
Old Age
– ↓ Liver function
diazepam, theophylline.
– ↓ Kidney function
Gentamycin ,Digoxin ,Pencillins are contraindicated in old
people.
– ↓ Plasma protein binding
– ↑ sensitivity to CNS depressants
diazepam, morphine
2. SEX
• Testosterone increases the
biotransformation of drugs.
rate
of
• Decreased metabolism of some drugs in
female (Diazepam).
• Females are more susceptible to autonomic
drugs ( estrogen inhibits choline estrase).
3. Pregnancy
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↑ Cardiac output
↑ GFR and renal elimination of drugs
↑ Vd
↑ Metabolic rate of some drugs
Lipophilic drugs cross placental barrier &
slowly excreted.
II. Pathological Factors
Diseases cause individual variation in drug
response
– ↓ Plasma protein binding for warfarin,
tolbutamide → adverse effects.
– ↓ Hepatic blood flow → ↓ clearance of
morphine-propanolol.
– Impaired liver microsomal enzymes
↓ Diazepam-rifampicin-theophylline
(B) Renal Disease
– ↓GFR.
– ↓tubular function.
– ↓Plasma albumin
↓excretion of digoxin-lithium-gentamycinpenicillin.
(C) Malnutrition
– ↓plasma protein binding of drugs.
– ↓amount of microsomal enzymes.
– ↑Increases portion of free, unbound drug
e.g. warfarin
III. Genetic Factors GENETIC POLYMORPHISM
The existence in a population of two or more
phenotype with respect to the effect of a drug.
e.g. Acetylation enzymes deficiency
• Acetyl transferase (non-microsomal).
(SHIP)
Sulphonamides, Hydralazine, Isoniazid,
Procainamide etc. metabolized by
acetylation.
• Slow acetylator phenotype → peripheral
neuropathy in INH .
• Rapid acetylator phenotype can decrease
effect of drug.
Pseudocholinesterase deficiency
• Succinyl choline ( Sk.muscle relaxant )
→ Succinylcholine
apnea due to
paralysis of respiratory muscles.
Malignant hyperthermia
• By succinyl choline due to inherited inability
to chelate calcium by sarcoplasmic reticulum.
• ↑ Ca release, muscle spasm, ↑ Temp.
Deficiency of Glucose–6 phosphate
dehydrogenase (G-6-PD).
G-6-PD Deficiency in RBCs → hemolytic
anemia upon exposure to some oxidizing
drugs.
–Antimalarial drug, primaquine.
–Long acting sulphonamides.
IV. Environmental Factors
Microsomal Enzyme Inducers
– Tobacco Smoke
– Smokers metabolize drugs more rapidly
than non smoker.
ADVERSE DRUG EFFECTS
Undesirable or harmful effects which
can occur at therapeutic doses and
need a reduction of dose or drug
withdrawal .
• Nausea and vomiting
• Deafness with gentamycin
• Death with penicillin
Types of adverse drug reactions
A, B, C, D and E
1) Type A reactions
–Excessive therapeutic effect
–Side effects
I) Type A reactions
– Common
– 75 % of all adverse reaction
– Related to pharmacological actions
– Dose-dependent
– Predictable
– Can be avoided by adjusting the dosage regimen
– Most of them are reversible upon stopping drug
e.g.
Hypotension (antihypertensives)
Hypoglycemia (insulin)
Type A reactions
1. Excessive therapeutic effect Unwanted
effects related to the main pharmacological
actions of the drug that occur when the drug
produce greater therapeutic effect than is
necessary.
• Warfarin → Anticoagulant → Bleeding
• Insulin → Normoglycemia → Hypoglycemia
2. SIDE EFFECTS
Unwanted effects unrelated to the main
pharmacological actions of the drug but due
to other normal actions of the drug.
e.g. Morphine cause constipation during its
use as analgesic.
II) Type B reactions
–Are bizarre reactions
–Not related to the normal pharmacological
actions of the drug.
–Unpredictable
–Not dose-related.
–Occur only in minority of patients.
Types
–Allergic reactions (Hypersensitivity )
–Genetic disorders (Idiosyncrasy)
Type B
1) Hypersensitivity ( allergic reactions)
Abnormal response to the drug due to
antigen-antibody reactions e.g. Penicillin
• Allergic response to a drug
• Rashes, hypotension and bronchospasm
(anaphylactic reaction)
Types of allergic reactions
• Type –I/ immediate type/acute hypersensitivity/anaphylatic –
Ig E mediated
• Type -II reaction/cytotoxic reaction – damage of cells e.g.
haemolytic anemia due to methyldopa or penicillin.
