Chemotherapy of Specific Diseases, Biology tutorial

Introduction to Chemotherapy of Chagas Disease:

Chagas disease is caused by protozoan Trypanosomacruzi, and it is common in Latin America. Mode of transmission is by hematophagousreduviid vectors like Triatomainfestans that establish the habitat in human dwellings. Over a long period, pathogenesis of Chagas disease was unclear and it was believed to be the autoimmune condition. Though, current knowledge points out that parasitic invasion coupled with the unbalanced immune response plays the significant role in characteristic pathology seen in both acute and chronic human chagas disease. Chemotherapeutic drugs most often utilized in treatment of chagas disease are nitroheterocyclic compounds like nitrofuran, nifurtimox andbenznidazole a nitroimidazole derivative, radanil. Trypanosomacruzi lacks mechanisms to detoxify oxygen metabolites particularly hydrogen peroxides, and are therefore more sensitive to oxidative stress than vertebrates. Nifurtimox therefore acts by decreasing nitro groups to unstable nitroanion radicals that in turn react to generate toxic reduced oxygen metabolites. The main limitations of nitroheterocyclic compounds is difference in the level of efficiency at the acute and chronic stages of disease, although the reason for this disparity is yet unknown. Studies have also shown that specific sterol inhibitors like itraconazole, utilized in treatment of fungal diseases, inhibit sterols needed by Trypanosomacruzi for cell viability and proliferation at all phases of cell division. Chemotherapeutic agent N-methyl-piperazine-urea-F-HF-vinyl-sulphone-phenyl inhibits cruzain, accountable for main proteolytic activity of all phases of parasites life cycle, and consequently prolongs survival and induces parasitological cure in acute and constant stages of human chagas disease with minimal toxicity.

Chemotherapy of Hodgkin's disease:

Hodgkin's disease is lymphoma, the cancer of lymphatic system. Hodgkin's disease is differentiated from non Hodgkin's lymphoma by presence of large abnormal cells, called as Reed-Sternberg cells. Hodgkin's disease is categorized in two types, classical Hodgkin's lymphoma that is more common and less common nodular lymphocyte-predominant Hodgkin's disease. Hodgkin's disease is regarded as one of the most curable forms of cancer, if diagnosed and treated early. Main kinds of treatments for Hodgkin's disease are radiation and chemotherapy. Standard chemotherapy regimens for Hodgkin's disease are ABVD and standard V. ABVD is four drug mixture; doxorubicin, bleomycin, vinblastine and dacarbazine, while standard V is seven drug combination; etoposide, prednisone, vincristine, mechlorethamine, doxorubicin, bleomycin, and vinblastine. BEACOPP (doxorubicin, bleomycin, vinblastine, cyclophosphamide, etoposide, prednisone, and precarbazine) is the chemotherapy regimen reserved for high risk patients, and has been proven to be very efficient particularly at advanced stage of disease. Common mild and temporary side effects are nausea, vomiting, weight loss, hair loss, diarrhea and depression. Serious side effects which may occur are; neutropenia, which is a severe drop in white blood cells, anemia, a drop in red blood cells, liver and kidney damage, allergic reaction and abnormal blood clotting. Though, drugs have been developed to decrease intensity of unfavorable effects of the combinations, but duration of combat actions of the drugs is short. Long term implications related with the use of the combinations are fatigue, infertility, heart failure, menopause, and bone thinning. Bleomycin has been related with lung toxicity, while vinblastine is seen to be toxic when utilized in combination with radiation. Combination of chemotherapy and radiation are utilized in treatment of advanced stages of Hodgkin's disease.

Pharmaco-dynamics and pharmco-kinetics:

Pharmacodynamics is the study of biochemical and physiological consequences of drugs on the body or on microorganisms or parasites inside or on body and mechanisms of drug action and relationship between drug concentration and effect. While pharamacokinetics engages determination of fate of substances managed externally to the living organism. Pharmacodynamics can be just referred to as what drug does to the body, while pharmacokinetics is what the body does to the drug.

