FACTORS MODIFYING DRUG
On administration of a drug ,a predicted response is obtained
but some times
Individuals may vary considerably in their responsiveness
Such as: respond differently to drugs both from time to time
and from other individuals.
Some would show less than the usual response , and some
may show more than usual response
Occasionally individuals exhibit unusual response
In new born there occurs
Decreases acid secretion
Decreased microsomal enzymes
Decreased plasma protein binding
There is increase in G.I.T absorption in newborns like
ampicillin due to decreased acidity.
Tetracyclines produce teeth staining in children
Corticosteroids cause growth and developmental retardation
Antihistamines cause hyperactivity instead of hypoactivity.
These are all different responses than adults
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
e.g. chloramphenicol causing gray baby syndrome.
sulphonamides causing kernicterus
Activity of hepatic microsomal enzyme also
decreases with age leading prolonged half life of
some drugs elderly people
e.g. Benzodiazepines, theophyllines
This may lead to accumulation of drug on repeated doses.
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
there is decrease in G.F.R
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 ,Pencillins are contraindicated in
Causes several physiological changes that influence drug
Volume of drug distribution is increased(total body water may
increase by up to 8 liters) providing large space for water soluble
Maternal plasma albumin concentration is reduced,more free drugs
will be available
Metabolic rate is increased, so the free drugs will be available for
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.
Evidences show that men and women may respond
differently to same drugs
This may be due to body size, and amount of body
But there are also some less easily explained
differences in gender –specific drug response
Aspirin shows greater benefit in men than women
in cardiovascular diseases
There appears to be difference in the activity of
liver enzymes b/w men and women
Since the activity of enzymes vary that can result
in major difference in drug response
This difference in liver activity may explain why
women routinely wakes up from general
anesthesia several minutes before a man given an
It has been observed that women with red hair
and fair skin are particularly responsive to effects
of the analgesic Pentazosine than man of same
Addition of mild to moderate hypothermia
decreases the systemic clearance of CY450
metabolizes drugs between 7-22% per degree
Celsius below 37c during cooling. The addition of
hypothermia decreases the potency and efficacy
of certain drugs .
The therapeutic index of certain drugs is
narrowed during hypothermia.
Therapeutic hypothermia has shown decrease in
neurologic damage in patients experiencing
It has been observed that endogenous
body clock (circadian cycle) may affect
the response of the drug.
In CHD(coronary heart dieseases)
short acting calcium channel blockers
seem to be less effective than beta
blockers in reducing ischemic events
during the night and early morning
Presence of fatty food in stomach delays gastric
emptying,the plasma concentration of
rifampicin and ampicillin may be much
reduced if taken on full stomach
Calcium in milk interferes with absorption of
tetracyclines and iron.
Substituting protein for fats and carbohydrates
in diet ,increases drug oxidation rates.
Charcoal grilled beef, cabbage, alcohol
Protein malnutrition affects pharmacokinetics
of several drugs.
Citrus flavinoids in grape fruit (but not in
orange juice) significantly increases absorption
of cyclosporin calcium antagonists and
probably other drugs
DISEASEScan cause individual variations in drug
Gastric and intestinal stasis during an attack of
Migraine interferes absorption of drugs
Resection of gut may lead to malabsorption of iron,folic
acid and fat soluble vitamins and of vit B12 after ileal
Diarrhea increases the motility of the gut and
Hypoalbuminaemia from any cause such as
nephrotic syndrome, burn,malnutrition,sepsis
allows higher proportion of albumin free drug in
plasma which is readily available for
metabolism and elimination but there can be risk
with initial dose for drugs which are to be highly
Acute and chronic diseases of liver affects the blood flow and
function of hepatocytes ,leading to decreased drug clearance,
and prolong half life.
Drug metabolism is increased in hyperthyrodism and
diminished in hypothyroidism
In acute and chronic renal impairment ,concentration of drugs
Asthma can be precipitated by beta blocking drugs
Raised intracrainal pressure ,severe pulmonary
insufficiency cuases patient to be inttolent to opioids
precipitate respiratory failure
Change in receptors (Myasthenia gravis).person
becomes intolerant to quinine , quinidine and
Increased sensitivity of adrenergic receptors in
These are known as idiosyncratic response
These are rare but very harmful.
Acetylator status (important for metabolism)
Slow acetylators:( isoniazid causing peripheral neuropathy on
standard dose and pyridoxine is added to T.B regime)
Rapid acetylators: hepatotoxicity (hepatocellular necrosis)in fast
Defective carbon oxidation
may cause poor oxidation of some drugs leading to some adverse
effects with standard doses of drugs like beta blockers.
Pseudocholine estrasedeficiency Failure to rapid inactivation of
Suxamethonium, leading to muscular block ,results paralysis.
G-6-PDdeficiency: ( haemolysis by primaquine) G6PD is
necessary to maintain reduced glutathione in red
cells and to prevent their hemolysis.