• Type- III/immune complex mediated- antigen antibody react
to make immune complex which is engulfed by leukocytes and
initiate inflammatory process- e.g. serum sickness,
nephropathy and vasculitis.
• Type IV/delayed hypersensitivity/cell mediated- occurs 2-3
days after exposure to antigen- T lymphocytes are involvede.g. contact dermatitis, urticarial rash and fever.
Type B
2) Idiosyncrasy
is abnormal response to the drug due to
genetic disorders.
•Succinylcholine apnea
•Malignant hyperthermia
•Porphyria
SECONDARY EFFECTS
• Unwanted effects that occur secondary to the
wanted actions of the drug.
• Overgrowth of microorganisms following use
of broad spectrum antibiotics
e.g. Pseudomembranous colitis
Type C reactions ( Continuous reaction)
–
Due to long term use e.g. NSAIDs
analgesic nephropathy
Type D reactions (Delayed adverse reactions)
Teratogenesis
Is congenital malformations occurring in the
fetus due to exposure to drugs during
pregnancy
e.g. Thalidomide → Phocomelia
Carcinogenesis
Ability of some substances to induce cancer.
e.g. Stilbesterol → adenocarcinoma of vagina in
female off springs.
Mechanisms
1. DNA alteration
Griesofulvin & alkylating cytotoxics
2. Immunosuppression
immunosuppressant increase incidence of cancer
e.g. organ transplantation & rheumatoid arthritis
3. Hormonal
long term use of estrogen replacement in PMW
induce endometrial cancer
Type E reactions (Ending of drug)
• Sudden discontinuation ( abrupt withdrawal).
• Rebound adrenal insufficiency
e.g. Corticosteroids
• Antihypertensive
• Antiepileptics
Treatment of drug allergy
• The offending drug must be immediately stopped.
• Most mild reactions (like skin rashes) subside by
themselves and do not require specific treatment.
• Antihistamines (H1) are beneficial in some type I
reactions (urticaria, rhinitis, swelling of lips, etc.) and
some skin rashes.
Treatment of drug allergy
• In case of anaphylactic shock or angioedema of larynx the
resuscitation council of UK has recommended the
following measures:
• Put the patient in reclining position, administer oxygen at high
flow rate and perform cardiopulmonary resuscitation if
required.
• Inject adrenaline 0.5 mg (0.5 ml of 1 in 1000 solution) i.m.
• Repeat every 5-10 min in case patient does not improve or
improvement is transient. This is the only life saving measure.
Treatment of drug allergy
• Adrenaline should not be injected i. v. (can itself be
fatal) unless shock is immediately life threatening.
• If adrenaline is to be injected i.v., it should be diluted to
1:10,000 or 1:100,000 and infused slowly with
constant monitoring.
• Administer a H1 antihistaminic (chlorpheniramine
10-20 mg) i.m./slow i.v. lt may have adjuvant value.
Treatment of drug allergy
• Intravenous glucocorticoid
(hydrocortisone sod.
succinate 100-200 mg) should be added in
severe/recurrent cases.
• Intravenous glucocorticoid acts slowly, but is specially
valuable for prolonged reactions and in asthmatics.
• Glucocorticoids are the only drug effective in type II,
type III and type IV reactions.
Photosensitivity
• It is a cutaneous reaction resulting from drug induced
sensitization of the skin to UV radiation.
• Phototoxic Drug or its metabolite accumulates in the skin,
absorbs light and undergoes a photochemical reaction resulting
in local tissue damage (sunburn-like), i.e. erythema, edema,
blistering followed by hyperpigmentation and desquamation.
• The shorter wave lengths (290-320 nm, UV-B) are responsible.
•
Drugs involved in acute phototoxic reactions are tetracyclines
(especially demeclocycline) and tar products.
Photosensitivity
• Photoallergic Drug or its metabolite induces a cell mediated
immune response which on exposure to light of longer wave
lengths (320- 400 nm, UV -A) produces a papular or
eczematous contact dermatitis like picture.
• Drugs involved are sulfonamides, sulgriseofulvin,
chloroquine, chlorpromazine.
fonylureas,
Drug dependence
• Psychological dependence
• Physical dependence
• Drug abuse
Drug interactions
• It is the modification of the effect of one drug
(the object drug ) by the prior or concomitant
administration of another (precipitant drug).
Outcomes of drug interactions
1)
2)
3)
4)
Loss of therapeutic effect
Toxicity
Unexpected increase in pharmacological activity
Beneficial effects e.g. additive & potentiation
(intended) or antagonism (unintended).