Pharmacodynamics:

The mode of most drug actions is in form of mimicry of main fundamental procedures of parasites and microorganisms, or rather through inhibition of these fundamental processes. Mode of drug actions, under these common techniques are; stimulating or depressing actions by directly binding to receptors to trigger response, blocking action by directly binding to receptor without starting it, stabilizing action by acting neither as stimulant or depressant, replacing or accumulating substances to create reserve, scavenging free radicals attained from oxidation, and direct injurious chemical reaction which may result in damage or destruction of cells by induced toxic or lethal damage. Only few drugs are specific in choice of receptor binding, but most have relative specificity. Ability of drug to affect the given receptor is determined by the affinity and intrinsic efficacies that are further determined by chemical composition. Though, there are some drugs which induce effects without binding to receptors or altering cellular functions, like antacids act by just decreasing gastric acidity through chemical reactions with acids to produce salts. The desired effect of the drug on the body is observed mostly because of one of the given reasons; interaction with structural or carrier proteins, interaction with ion channels, or disruption of cell membranes. Pharmacodynamics is not limited to advantages alone, there are also unfavorable effects related with use of drugs, like induced physiological damage or abnormal chronic conditions, or increasing likelihood of cell mutation. It has been seen that drug's pharmacodynamics can be influenced by physiological changes because of disorders, aging or effects of other drugs. Disorders like genetic mutations, Parkinson's disease, malnutrition, or insulin-resistant diabetes mellitus are affected.

Pharmacokinetics:

This is frequently studied in association with pharmacodynamics. Pharmacokinetics comprises the study of mechanisms of absorption and distribution of the administered drug, the rate at which the drug action starts and duration of the effect, the chemical changes of the substance in the body and the effects and routes of excretion of metabolites of drug. Drug pharmacokinetics determines onset, duration and intensity of the drug's effects. Procedures of pharmacokinetics can be described and summarized by absorption, metabolism, distribution and excretion.

i) Absorption:

Drug absorption is determined by drug's physiochemical properties, formulation and route of administration. The majority of drugs are weak organic acid or bases, existing in ionized or non-ionized forms. Non-ionized forms are lipid soluble, and readily diffuse across membranes, whereas the ionized forms are water soluble. Drugs are generally administered orally, and should be in the solution to be absorbed. Drugs should cross several semi-permeable membranes prior they reach the systemic circulation. Therefore mode of drug transport across membranes is by passive diffusion, pinocytosis or active transport. Perfusion, which is blood flow per gram of tissue, also influences absorption of drugs. In other words, site of injection affects absorption rate. Rate and extent to which the drug enters systemic circulation to gain access to site of action, called as bioavailability is dependent on properties of dosage sex, form, physical activity, age, stress, disorders etc.

ii) Distribution:

Drugs are distributed to tissues after they gain entry in systemic circulation. Distribution is influenced by differences in regional pH, cell membrane permeability, tissue binding and blood perfusion, and these results to the uneven distribution of drugs to tissues. Rate of blood flow to tissue, tissue mass, and partition characteristics between blood and tissue determine rate of entry of drug in tissue.

iii) Metabolism:

This is a irreversible transformation of the compound in daughter metabolites, and the principal site for this is in liver. Drugs can be metabolized by isomerisation, oxidation, conjugation, hydrolysis, reduction, condensation or hydration, mostly for easier excretion by body. Rate of drug metabolism is dependent on the individual genetic components, disorders or drug effects affecting metabolic rates, and age of patients.

iv) Excretion:

This is just the elimination or exclusion of broken down metabolites from the body, though hardly ever, these substances may collect in the body tissues. The majority of drugs and their metabolites are excreted from the body by renal and biliary excretion. Renal excretion gives the most common form of mechanism of drug excretion.

Patients- related factors like genetic properties, sex and age can be utilized to forecast pharmacological response of populations. For instance, half-life of some drugs is amazingly longer in elderly.

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