Transcript FACTORS MODIFYING DRUG EFFECTS

FACTORS MODIFYING
DRUG EFFECTS/DRUG
VARIATIONS
BY
Dr. Abdul Latif Mahesar
Medical pharmacology
King Saud University
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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
IDIOSYNCRACY
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Physiological factors
AGE:
Pregnancy
Sex/gender
Body weight
Food
Timings
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AGE
In new born there occurs
Decreases acid secretion
 Decreased microsomal enzymes
 Decreased plasma protein binding
 Decreased G.F.R

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
There is increase in G.I.T absorption in newborns like
ampicillin due to decreased acidity.
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Tetracyclines produce teeth staining in children
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Corticosteroids cause growth and developmental retardation
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Antihistamines cause hyperactivity instead of hypoactivity.
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These are all different responses than adults
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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
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.
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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
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 old
people.
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Pregnancy

Causes several physiological changes that influence drug
disposition.

Volume of drug distribution is increased(total body water may
increase by up to 8 liters) providing large space for water
soluble drugs.
Maternal plasma albumin concentration is reduced,more free
drugs will be available

Metabolic rate is increased, so the free drugs will be available
for elimination.

Cardiac out put is increased, leading to increased renal blood
flow and glomerular filtration and increased renal elimination
of drugs.
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Gender

Evidences show that men and women may respond
differently to same drugs

This may be due to body size, and amount of body
fats.
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
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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 equal dose.
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 character.
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Temperature



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 cardiac
arrest.
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Timings

It has been observed that endogenous body clock
(circadian cycle) may affect the response of the drug.
e.g.
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
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Food
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.
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Charcoal grilled beef, cabbage, alcohol increases
metabolism
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
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PATHOLOGICAL FACTORS

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DISEASES can cause individual variations in drug response.
Pharmacokinetic variations;
Absorption:

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 resection
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

Diarrhea increases the motility of the gut and
decreases absorption.
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 protein bound

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Metabolism:

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

Excretion
In acute and chronic renal impairment ,concentration of drugs
is altered.
.
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Pharmacodynamic variations:

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
aminoglycoside
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 Genetic
factors:
These are known as idiosyncratic response
These are rare but very harmful.
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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 acetylators
Defective carbon oxidation
may cause poor oxidation of some drugs leading to some
adverse effects with standard doses of drugs like beta blockers.
Pseudocholine estrase deficiency Failure to
rapid inactivation of Suxamethonium, leading to muscular
block ,results paralysis.
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 G-6-PD deficiency: (
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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 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.
Cigarette smokers metabolize some drugs more rapidly than
non smokers.
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
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Other
variations(quantitative )
More common
 More clinically important
 Patient may be
Hypo reactive:
Hyper-reactive: to drug to a given dose
 Hypersensitivity:
allergic or other immunologic responsiveness to
drugs
e.g. Penicillins

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Tolerance
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
 Tachyphylaxis:
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when responsiveness diminishes rapidly after
administration of drug
e.g. ephedrine
Amphetamine
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Idiosyncrasy:

Is an abnormal genetic response and is usually
harmful

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
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Anaphylaxis
 It
is an immediate hypersensitivity reaction on
exposure to specific antigen leading to life
threatening respiratory distress followed by
vascular collapse
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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 response .

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.
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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
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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 βadrenergic 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.
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Before starting a drug therapy clinician should be aware
of
 age
 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
compensatory mechansim

e.g. Vasodilator drug for hypertension leads to
reflex tachycardia and sodium retension by kidneys.
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Drug resistance
When drug looses the effectiveness.
usually this happens with the improper use of
antibacterial drugs
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Synergism:
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 antihypertensive
effect
 Potenciation: when one drug increases the effect of
other drug
 e.g. levodopa +cabidopa

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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 hamful

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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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Distribution:
altered plasma protein binding ( binding of
penytoin in chronic renal failure decreases
Impaired blood brain barrier ( infilitration
of Penicillin in meningitis increases
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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

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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
1.
2.
3.
4.
5.
6.
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.

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Gut motility: drugs which reduce gastric emtying delay
absorption of other drugs
e.g anti cholinergics , antidepressants
.
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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 co-administered ,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.
 Eg. 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
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
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Phenylbutazone
Metronidazole
Cimetidine
Omperazole
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Interaction during excretion
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
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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.
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Haemodynamic flow

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.
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