Download FACTORS MODIFYING DRUG EFFECTS

FACTORS MODIFYING
DRUG EFFECTS
BY
Dr. Abdul Latif Mahesar
Medical pharmacology
King Saud University 2008

Individuals respond differently to drugs both from time to time and from
other individuals.

Some would show less than the usual response , most would show the
unusual response
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and some would show more than usual response
FACTORS
Physiological
Pathological
Genetic
Environmental
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PHYSIOLOGICAL FACTORS:
Age
Sex
Pregnancy
Body weight
PATHOLOGICAL FACTORS
Diseases of liver and kidney
Malnutrition
GENETIC FACTORS
Slow acetylators
Fast acetylators
G-6-phosphate dehydrogenase deficiency
Deficiency of pseudocholinestrase
Malignant hyperthermia
ENVOIRNMENTAL FACTORS
Smoking
Alcohol
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AGE
In new born there is
Decreases acid secretion (gastric secretion )
Decreased microsomal enzymes (glucuronyltransferase)
Decreased plasma protein binding
Decreased G.F.R and tubular secretions
Immature blood brain barrier.
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Due decreased gastric acidity absorption of ampicillin and
amoxicillin is greater in neonates.
Tetracyclines produce teeth staining in children
Corticosteroids cause growth and developmental
retardation
Antihistamines cause hyperactivity instead of hypoactivity.
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Several enzymes are important for drug metabolism , ( hepatic
microsomal oxidase, glucuronyl and acetyl transferase) have
low activity in neonates
Certain drugs may lead to serious consequences
chloramphenicol causing gray baby syndrome.
sulphonamides causing kernicterus
Activity of hepatic microsomal enzyme also
decreases with age leading prolonged half life of
some drugs.
Benzodiazepines, theophyllines
This may lead to accumulation of drug on repeated doses.
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Drug elimination is less efficient in new born babies , and in old
people so that drug produces greater and more prolonged
effects at extremes of age , especially drugs which are excreted
through kidneys as GFR is reduced.
Tubular function is also diminished.
e.g. Normal plasma half life of gentamicin is 1-4 hrs, in
babies it is 10 hrs and in premature babies it may be up to 18
hrs.
G.F.R declines to 25% ,in person of 50 years of age and 50%
in person 75 years of age.
gentamycin ,Digoxin ,pencillin are contraindicated in old people.
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PREGNANCY:
causes several physiological changes that influence drug disposition.
Volume of distribution is increased
Metabolic rate is increased due to placenta.
Maternal plasma albumin concentration is reduced
Cardiac out put is increased, leading to increased renal blood flow and
glomerular filtration and increased renal elimination of drugs.
Lipophilic molecules readily traverse placental barrier. Drugs that are
transferred to fetus are slowly eliminated.
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Sex
Testosterone increases the rate of metabolism in males
benzodiazepines decrease metabolism of some drugs in females
females are more susceptible to autonomic drugs drugs ( estrogen
inhibits choline estrase)
Body weight
People with more weight and larger body surface require larger dose of
the drug to produce required therapeutic effect.
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PATHOLOGICAL FACTORS
Certain diseases of kidneys ,liver and other systems
can cause individual variations in drug response.
Pharmacokinetic variations;
Changes in Absorption:
Gastric stasis (Migraine)
Malabsorption (Pancreatic insufficiency)
Drug absorption is incomplete in pts with malabsorption, edema
of ileal mucosa due to heart failure or nephrotic syndrome.
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In nephrotic syndrome plasma albumin is reduced, this
alters disposition and protein binding
Diarrhea increases the motility of the gut and decreases
absorption.
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Distribution:
altered plasma protein binding ( binding of penytoin in
chronic renal failure decreases
Impaired blood brain barrier ( infiltration of Penicillin
in to meningitis increases
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Metabolism:
of drugs is decreased in Chronic liver disease ,altering
the drug effects
Excretion:
Acute and chronic renal failure ,concentration of drugs is
altered.
Hypothermia reduces clearance of many drugs in elderly .
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Pharmacodynamics variations:
Change in receptors (Myasthenia gravis)
Increased sensitivity of adrenergic
receptors in hyperthyroidism.
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Genetic factors:
Acetylator status ( to isoniazid causing peripheral neuropathy)
hepatotoxicity in fast acetylators
Defective carbon oxidation
Pseudocholine estrase defeciency Failure to rapid
inactivation of Suxamethonim, leading to muscular block
,results paralysis.
G6PD deficiency: ( haemolysis by primaquine) G6PD is
necessary to maintain reduced glutathione in red cells and to
prevent their hemolysis.
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Hepatic porphyria
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Polymorphism
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Malignant hyperthermia: (by suxamethonium due to
