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.

Drug Development: Non-Clinical Toxicity Study

Majority of allopathic drugs are developed from the organic or inorganic chemicals. The most important part of the process of drug development is the decision to take a new chemical entity (NCE) from a non-clinical to clinical phase. A lot of data needs to be generated through non-clinical safety study to evaluate the toxicity level of the NCE before it could be passed on for clinical phase of testing. The fundamental aim of non-clinical or pre-clinical studies is to generate biological, pharmaceutical and toxicological data to ascertain that NCE would not cause any serious harm to the humans. The limits of toxicological study of a NCE are decided with reference to the mode and duration of its use as a drug. Guidelines for such studies can be obtained from the regulatory agencies like FDA (USA), DCGI (India) and EMEA (Europe).

Why toxicity studies are necessary?

All chemical substances are poisons. Even the large doses of common salt (Sodium chloride) are poisonous and may affect our kidneys, heart and liver. Only a right dose differentiates a poison from a remedy. So, it is mandatory to conduct non-clinical or pre-clinical toxicity study for a NCE to generate pharmacological, toxicological and physicochemical data. There may be a dose which is safe and effective for humans otherwise a low dose would not generate any ill effect and a higher dose may produce deleterious effects. Non-clinical or pre-clinical toxicity studies of a NCE are performed in animals before it is declared as a drug and given to humans. Animal species usually used are mice, rats, guinea pigs, dogs and rabbits as lot of background knowledge about biological and physiological parameters of these animals is available.

Major goals of non-clinical toxicity studies:

1. Generation of data regarding dose response and physiological and biological toxic effects.
2. Identification of toxicities with respect to target organs if any.
3. Evaluation of time-dependence of effects or reversibility of toxic effects
   after discontinuation of NCE under study.
4. Identification of parameters required to be monitored effectively in human beings. Like liver function, renal function or thyroid function studies.
5. Evaluation of safe starting dose for the first-in human trial, and
6. Detection, identification and management of consequences of overdoses.
   

Anti-thyroid Drugs: Precautions in Pregnancy, Lactation and Asthma

The thyroid gland of our body controls the body metabolism through its iodine containing hormones. Normal thyroid gland is not palpable but the enlarged thyroid gland could be felt in front of the neck and may be associated with non-toxic or toxic goitre. Goitrous gland may have normal function or under function (hypothyroidism) or over function hyperthyroidism). The exophthalmic goitre is known as Graves's disease and in this
disease the eye balls protrude due to thyrotoxicosis.

The compounds used as anti-thyroid drugs include carbimazole and propylthiouracil. Anti-thyroid drugs inhibit the formation of thyroxine and triiodothyronine (T3) in the thyroid gland. Propylthiouracil also retard the peripheral conversion of thyroxine into triiodothyronine (T3). The same drugs are also used for the treatment of thyrotoxicosis and preparation for thyroidectomy. Anti-thyroid drugs may suppress the bone marrow so blood cell counts are advisable at regular intervals during the course of treatment. Pregnant and/or lactating patients with thyrotoxicosis need to consult the endocrinologist and to reduce the dose to minimum. Patients with tracheal obstruction or asthma also need extra care during the treatment of hyperthyroidism or thyrotoxicosis. Anti-thyroid drugs may cause nausea, gastro-intestinal upset, thyroid enlargement, agranulocytosis, granulocytopenia ( low count of neutrophils and eosinophils), leucopenia (low count of white blood cells) and thrombocytopenia low count of platelets); that is why regular blood counts are advisable. Self-treatment of hyperthyroidism or thyrotoxicosis is not advisable, as it needs investigative follow up. However, carbimazole oral drug is started with a dose of 15-45mg daily in divided doses depending on the severity of the disease and maintenance dose could be 2.5-25mg daily for 12 months. For thyroidectomy preparation, the dose may be 15-45mg daily in divided doses for 2-4 weeks depending on the severity of the disease.

To know more about thyroid gland and its functions-click here: http://ntips4u.blogspot.com/2009/07/thyroid-gland-and-its-functions.html

 

Thyroid Drugs: Precautions in Diabetes and Heart Disease

Thyroid drugs are used for treatment of hypothyroidism a condition caused by under function of thyroid gland. These drugs are based on thyroid extract and increase the metabolic rate with a subsequent increase in catabolism. Thyroid gland is associated with the general metabolism of all body tissues. Suboptimal activity of thyroid gland at birth leads to hypo-secretion of thyroid hormones and causes cretinism, impairing the mental and physical growth of an infant or child. The child grows up a mentally retarded dwarf, unless diagnosed and treated with thyroid drugs. Patients affected by under function of thyroid gland or hypothyroidism, develop generalized oedema called myxoedema (swelling of body). In myxoedema metabolic processes slow down with a tendency to gain weight. There is slowness of mind and speech and one feels lethargic.

Thyroid drugs used for hypothyroidism as well as cretinism contain thyroglobulin, thyroxine or liothyronine. Same drugs are also used for thyroid replacement therapy in cases of thyroidectomy. Treatment is started with low initial dose of 50-100 mcg daily, increased 25-50mcg at 3-4 weeks interval and maintenance dose may be 200-300mcg.
Overdosage or too rapid increase may produce signs and symptoms of hyperthyroidism, so self-treatment of hypothyroidism is not advisable. Patients receiving diabetic treatment, anticoagulant therapy, corticosteroid therapy or anti-hypertension therapy may need readjustment of treatment. There are many side effects of thyroid drugs. Patients receiving treatment for hypothyroidism, myxoedema, or cretinism may feel restlessness and have headache, transient diarrhoea, weight loss, anginal pain and palpitations. Overdosage of thyroid drugs in patients with heart disease may lead to serious complications.

To know more about thyroidisms click here: http://ntips4u.blogspot.com/2009/07/signs-and-symptoms-of-thyroid-disorders.html