Understanding Drug Action, Interaction and Reaction

Monitoring of physical, cellular, biochemical, immunological and psychological parameter during the course of any drug therapy imparts us valuable information regarding drug action (expected relief), interaction (action in association dietary items and other drugs) and reaction (adverse effect of the drug or adverse drug reaction or ADR). Let us take the treatment of psoriasis, a chronic, immunological and inflammatory disease of skin for understanding drug, action, interaction and reaction. Psoriasis presents with erythematous, scaly (pustular) or indurated plaques over the extensor aspects of limbs, trunk, head and face and is widely treated with acitretin (synthetic aromatic analogue of retinoic acid).

Action of acitretin:

Systemic treatment with acitretin promotes cellular differentiation of epidermis and decrease proliferation rate in psoriatic plaques. It also exerts anti-inflammatory effect by modulating lymphocyte functions and inhibition of neutrophil migration. Psoriatic inflammation generally subsides within 6-12 weeks' period of treatment with acitretin. It is indicated for the treatment of moderate to severe psoriasis in adult patients. Pregnancy should be ruled out in female patients and they should be advised to use effective contraception at least for a period of three years to avoid pregnancy.

Interactions of acitretin:

• Acitretin interferes with the contraceptive action of minipill contraceptives and may result in failure of contraception.


• Use of alcohol during acitretin treatment should be avoided as ethanol converts acitretin to etretinate and thus prolongs clearance of acitretin.


• There is a risk of hypervitaminosis-A if acitretin is given along with vitamin-A.


• Risk of hepatitis increases if acitretin is administered in combination with methotrexate.


• Use of tetracyclines or its derivatives should be avoided in patients on acitretin therapy as there are chances of development of pseudotumor cerebri.


• Acitretin may decrease night vision, so patients should be advised to avoid driving at night.


• Acitretin should not be used in lactating mothers as it is excreted in the breast milk and may harm the baby as the drug is teratogenic.


• Acitretin sensitizes the skin to UV light so patient should be advised to avoid excessive exposure to sunlight.

Adverse drug reactions:

• Use of acitretin is contraindicated in pregnancy and during lactation. Fetal deformities like dysmorphia and cardiovascular malformations have been reported with the use of acitretin and/or etretinate.


• The drug has teratogenic.


• Commonly encountered adverse effects with acitretin are mucocutaneous effects like chelitis, xerosis, rhinitis, skin peeling over palms & soles, nail dystrophy, and hair loss.


• Dryness and irritation of eyes.


• Use of tetracycline or minocycline along with acitretin may lead to the development of pseudotumor cerebri.

Happy New Year

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Wish you a "Very Happy and Memorable New Year".

Pre and Post Approval Carcinogenicity Studies

Carcinogenicity studies are needed in adequate number and multiple species of animals before the marketing approval of a drug to evaluate trans-species carcinogenicity. However, for infrequently administered drugs or short duration exposure compounds like anesthetics and radiolabelled imaging agents, these studies are not mandatory. Post-approval carcinogenicity studies must be conducted for the pharmaceutical compounds developed to treat serious diseases. Endogenous peptides or their analogs or protein substances like animal insulin, pituitary-derived growth hormone and calcitonin, which are administered in very low doses, are exempt from pre or post approval carcinogenicity studies. Carcinogenicity studies should essentially be conducted for the analogs if:

• The dose to be administered is higher than the physiological dose.


• Significant variation in biological effects as compared to the natural counterpart.


• There is significant difference in the structure of synthetic compound as compared to natural counterpart.

Animals and doses for carcinogenicity studies:

The strains of animals selected for carcinogenicity studies should not have very high or very low incidence of spontaneous tumors. Rats are the most commonly used and accepted animals for such studies. However, the study may also be conducted on mice if the morbidity and rate of mortality of animals is not high during the period of study. Pre or post approval carcinogenicity studies should be conducted using at-least three dose levels. The highest dose should be sub-lethal and that should not reduce the life span of animals by more than 10% of expected normal life of animals. The lowest dose should be twice the intended therapeutic dose or same as therapeutic dose. The third dose should be intermediate dose between the highest and the lowest dose. An untreated group of animals as well as a vehicle control group should also be included in the study. There should be three groups of animals (50, 20 and 10 animals in each group) for high, intermediate and low dose of a drug. The period of dosing should be 24 months for rats and 18 months for mice. Equal number of animals of each sex should be included in each group of animals.The sacrificed and/or dead animals should be evaluated for neoplasia and histopathological changes in various organs and tissues. The effect on body weight, signs of intoxication and food intake should be recorded periodically. Urine analysis, hematology, biochemistry parameters, organ weights, gross pathology and detailed histopathology should be done for each animal under study. The description, site and dimensions of benign or malignant tumors developed should be recorded along with time of detection and histological typing should be worked out and recorded. Any benign or carcinogenic lesions detected during the post-approval carcinogenicity study should immediately be communicated to the Food and Drug Administration (FDA) or Drug Controller or Drug Research and Development Organization of you zone.

