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7/28/2019 Factors Modifying Drug Effect
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FACTORS MODIFYING A
DRUG EFFECT
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Drug effect
Refers to the normal spectrum of biological response evoked
by a drug when used at a recommended dose.
Variations in drug response are attributable to :
Factors that influence drug action qualitatively and/or
quantitatively.
Broadly divided into 4 groups:
Drug related
Exposure conditions
Individual: Subject
Environmental conditions.
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Types of dosage
form Type of salt form
Type of formulation
Physico-chemicalproperties of drug
Dose
Route of administration
Rate of administration
Time of administration
Schedule of dosage
Duration and frequencyof administration
Concentration
Drug interactions
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Species
Breeds Strains
Sex
Age
Pregnancy
Lactation Hormonal status
Body weight and composition
Genetic status
Nutritional status
Emotional status andtemperament
Tolerance
Individual variations
Physiological/ Pathological states
Temperature
pH Atmospheric pressure and
altitude
Light and other radiations
Relative humidity
Environmental pollution
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The dosage form of that drug.
For a given drug, 2 to 5 fold or more
difference could be observed in the
oral bioavailability of a drugdepending on the nature and type of
dosage form.
As a general rule, absorption andaction of drug from solution are
fastest, whereas from a sustained
release product are slowest.
I. THE DRUG RELATED FACTORS
i) Types of dosage form:
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ii) Type of salt form:
Most drugs are weak electrolytes
The nature and type of salt formation influence drug
solubility and bioavailability.
For example; choline and isopropanolamine salts of
theophylline dissolve 3 to 4 times more rapidly than the
ethylene diamine salt and show better bioavailability.
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iii) Type of formulation:
The pharmacological effect of a drug may be influenced by thetype and number of excipients (non-drug components) presentin the formulation.
For example,
Physiological surfactants like bile salts and LysolecithinHydrophobic drugs (steroids, oil soluble vitamins
and griseofulvin)
On the other hand, certain dyes (e.g. brilliant blue) when usedas colorants inhibit impair absorption of hydrophobic drugs.
The macromolecular gums (e.g., sodium carboxymethylcellulose and methyl cellulose) often used as mechanicalbarrier to diffusion of drug by forming a viscid layer on the GI
mucosa.
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iv) Physico-chemical properties of drug:Important physico-chemical properties that
influence drug effect are partition coefficient,degree of ionisation and molecular size.
a) Partition coefficient: Drugs having high oil: water
coefficient (high lipid solubility) - readily absorbed
For example; Thiopentone, a derivative of barbituric acid, has
high partition coefficient, so it is rapidly absorbed and
rapidly produces anaesthesia.
On the other hand, barbituric acid has low lipid solubility and
it is inefficient as an anaesthetic agent.
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b) Degree of ionisation: Ionised- more water-soluble less absorption
Unionised- have greater penetrability across the biologicalmembranes.
For example, quaternary ammonium compounds remain
ionised at plasma pH, therefore, they do not cross the bloodbrain barrier and have no effect on CNS.
c) Molecular size and weight:Drugs of low molecular weight
and size are more rapidly absorbed and distributed than those
having large complex molecules.
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II. EXPOSURE/ ADMINISTRATION CONDITIONS
RELATED FACTORS
Dose: The magnitude of pharmacologic effect depends on the amount
of drug absorbed into blood stream that further depends on the
dose administered.
Normally, response of a drug increases with increase in the
dose, but within a limit.
A sufficiently large dose of an ordinarily harmless drug (e.g.,
sodium chloride) may prove fatal
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Route of administration:
Route of drug administration governs the speed and intensity
of drug response. For some drugs, type of drug effect may vary with the route
of drug administration.
For example;
Magnesium sulphate (orally) Purgation, applied topicallyon inflamed area decreases swelling
Intravenously Muscle relaxation, CNS depression,
hypotension and even cardiac arrest.
Similarly, lignocaine infiltrated into the vicinity of a nerve
produces local anaesthetic effect
Intravenously Antiarrhythmic effect.
