Factors Modifying Drug Action.

Factors Modifying Drug Action.

• Various factors modify actions of the drugs they are discussed as follows,

1) Age:

• The four important stages of life Infant, Children, Adult and older age shows a great physiological difference.

• The infants don't have well developed metabolic machinery and have lower glomerular filtration rate, hence drugs administrated gets very slowly metabolised and excreted slowly resulting in toxic effects of the drug.

• The metabolic machinery is still not well developed in childhood, moreover, the children are more susceptible to CNS depressants.

• In older days of life due to wear and tear of body tissues, the metabolism and excretion of drugs get affected.

• Hence the dose required for children and elderly patients should be calibrated to avoid toxic effects. 

• The doses of the drugs can be calculated by using following formulae. 

2) Body Weight:

• Normal doses of the drugs are decided for considering 70kg body wt. as the normal body weight of an adult.

• However, such doses fail miserably for excessively obese patients and children.

• Hence for obese patients and children the dose is calculated by using Hamburger's formula.

3)Sex:

• Females are delicate in the physical as well as physiological way as compared to males.

• Due to smaller body size, they require lesser dose as compared to the males.

• As females have to pass through delicate conditions of life like, Menstruation, Pregnancy, lactation, Menopause, the drugs should be very carefully administered as responses may vary in these situations.

• e.g.

1. Drugs which produce uterine congestion like purgatives should be avoided during menstruation as they may cause dysmenorrhoea (Painful menstruation).2.Uterine stimulants like quinine, ergotamine must not be administered during pregnancy as they may cause miscarriage.

1. Certain drugs which get excreted through milk may cause disliking of breastfeeding, may appear in infants blood and can cause complications.

1. Menopause means the complete stoppage of menstrual cycle which is confirmed after 12 months of amenorrhoea (absence of menses). Drugs which cause mood alterations should be given cautiously during these days.

4)Route of drug administration:

• Drugs given by oral route gets absorbed slowly and incompletely as compared to those given by the parenteral routes.

• Faster and complete the drug absorption quicker will the therapeutic response of the drug.

5)Time of drug administration:

• Our body follows a typical circadian rhythm, hence the hypnotic drugs require lesser dose to induce sleep during the night as compared to during day time. 

• Oral hypoglycemics are more effective when given in morning time.

6)Emotional Factors:

• Placebos (Duplicate dosage forms which copy the external appearance of original one but lack active drug) are found useful in controlling certain psychological aggravation of disorders like angina, asthma, insomnia etc. 

7)Genetics of the patient:

• Drug metabolism is carried out by the enzyme machinery of the patient, lacking certain enzymes due to genetics the patient may suffer from complications e.g

1. Isoniazid an antitubercular drug gets metabolised by N-Acetylation reactions the rate of such reactions may vary as per genetical availability of the required enzymes and hence classifies drug receiving patients into fast acetylators and slow acetylators.

1. Antimalarials like primaquine require "Glucose 6 Phosphate Dehydrogenase" enzyme for metabolism, the absence of which results in haemolysis.

8)Previous drug therapy:

• Certain drugs like Phenobarbitone are very powerful enzyme inducers which increase metabolism of other drugs administered.

9)Diseased conditions:

• Absorption of iron gets increased during anaemia.

• In the case of kidney failure drugs which gets primarily through kidney like penicillins may cause toxicity.

• Liver cirrhosis is characterised by decreased metabolic activity of the liver, inability to metabolise drugs like barbiturates may produce their toxicity.

10)Metabolic disturbances:

• Metabolic disturbances like water, pH, temperature can also influence actions of the drugs.

• e.g. Antipyretics like Paracetamol can lower body temperature only in presence of hyperpyrexia (Increased body temperature).

11)Cumulative Effect:

• Certain drugs on repeated administration get accumulated in the body due to slower excretion, and produce toxicity the phenomenon is called as "Cumulation".

• The dose of drugs which show cumulative effect should be calibrated to avoid the complications.

• e.g.

1. Cardiotonic Digitalis.
2. Purgative Senna.

12)Additive effect:

• When two or more drugs acting on the same system and producing same pharmacological effect administered together the net response obtained is more, the phenomenon is called as "Additive Effect".

• The response obtained by additive effect is equal to the sum of individual responses to the drugs.

• e.g. Salbutamol and Terbutaline in the treatment of bronchial asthma: both the drugs act on respiratory system by producing bronchodilation.

12)Synergistic effect:

• When two or more drugs acting on different systems by different mechanisms but producing similar pharmacological response are given together, the net effect obtained is more than the sum of their individual effects the phenomenon is called as "Synergistic Effect".