Renal impairment and Drug Metabolism

Renal diseases can cause considerable variability in drug response, which may present as enhanced or diminished drug response. Renal diseases (kidney diseases) affect the glomerular blood flow, glomerular filtration, tubular reabsorption and secretion. Renal bioactivation affects the drug metabolism, which causes alterations in drug absorption, bioavailability, distribution, binding of drugs to proteins and renal or non-renal clearance. Accumulation of drug metabolites and exogenous substances may make it necessary for the clinician to adjust the dose of drugs for the renal disease and associated ailments otherwise this variability can lead to either enhanced efficacy or enhanced toxicity depending on the drug characteristics. Renal diseases (renal disorders) may affect both pharmacokinetic and pharmacodynamic characteristics of a drug (as thiopental has been observed to cause prolongation of its anesthetic action and gentamycin to cause increased toxicity).

Dosage adjustment is usually needed if >30% drug is excreted unchanged in urine or is removed by dialysis in patients with renal impairment or renal failure. Impaired and compromised renal function effects the drug elimination and leads to accumulation of drug. The accumulation of drug further depends on the frequency of drug administration and half life of drug. The treating physician needs to know the pharmacokinetics and pattern of accumulation of drugs in renal failure and tentative time to achieve the steady concentration in plasma for the adequate dose adjustments.

Primary influence of renal disease on drug absorption is almost negligible. However, a few secondary influences like vomiting and diarrhoea due to uremia lead to dehydration and further lead to decreased perfusion and absorption of drugs from intramuscular and intestinal sites. Diabetic and uremic gastroparesis leads to altered rates of absorption of short acting drugs like sulfonylureas. Acid base imbalance and alteration in the levels of potassium in serum affects gastrointestinal tract mobility and rate & extent of drug absorption. Commonly used antacids bind and chelate dietary phosphates and lead to hypophosphatemia, also impair the absorption of drugs like iron and ketaconazole which need an acidic pH for optimal absorption. Impaired protein binding may also impair absorption of drugs. Edema caused by nephrotic syndrome or congestive heart failure has been documented to slowdown the drug absorption and cause increased bioavailability of drugs.

Drug Development: Non-Clinical Mutagenicity and Carcinogenicity Studies

The fundamental aim of non-clinical or pre-clinical studies in relation to new chemical entity (NCE) is to generate biological, pharmaceutical and toxicological data to ascertain that NCE would not cause any serious harm to the humans or would not cause cancer and/or genetic disorders through mutations. The limits of toxicological study of a NCE are decided with reference to route and duration of its intended use as a drug. Studies to evaluate carcinogenicity and mutagenicity of a NCE are performed in animals before it is declared as a drug and given to humans. Animal species usually used for carcinogenicity and mutagenicity are rats and mice, as some strains of these animals have very low incidence of spontaneous tumors and sufficient background knowledge about physiological parameters of these animals is available. Guidelines for such studies can be obtained from the regulatory agencies like FDA (USA), DCGI (India) and EMEA (Europe). The NCE is generally administered to the animals by at least two routes, one of which is usually the intended clinical route. The other route is usually intravenous so as to ensure adequate exposure of the animal to the new chemical entity. It is highly desirable to develop sensitive analytical methods for detecting the drug and its metabolites in the body fluids before starting the pre-clinical studies, as this would help in elucidating the toxicokinetics, pharmacokinetics, mutagenicity and carcinogenicity of the NCE. All studies need to be conducted in Good Laboratory Practice (GLP) compliance laboratories.

Carcinogenicity studies are needed to be done in adequate number of animals, depending on the regulatory requirements, before obtaining the approval for marketing of a drug. The drugs or compounds on which mutagenicity, carcinogenicity, teratogenicity and reproductive performance related effects need to be elucidated are of following types:

1. When the drug product is to be used for three months or longer period for at least six months - Carcinogenicity studies are must.
2. When the drug or compound is to be used frequently or in an intermittent manner in chronic or recurrent conditions like depression, anxiety and allergic rhinitis.
3. Prolonged exposure due to certain drug delivery systems makes it mandatory to carry out carcinogenicity studies.

Relaxations and Exemptions:

1. Genotoxic compounds are presumed to be trans-species carcinogens; hence long-term carcinogenicity studies are usually not needed.
2. Pharmaceuticals administered infrequently or for short duration of exposure (such as anesthetics and radiolabelled imaging agents) are exempted from carcinogenicity studies.
3. Carcinogenicity testing need not be conducted before market approval for the drugs developed for treating serious diseases.
4. If the life expectancy in the indicated population is short (less than 3 years), no long-term carcinogenicity studies are not required for the compounds to be administered to these subjects.