This occurs in small portion of people
Such as chloramphenicol causes aplastic anemia
1 in 50,000.
Malignant hyperthermia: caused by suxamethonium in
prone person due to inherited abnormality in Ca
2+ release from sarcoplamic reticulum in striated
Envoirmental and diet:
Pollutants are capable of inducing P450 enzymes, such as
hydrocarbons present in tobacco smoke, charcoal broiled meat
induce CYP 1A.
Cigarette smokers metabolize some drugs more rapidly than
Industrial workers exposed to some pesticides metabolize
certain drugs more rapidly than who are non exposed
Polychlorinated biphenyls used in industry, cruciferous
vegetables also induce CYP 1A
Grapefruit juice induce CYP3A
Other variations(quantitative )
More clinically important
Patient may be
Hyper-reactive: to drug to a given
allergic or other immunologic
with some drugs intensity of response to given
dose may change during course of therapy,
usually decrease in response to continued
administration of drug.
e.g. Salbutamol (β-adrenergic agonist)
Opium ,barbiturates , Alcohol
when responsiveness diminishes rapidly after
administration of drug
Is an abnormal genetic response and is usually
It occurs in small portion of population.
e.g. aplastic anaemia due to chlormaphenicol
haemolysis by primaquine in G-6-PD defiency
Hepatic porphyria by carbamazipine
Malignant hyperthermia by suxamethonium
◦ It is an immediate hypersensitivity reaction on
exposure to specific antigen leading to life
threatening respiratory distress followed by
Change in response due to altered drug concentration
This may be due to change in rate of
absorption ,distribution and elimination of
drug. alteration in drug concentration that
reaches relevant receptor may alter clinical
Variation in response may be due to variation
in concentration of endogenous receptor ligand
,alteration in number of functional receptors,
change in components distal to receptors.
variability in response to pharmacologic antagonist
as propranolol will markedly slow the heart
rate of patient whose endogenous
catecholamine are elevated (in
pheochromocytoma ) but will not affect the
resting H.R of well trained marathon runner
A partial agonist SARALACIN at
angiotensin II lowers blood pressure in pts
with hypertension caused by increase in
angiotensin II production and raises blood
pressure in patients who produces low
amount of angiotensin
Alteration in number of receptors
there occurs change in responsiveness caused by
increase or decrease in number of receptor sites or
alteration in efficiency of coupling of receptor to
distal effectors mechanism.
e.g. 1) Receptors for hormones
Thyroid hormones cause increase in number of β-
adrenergic receptors and hence increase in cardiac
sensitivity to catecholamines
ii) Agonist ligand induces a decrease in
number( down regulation) or coupling efficiency
of its receptors.e.g salbutamol.
Before starting a drug therapy clinician should be
general health specially severity and pathologic
mechanism of disease.
Drug therapy always be most successful when it
is accurately directed at pathophysiologic
mechanism responsible for disease.
even then there may be no benefit due to
e.g. Vasodilator drug for hypertension leads to
reflex tachycardia and sodium retension by
When drug looses the effectiveness.
usually this happens with the improper
use of antibacterial drugs
when two drugs are administered at the same
time , the effect increases.
Summation: the effect of two drugs having same
action are added have aditie effect.
e.g. beta blocker + diuretic have additive
Potenciation: when one drug increases the effect
of other drug
e.g. levodopa +cabidopa
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 hamful
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
altered plasma protein binding (
binding of penytoin in chronic renal
Impaired blood brain barrier (
infilitration of Penicillin in meningitis
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
Both drugs act at same target site exerting
synergism or antagonism
Drugs may act at same or different receptors or
eg alcohal + benzpdiazepines (sedation)
Morphine + Naloxone ( to reverse opoid
Rifampicin + INH ( effective anti TB
Drug act remotely from target site to alter plasma
e.g. enzyme induction /inhibition
interaction may be synergistic or antagonistic.
Drug interaction can occur at
1. out side the body
2. At site of absorption
3. During drug distribution
4. During drug metabolism
5. During drug excretion.
6. On receptor or body system.
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
Dilution in reservoir may also lead to loss of
Protamine in zinc may bind with soluble
insulin and delay its effects.
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.
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
Displacement from plasma proteins
e.g. Sodium valproate displaces Phenytoin
Sulphonamides displaces bilirubin ( in
Displacement from tissue binding sites
e.g. Quinidine displaces Digoxin.
Interaction during metabolism
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 co-administered ,leading to unplanned
eg loss of anticougulant effect of Warfarin leading to
danger of thrombosis if barbiturates are administered.
chronic use of alcohal shows tolerance to general
Certain drugs inhibit the liver
microsomal enzymes ,hence increase
the activity of drugs which are to be
metabolized by these enzymes.
Eg. Cimetidine potenciates the effects
of propranolol ,theophylline, warfarin
Interaction during excretion
this occurs in kidney
by latering binding and hence filtration
by inhibitin tubular secretion
eg probenecid and pencillins
by latering urine flow and or urine PH.
variation in heaptic 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.