• e.g. Antihypertensive Therapy.

13)Antagonism:

• When two drugs having opposite action on the same physiological system are administered together they nullify each others action and net pharmacological action will be zero, the phenomenon is called as antagonism.

• Antagonism is of three types as follows,

1. Chemical Antagonism:

• The type of antagonism where two drugs nullify each others action by chemical reaction is called as chemical antagonism.

• e.g. Sodium bicarbonate reacts chemically with gastric Hydrochloric acid and neutralise it, and hence is used in the treatment of hyperacidity.

• NaHco3+HCl = NaCl + H2o + CO2↑.

   2.Competitive Antagonism:

• In this type of antagonism both the drugs compete for binding to the same receptor however the binding depends on effective concentration at the site of action.

• As effective concentration changes can reverse the binding of drugs this phenomenon is also called as reversible antagonism.

• e.g. Flumazenil is a competitive antagonist of benzodiazepines used to reverse the binding of benzodiazepines from its receptor and hence is useful as an antidote in benzodiazepine poisoning.

  3. Noncompetitive Antagonism:

• In this type of antagonism, the antagonist binds with receptor site in such a way that even the increased concentration of agonist at the site of action will not be able to reverse the binding.

• As this phenomenon is irreversible it is also called as irreversible antagonism.

• e.g. Naloxazone irreversibly binds with opioid receptors in such a way that even the increased concentration of morphine fails to produce its effect and hence Naloxazone is used in the treatment of morphine addiction.

   4. Physiological Antagonism:

• In this phenomenon, one drug reverses pharmacological actions of the other drug on a physiological system.

• e.g. Adrenaline reverses bronchoconstriction caused due to histamine release in penicillin allergy.

14)Drug Tolerance:

• A Requirement of a higher dose to produce the pharmacological effect of therapeutic dose of the drug is called as Drug Tolerance. 

• Drug tolerance in short shows reduced sensitivity of the drug towards receptors due to repeated administration.

• Drug tolerance is of following types,

1)True Tolerance:

• This type of tolerance can be observed after oral or parenteral administration of the drug.

• The true tolerance can be further classified into,

A) Natural Tolerance.

B) Acquired Tolerance.

A) Natural Tolerance:

• This is observed naturally no human intervention is there.

• It is further classified as,

a) Special Tolerance.

b) Racial Tolerance.

a) Special Tolerance:

• This type of tolerance is observed among various animal species.

• e.g. Rabbits can tolerate high amount of belladonna doses because of enzyme atropine esterase present in liver, while humans can not tolerate high doses of the plant.

b) Racial Tolerance:

• Certain human races can tolerate higher doses of certain drugs and foods as compared to other races.

• e.g. Negros require higher doses of sympathomimetic amines like adrenaline to induce mydriasis as compared to the Europeans.

• Asian people can tolerate high doses of antibiotics as compared to the Europeans.

• Eskimos can tolerate a higher amount of fatty meals than any other races.

B) Acquired Tolerance:

• This type of tolerance occurs due to the repetitive administration of a drug in higher doses.

• This takes years to establish however one can still continue to get the effect of the drug by increasing the dose.

• This type of tolerance is very common with the drugs or substances which are used for habituation e.g. alcohol, benzodiazepines, caffeine etc.

• True tolerance is of two types as follows,

a) Tissue Tolerance.

b) Cross Tolerance.

a) Tissue Tolerance:

• The tolerance is said to be a tissue tolerance when it affects the effect on a specific tissue or system only.

• e.g. After the development of tolerance euphoriant effect of morphine diminishes while the effects on GI (constipation), Eye (Pinpoint Meiosis) continues to appear.

b) Cross Tolerance:

• When a patient develops tolerance towards a drug of a particular group, he also acquires tolerance to the other drugs of that group. 

• e.g. If a patient develops tolerance towards glyceryl trinitrate, he develops tolerance to all drugs belonging to Nitrate category.

• Alcoholic patients require higher doses of general anaesthetics during surgery.

1)Pseudo Tolerance:

• This type of tolerance is related to a specific route of administration.

• e.g. A patient can develop tolerance towards a poison or a drug if given in smaller quantities regularly for a longer duration by the oral route however effects after parenteral administration remains unaffected.

What is tachyphylaxis?

• It is defined as acute tolerance and occurs on repeated administration of certain drugs at very short intervals.

• This develops very rapidly and even increase in dose of the drug fails to produce the response.

• e.g. Ephedrine, Amphetamine etc.