5) Chemical or physical interaction
e.g. IV incompatibility in fluid or syringes mixture
Mechanisms of drug interactions
Pharmacokinetics
Involve the effect of a
drug on another from the
point of view that
includes absorption
,distribution , metabolism
and excretion.
Pharmacodynamics
Are related to the
pharmacological activity
of the interacting drugs
e.g. synergism,
antagonism, altered
cellular transport, effect
on the receptor site.
Pharmacodynamic interactions
1. Excessive sedation, respiratory depression, motor
incoordination due to concurrent administration of a
benzodiazepine,
a
sedating
antihistaminic
(promethazine), a neuroleptic (chlorpromazine), an
opioid (morphine) or drinking alcoholic beverage while
taking any of the above drugs.
2. Fall in BP and fainting due to concurrent administration
of α1 adrenergic blockers, vasodilators, ACE inhibitors,
high ceiling diuretics and cardiac depressants.
Pharmacodynamic interactions
• Pronounced and asymptomatic hypoglycaemia can
occur when propranolol is administered to diabetics
receiving insulin/ sulfonylureas, due to blockade of
β adrenoceptors which contribute to recovery from
hypoglycaemia as well as some hypoglycaemic
symptoms.
• Increased risk of bleeding due to concurrent use of
antiplatelet drugs (aspirin, clopidogrel) with
anticoagulants (warfarin).
Pharmacodynamic interactions
5. Severe hyperkalaemia by concurrent use of ACE
inhibitors and K+ sparing diuretics.
6. Additive ototoxicity due to use of an aminoglycoside
antibiotic in a patient receiving furosemide.
7. Antagonism of bactericidal action of β lactam
antibiotic by combining it with a bacteriostatic drug
like tetracycline, erythromycin or clindamycin.
Drug interactions before administration
• Certain drugs react with each other and get inactivated if their solutions
are mixed before administration.
• In practical situations, these in vitro interactions occur when injectable
drugs are mixed in the same syringe or infusion bottle. Some examples
are:
1. Penicillin G or ampicillin mixed with gentamicin or another
aminoglycoside antibiotic.
2. Thiopentone sodium when mixed with succinylcholine or
morphine.
3. Heparin when mixed with penicillin/ gentamicin/hydrocortisone.
4. Noradrenaline when added to sodium bicarbonate solution.
• In general, it is advisable to avoid mixing of any two or more parenteral
drugs before injecting.
Fixed dose ratio combination preparations
Advantages
1. Convenience and better patient compliance
2. Certain drug combinations are synergistic, e.g.
sulfamethoxazole + trimethoprim
levodopa + carbidopa/benserazide
combination oral contraceptives.
3. The therapeutic effect of two components being same may add up while the
side effects being different may not, e.g. amlodipine + atenolol as
antihypertensive.
4. The side effect of one component may be counteracted by the other, e.g.
a thiazide + a potassium sparing diuretic.
5. Combined formulation ensures that a single drug will not be administered.
This is important in the treatment of tuberculosis and HIV-AIDS.
DISADVANTAGES OF FIXED DOSE RATIO COMBINATIONS
1. The patient may not actually need all the drugs present in a combination: he is
subjected to additional side effects and expenses.
2. The dose of most drugs needs to be adjusted and individualised. When a combined
formulation is used, this cannot be done without altering the dose of the other
component(s).
3. The time course of action of the components may be different: administering them at
the same intervals may be inappropriate.
4. Altered renal or hepatic function of the patient may differently affect the
pharmacokinetics of the components.
5. Adverse effect, when it occurs, cannot be easily ascribed to the particular drug
causing it.
6. Contraindication to one component (allergy, other conditions) contraindicates the
whole preparation.
7. Confusion of therapeutic aims and false sense of superiority of two drugs over one is
fostered, specially in case of antimicrobials whose combinations should be avoided.
8. Corticosteroids should never be combined with any other drug meant for internal use.
Bibliography
• Essentials of Medical Pharmacology -7th edition by KD Tripathi
• Goodman & Gilman's the Pharmacological Basis of Therapeutics 12th
edition by Laurence Brunton (Editor)
• Lippincott's Illustrated Reviews: Pharmacology - 6th edition by Richard A.
Harvey
• Basic and Clinical pharmacology 11th edition by Bertram G Katzung
• Rang & Dale's Pharmacology -7th edition
by Humphrey P. Rang
• Clinical Pharmacology 11th edition By Bennett and Brown, Churchill
Livingstone
• Principles of Pharmacology 2nd edition by HL Sharma and KK Sharma
• Review of Pharmacology by Gobind Sparsh