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Time of administration:
Response to a drug may be related to the time of day at which itis administered. This may be related to the eating and sleeping
habits of the animal or to the diurnal factors.
For example;
Nocturnal animals like rats, there is more food in stomach in
the morning than that in the afternoon. So absorption of drugis variable depending on time of its administration.
Dosing with glucocorticoids at night has been recommended
for cats in order to mimic endogenous release patterns.
In humans, hypnotics are more effective during night, becausedarkness itself has sedative effect and also because peoplesleep during night.
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Schedule of dosage:
Generally, a single large dose produces more response thanthe same amount given in divided doses.
However for a drug that is cumulative in nature, divided
doses may produce more pharmacological effect.
For example, cardiac glycosides have a low therapeutic
index; therefore multiple divided doses are recommended
over a period of 24 to 36 hours for the initial digitalisation.
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For some agents, pharmacological or toxicological effects of
single administration are quite different from those produced byrepeated administration.
For example, some organophosphorus insecticides (e.g.,
monocrotophos) in acute toxicity produce characteristic anti-cholinesterase manifestations like salivation, muscle
tremors,dyspnoea and convulsions, but they on repeated
exposure produce delayed neuropathy (e.g.,
paralysis of limbs).
Duration and frequency of administration:
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Concentration:
Greater the concentration of a drug in a preparation, faster is
the rate of absorption and rapid onset of pharmacological
effect.
For some drugs, the pharmacological effect may vary with
different concentrations.
Eg:
weak solution of iodine (2.5%)-antiseptic; strong solution of
iodine (10%) -counterirritant and parasiticide.
Red mercuric iodide ointment at lower strength (1:40)-
rubefacient action; higher concentration (1:4 or 1: 8)- vesicant
action.
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Drug Interaction during metabolism
Enzme induction:
Liver micsrosomal enzymes are induced by a wide varietyof drugs and these affect the metabolism of other drugsreducing their concentration and hence effect.
Eg, loss of anticougulant effect of Warfarin leading todanger of thrombosis if barbiturates are administered.
Chronic Use of alcohal shows tolerance to generalanesthetics.
17
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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
18
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Enzyme inducers
Phenobarbital
Rifampin
Griseofulvin
Phenytoin
Ethanol
Carbamazepine
Enzyme inhibitors
Phenylbutazone
Metronidazole
Cimetidine
Omperazole
Chloramphenicol
19
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III. FACTORS RELATED TO THE SUBJECT
Species:
There is wide biological diversity among different species inthe rate and pattern of metabolism to detoxify a compound.
For example,
Belladonna or atropine is toxic to most species, but not to
rabbits due to the presence of liver enzyme atropinase, which
rapidly hydrolyses it.
Morphine produces CNS depression in human beings,
monkeys and dogs but it causes CNS excitation in cats.
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The extent of drug absorption following oral administration
also varies with species and is related mainly to their
digestive tract.
The absorption of drugs following oral administration is fast
and complete in monogastric animals, and comparatively
slow and incomplete in ruminants.
Several drugs (e.g., antibiotics) are not effective by oral route
in ruminants because these drugs are either inactivated by
ruminal micro flora or they may fail to diffuse into the largecompartments of the G-I tract.
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Breeds:
Breed differences influence the drug effect, although theyhave not been well described.
For example,
Greyhounds are more susceptible to thiobarbiturates becausetheir lean body weight provides little fat for drug
redistribution.
Brachycephalic breeds are more susceptible to cardiacarrhythmias (sinoatrial block) caused by acepromazine.
Some breeds of pigs (e.g., Poland China and Pietrain) arefound to be highly susceptible to halothane induced malignanthyperpyrexia.
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Strains:
Different strains of same animal may show variations in drug
response.
For example, different strains of mice vary widely in their
ability to metabolise barbiturates and consequently the
magnitude of pharmacological response.
In humans, differences have been observed in the metabolismof drugs among different races called as ethnic variations.
For example,
45% of whites in USA and Canada are slow acetylators and
55% are rapid acetylators of isoniazid. Dose adjustment in slow acetylators is essential because they
are susceptible to isoniazid induced peripheral neuritis-and
hepatic damage.
