FACTORS MODIFYING A DRUG EFFECT

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.

 Types of dosage form Type of salt form Type of formulation Physico-chemical properties of drug

Dose Route of administration Rate of administration Time of administration Schedule of dosage Duration and frequency of administration Concentration Drug interactions

Species Breeds Strains Sex Age Pregnancy Lactation Hormonal status Body weight and composition Genetic status Nutritional status Emotional status and temperament Tolerance Individual variations Physiological/ Pathological states

Temperature pH Atmospheric pressure and altitude Light and other radiations Relative humidity Environmental pollution

I. THE DRUG RELATED FACTORS i) Types of dosage form:

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 drug depending on the nature and type of dosage form.
As a general rule, absorption and action of drug from solution are fastest, whereas from a sustained release product are slowest.

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.

iii) Type of formulation:

The pharmacological effect of a drug may be influenced by the type and number of excipients (non-drug components) present in the formulation. For example, Physiological surfactants like bile salts and Lysolecithin Hydrophobic drugs (steroids, oil soluble vitamins and griseofulvin)
On the other hand, certain dyes (e.g. brilliant blue) when used as colorants inhibit impair absorption of hydrophobic drugs. The macromolecular gums (e.g., sodium carboxymethyl cellulose and methyl cellulose) often used as mechanical barrier to diffusion of drug by forming a viscid layer on the GI mucosa.

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.

b) Degree of ionisation: Ionised- more water-soluble less absorption Unionised- have greater penetrability across the biological membranes.
For example, quaternary ammonium compounds remain ionised at plasma pH, therefore, they do not cross the blood brain 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.

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

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 topically on 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.

Time of administration:
Response to a drug may be related to the time of day at which it is 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 drug is 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, because darkness itself has sedative effect and also because people sleep during night.

Schedule of dosage:
Generally, a single large dose produces more response than the 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.

Duration and frequency of administration:

For some agents, pharmacological or toxicological effects of single administration are quite different from those produced by repeated administration. For example, some organophosphorus insecticides (e.g., monocrotophos) in acute toxicity produce characteristic anticholinesterase manifestations like salivation, muscle tremors,dyspnoea and convulsions, but they on repeated exposure produce delayed neuropathy (e.g., paralysis of limbs).

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.

Drug 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.
Eg, loss of anticougulant effect of Warfarin leading to danger of thrombosis if barbiturates are administered.

Chronic Use of alcohal anesthetics.

shows tolerance to general

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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 Griseofulvin Phenytoin Ethanol Carbamazepine

Enzyme inhibitors Phenylbutazone Metronidazole Cimetidine Omperazole Chloramphenicol

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III. FACTORS RELATED TO THE SUBJECT Species:

There is wide biological diversity among different species in the 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.

 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 large compartments of the G-I tract.

Breeds:
Breed differences influence the drug effect, although they have not been well described.

For example, Greyhounds are more susceptible to thiobarbiturates because their lean body weight provides little fat for drug redistribution.
Brachycephalic breeds are more susceptible to cardiac arrhythmias (sinoatrial block) caused by acepromazine.

Some breeds of pigs (e.g., Poland China and Pietrain) are found to be highly susceptible to halothane induced malignant hyperpyrexia.

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 metabolism of 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.

Sex:
sex related differences in the rate of biotransformation and elimination of drugs are related mainly to variation in sex hormones. For example, Male mice are highly susceptible to nephrotoxic effect of chloroform, but female mice show little effect. Female rats are 2 times more susceptible to red squill toxicity than male rats. In humans, ephedrine more frequently produces excitation and tremors in women than in men. In experimental studies it has been demonstrated that castration increases chances of drug toxicity in males, while administration of testosterone in females increases resistance to poisoning.

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 6-7 times more than in adults. Chloramphenicol induced grey-baby syndrome in human infants is due to inadequate conjugation of the drug with glucuronic acid.

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

 High progesterone levels during increase hepatic microsomal enzymes Lactation: Similar to pregnancy, pharmacokinetics of certain drugs.

pregnancy

may

lactation

alters

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.

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.

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 weight should be taken when dealing with conditions like obesity, starvation, ascites, generalised oedema, starvation, old age, etc.

In obese animals, water soluble drugs generally do not distribute into increased body fat which may result in higher than expected plasma drug concentration and hence adverse effects.
On the other hand, highly lipid soluble drugs (e.g., anaesthetics) are required in high dosage in an obese animal

Nutritional status:
In animals suffering from protein caloric malnutrition, absorption, distribution, metabolism and excretion processes may all be impaired. Starvation for few hours may reduce blood glucose level and result in decreased amount of glucuronides formed than the normal conditions. Protein deficiency for longer period results in lesser percentage of microsomal enzyme activity and thus increases in toxicity of a variety of drugs and poisons.

 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, C and E) and minerals (e.g., Fe, Ca, Mg, Cu, and Zn) retard metabolic activity of several enzymes.

Emotional status and temperament:

This is particularly applicable to centrally acting drugs. For example, 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 stimulants is affected by crowding (more number of animals per cage), size of cage, bedding and handling of animals.

Individual variations:
Individual variations to drugs are common in a homogenous population. Within a population, some animals are hypersensitive and some are hyposensitive to drugs.

For example, first generation antihistamines produce variable degree of drowsiness and sedation in individuals in a population.

Pathological states:
Liver diseases:
i) Liver diseases may reduce activity of microsomal enzymes, thus altering biotransformation and action of drugs and toxicants. ii) Liver diseases can also reduce synthesis of protective binding molecules (e.g., glutathione) allowing increased adverse effect of drugs. iii) Reduce synthesis of plasma proteins, particularly albumin, may alter the drug binding capacity. For example, hepatitis impairs biotransformation and prolongs action of IV anaesthetics as a result of which ultra-short acting barbiturates become toxic.

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 uraemiainduced 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: 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.

IV. FACTORS RELATED TO THE ENVIRONMENTAL CONDITIONS

Temperature:
Low ambient temperature usually enhances metabolism of drugs because metabolic activity generally increases in low temperature to keep the body warm. The high ambient temperature favours administration of inhalant volatile anaesthetics by open drop method mainly by increasing their volatility and vapour pressure. On the other hand, low ambient temperature can increase duration of action and toxicity of general anaesthetics because they impair the thermoregulatory mechanism and lower the body temperature.

 Ethanol toxicity also increases in winter because cutaneous vasodilation caused by ethanol results in excessive 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.

Atmospheric pressure and altitude:

The changes in response to drugs and poisons are generally associated with changes in environmental oxygen tension.

High altitude with low atmospheric pressure reduces the potential of body to oxidise drugs, as low oxygen is available to the body.
Similarly, low oxygen concentration resulting from high altitude may be a factor in the toxicity of compounds that primarily affects cardiovascular functions. For example, carbon monoxide, barbiturates and cyanide are more toxic in low oxygen conditions.

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 dosedependent decrease in the pseudocholinesterase activity of ilea of intestine in rodents thus changing response to drug like acetylcholine and physostigmine.

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 rapid absorption) to affect cooling.

Environmental pollution:
Several chemicals in environment, especially in air and water, - can substantially alter the pharmacokinetics and pharmacodynamics 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 and organic matter produces pulmonary diseases, which may indirectly affect action of some drugs.

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