inherited abnormality in Ca 2+ release from
sarcoplamic reticulum in striated muscles.)
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Envoirmental and diet:
Pollutants are capable of inducing P450 enzymes, such as
hydrocarbons present in tobacco smoke, charcoal broiled meat
induce CYP 1A.
Polychlorinated biphenyls used in industry, cuciferous
vegetables also induce CYP 1A
grapefruit juice induceCYP3A
Cigrate smokers metabolise some drugs more rapidly than non
smokers.
Industrial workers exposed to some pesticides metabolisze
certain drugs more rapidly than who are non exposed.
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DRUG – DRUG INTERACTION
when one drug is administered, a response occurs, if a
second drug is given and response to 1st drug is
altered ,a drug interaction is said to have occurred
This may be
Desired or beneficial
e.g. Multi drug treatment of T.B
Naloxone to treat Morphine overdose
Undesired or harmful
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Clinically important drug interactions
1. Drugs that have steep dose response curve and small
therapeutic index, small change in concentration at site
will lead to substantial changes in effect.
e.g. Digoxin , Lithium
2. Drugs that are known enzyme inducers/inhibitors
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3. Drugs that exibit saturable metabolism
e.g. Phenytoin , Theophylline
4. Drugs used for prolong period and precise plasma concentration are
required
e.g. oral contraceptive ,lithium, antiepileptic drugs
5.
Different durgs used to treat same disease
e.g. Theophylline, Salbutamol
6. In patients with impaired kidney and liver function
7. In elderly who receive several drugs at the same time
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PHARMACODYNAMIC INTERACTIONS
Both drugs act at same target site exerting synergism or
antagonism
Drugs may act at same or different receptors or process.
eg alcohal + benzpdiazepines (sedation)
Morphine + Naloxone ( to reverse
opoid overdose)
Rifampicin + INH ( effective anti TB combination.)
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PHARMACOKINETIC INTERACTIONS
Drug act remotely from target site to alter plasma concentration
e.g. enzyme induction /inhibition
interaction may be synergistic or antagonistic.
Drug interaction can occur at
Out side the body
At site of absorption
During drug distribution
During drug metabolism
During drug excretion.
On receptor or body system.
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Interaction out side the body
Drugs are added to reservoir or syringes to make drugs
soluble they are prepared in salt forms, mixing these
drugs may lead to precipitation (incompatibility)
Dilution in reservoir may also lead to loss of stability.
Protamine in zinc may bind with soluble insulin and
delay its effects.
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AT THE SITE OF ABSORPTION
Direct chemical interaction
e.g. Antacids + Tetracycline's ,Iron form insoluble complexes
,this can be prevented if drugs are administered at 2hrs apart.
Gut motility: drugs which reduce gastric emtying delay
absorption of other drugs
e.g anti cholinergics , antidepressants
.Other than gut : Local anesthetics and adrenaline.
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Purgatives reduce time spent in small intestine and reduce
absorption.
Alteration in gut flora: antimicrobials potentiates ant coagulants
by reducing bacterial synthesis of vit.K
Other than gut : Local anesthetics and adrenaline.
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DURING DISTRIBUTION
Displacement from plasma proteins binding
e.g. Sodium valproate displaces Phenytoin
Sulphonamides displaces bilirubin ( in
neonates)
Displacement from tissue binding sites
e.g. Quinidine displaces Digoxin.
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Interaction during metabolism
Enzme induction:
liver micsrosomal enzymes are induced by a wide variety of
drugs and these affect the metabolism of other drugs reducing
their concentration and hence effect.
e.g oral contraceptive metabolism is enhanced if Phenytoin is coadministered ,leading to unplanned pregnancy
eg loss of anticougulant effect of Warfarin leading to danger of
thrombosis if barbiturates are administered.
chronic use of alcohal shows tolerance to general anesthetics.
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Enzyme inhibition
Certain drugs inhibit the liver microsomal
enzymes ,hence increase the activity of drugs
which are to be metabolized by these enzymes.
e.g. Cimetidine potenciates the effects of
propranolol ,theophylline, warfarin and others
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Enzyme inducers.
Phenobarbital
Rifampin
Grisofulvin
Phenytoin
Ethanol
Carbamazepine
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Enzyme inhibitors
Phenylbutazone
Metronidazole
Cimetidine
Omperazole
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Interaction during excretion
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this occurs in kidney
 by binding at glomeruli and hence by pass filtration
 by inhibitin tubular secretion
 eg probenecid and pencillins
 by changing urine PH.
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Haemodynamic flow
variation in hepatic blood flow may influence the rate
of inactivation of drugs as in reduced cardiac out put.
drugs which reduce cardiac out put like Propranolol
may reduce the metabolism of other drugs.
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