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Sex:
sex related differences in the rate of biotransformation andelimination of drugs are related mainly to variation in sex
hormones.For example,
Male mice are highly susceptible to nephrotoxic effect ofchloroform, but female mice show little effect.
Female rats are 2 times more susceptible to red squill toxicitythan male rats.
In humans, ephedrine more frequently produces excitation andtremors in women than in men.
In experimental studies it has been demonstrated thatcastration increases chances of drug toxicity in males, whileadministration of testosterone in females increases resistanceto poisoning.
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Age:
Very young (neonates) and very old (geriatric) animals are
more susceptible to harmful effect of drugs when compared
with adults.
Neonates have under-developed and inefficient hepatic
microsomal enzyme system, while geriatric animals have
reduced liver mass, decreased hepatic blood flow and deceased
microsomal enzyme activity.
For example half-life of chloramphenicol in piglets is about 6-7times more than in adults. Chloramphenicol induced grey-baby
syndrome in human infants is due to inadequate conjugation of
the drug with glucuronic acid.
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Pregnancy:
Pregnancy causes marked hormonal and metabolic changes thus
affecting response of certain drugs.
For example,
oral anticoagulants are more toxic to pregnant animal.
During pregnancy, plasma and ECF volume expands,
therefore, volume of drug distribution may increase.
Renal blood flow also increases markedly during pregnancy as
a result of which renal excretion of some drugs
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High progesterone levels during pregnancy may
increase hepatic microsomal enzymes
Lactation: Similar to pregnancy, lactation alters
pharmacokinetics of certain drugs.
Lactation may enhance excretion of some lipophilic drugs
and toxicants (e.g., DDT, polychlorinated biphenyls) in the
milk.
Drugs in milk may have their own unwanted effects on the
suckling youngones and consumers.
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Hormonal status:
For example,hyperthyroidism and hypothyroidism can affect
drug disposition.
In human beings, the elevated thyroid hormones activate some
cytochrome P-450 enzymes (e.g., hydroxylation), while
activities of others (e.g.,N-demethylation) are decreased.
Digoxin doses necessary to induce clinical response are in
general increased in hyperthyroidism, whereas smaller doses
than normal are needed in hypothyroidism.
Adrenalectomised rats are generally more susceptible to
adverse effects of drugs due to low levels of anti-stress
hormone adrenaline.
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Body weight and composition:
Normally dose of a drug is adjusted on the basis of body weight(i.e., mg/kg).
Differences between body weight and true lean body weightshould be taken when dealing with conditions like obesity,starvation, ascites, generalised oedema, starvation, old age, etc.
In obese animals, water soluble drugs generally do notdistribute into increased body fat which may result in higherthan expected plasma drug concentration and hence adverseeffects.
On the other hand, highly lipid soluble drugs (e.g., anaesthetics)are required in high dosage in an obese animal
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Nutritional status:
In animals suffering from protein caloric malnutrition,
absorption, distribution, metabolism and excretion processesmay all be impaired.
Starvation for few hours may reduce blood glucose level and
result in decreased amount ofglucuronides formed than thenormal conditions.
Protein deficiency for longer period results in lesser percentage
ofmicrosomal enzyme activity and thus increases in toxicity ofa variety of drugs and poisons.
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For example, paracetamol is more hepatotoxic in protein
deficient animals, possibly due to decreased hepatic
glutathione levels.
Additionally, deficiency of any essential vitamin or trace
elements is injurious in itself.
For example,
vitamins deficiency, especially antioxidant vitamins E and C
can result in increased damage from free radicals.
Dietary deficiency of vitamins (e.g., vitamins A, B2, B3, Cand E) and minerals (e.g., Fe, Ca, Mg, Cu, and Zn) retard
metabolic activity of several enzymes.
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Emotional status and temperament:
This is particularly applicable to centrally acting drugs. Forexample, an excited animal may require higher dose of a CNS
depressant than the animal which is already depressed.
Toxicity of drugs like amphetamine and other CNS stimulantsis affected by crowding (more number of animals per cage),
size of cage, bedding and handling of animals.
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Individual variations:
Individual variations to drugs are common in a homogenouspopulation.
Within a population, some animals are hypersensitive and
some are hyposensitive to drugs.
For example, first generation antihistamines produce variabledegree of drowsiness and sedation in individuals in a
population.
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Pathological states:Liver diseases:
i) Liver diseases may reduce activity ofmicrosomal enzymes,thus altering biotransformation and action of drugs and
toxicants.
ii) Liver diseases can also reduce synthesis ofprotective binding
molecules (e.g., glutathione) allowing increased adverseeffect of drugs.
iii) Reduce synthesis ofplasma proteins, particularly albumin,
may alter the drug binding capacity.
For example, hepatitis impairs biotransformation and prolongsaction of IV anaesthetics as a result of which ultra-short
acting barbiturates become toxic.
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ii) Kidney diseases:
Kidney diseases often result in decreased drug clearance and,
thus slower removal of drug from the body.
A usual dosage regimen in such cases leads to accumulation of
drug in body and ultimately to
toxicity.
Drug induced toxicity in renal insufficiency may also result
either from increased sensitivity to the drug due to uraemia-
induced alterations in tissue receptors or from derangement of
acid-base balance.
For example, in patients with impaired renal function, drugs like
streptomycin, gentamicin, penicillins, etc. may accumulate to
toxic levels in body.
iii) Other diseases:
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iii) Other diseases:
Several GI diseases can alter the absorption rates of drug
administered by oral route. Conditions like diarrhoea and
constipation
Cardiovascular insufficiency either due to cardiac failure or due
to circulatory shock potentially affects disposition of drugs by
altering drug distribution and elimination.
For example, decompensated heart results in decreased volume
of distribution and decreased clearance of several drugs like
lignocaine, procainamide and quinidine.
Similarly, neurological disturbances may influence animal's
response to several CNS acting drugs. Inflammation of meninges
may precipitate toxicity of several drugs (e.g., penicillins) by
allowing their penetration into the brain.
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Ethanol toxicity also increases in winter because cutaneous
vasodilation caused by ethanol results inexcessive heat loss
on exposure to cold.
Toxicity of some insecticides like organochlorines and
pyrethroids show negative correlation with environmental
temperature (more toxic in winter).
However, pesticides like oxidative uncouplers (e.g.
dinitrophenols) increase body temperature and, thus, are
more toxic in hot conditions.
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Li h d h di i
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Light and other radiations:
Radiation exposure is known to affect blood-tissue barriers,
modify enzyme systems and produce disturbances in the
normal excretory pattern of numerous species.
Toxicity of atropine usually increases if the intoxicated animal
is exposed to direct sunlight because the drug has mydriatic and
cycloplegic effects on eyes.
Certain drugs (e.g., phenothiazine, demeclocycline, tar
products) show photosensitization reactions when the
individual is exposed to sunlight or UV radiations.
Whole body irradiation has been shown to produce a dose-
dependent decrease in the pseudocholinesterase activity of ilea
of intestine in rodents thus changing response to drug like
acetylcholine and physostigmine.
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Relative humidity:
Relative humidity might influence the response of some drugs,
especially those applied by dermal routes.
For example, dermal absorption of some ectoparasiticides (e.g.,
organophosphorus insecticides) is more in hot and humid
environment because more blood is diverted to skin (so rapidabsorption) to affect cooling.
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Environmental pollution:
Several chemicals in environment, especially in air and water,
- can substantially alter the pharmacokinetics andpharmacodynamics of many drugs.
Eg:
Insecticides (e.g., DDT) and tobacco smoke-induce drug
metabolism. Chronic exposure to air pollutants (e.g., sulphur oxide gases)
causes thickening of respiratory tract mucous membranes that
may impair absorption and action of some inhalant drugs.
Long-term inhalation of dusts containing minerals andorganic matter produces pulmonary diseases, which may
indirectly affect action of some drugs.
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