Responses to Drug Administration Popoola Temidayo B.Pharm, M.Sc, FPCPharm 12/2/2018

Introduction Responses to the same dose of drug are not always the same Inter- and even intra-individual variation can occur Variations can be: Pharmacokinetic – due to differences in the extent of absorption, distribution, metabolism and excretion Pharmacodynamic – due to differences in the expression of target enzymes, receptors and other proteins 12/2/2018

Introduction the drug produces a larger or smaller effect, or Variations are usually seen as the drug produces a larger or smaller effect, or The drug produces the same effect however it acts for a longer or shorter time In some cases though a completely unexpected effect occurs. These are usually due to genetic or immunological differences between individuals 12/2/2018

Introduction Basically, we could have Side Effects Adverse effects Hypersensitivity reactions Idiosyncrasies 12/2/2018

Side Effects Predictable Well understood Reversible Effects related to the main pharmacological action of the drug Predictable Well understood Reversible Dealt with by reducing the dose They are sometimes referred to as type A ('augmented') adverse reactions 12/2/2018

Side Effects E.g. postural hypotension occurs with α1- adrenoceptor antagonists (Prazosin) bleeding with anticoagulants (e.g. warfarin) cardiac dysrhythmias with glycosides (e.g. digoxin) sedation with anxiolytics (e.g. diazepam) 12/2/2018

Adverse Effects There could be effects unrelated to the main pharmacological effect that may be predictable when a drug is taken in excessive dose e.g. Paracetamol hepatotoxicity, Aspirin induced tinnitus Aminoglycoside ototoxicity 12/2/2018

Hypersensitivity reactions The term hypersensitivity usually refers to allergic or other immunologic responses to drugs Immunologically mediated adverse reaction to a drug results from previous sensitization to that drug or to a structurally similar one Once sensitization has occurred, allergic reactions may result from exposure to relatively very low doses of the drug Sometimes very severe and may be fatal. 12/2/2018

Hypersensitivity reactions Most drugs and their metabolites are not large enough to be recognized by the immune system as a foreign substance They combine with an endogenous protein to form an antigen (or immunogen). A molecule that must combine with an endogenous protein to elicit an allergic reaction is called a hapten. 12/2/2018

Hypersensitivity reactions Clinical spectrum of these reactions range from dermatitis, urticaria, itching, conjunctivitis (most common) to Bronchiolar constriction and fatal anaphylactic shock. Examples include hypersensitivity reactions to β- Lactams (e.g. penicilins), diuretics e.g. Carbonic Anhydrase Inhibitors (acetazolamide), Stevens- Johnson Syndrome with pyrimethamine, lamotrigine and ibuprofen. 12/2/2018

Idiosyncrasies An idiosyncratic reaction is a qualitatively abnormal, usually harmful drug effect that occurs in a small proportion of individuals Idiosyncratic reactions are often initiated by a chemically reactive metabolite rather than the parent drug. Such indirect toxicity may be direct or immunological in nature. 12/2/2018

Idiosyncrasies May occur with even with low doses Genetic factors are usually responsible (e.g. primaquine-induced haemolysis in patients with glucose-6-phospate dehydrogenase (G6PD) deficiency) However, mostly poorly understood (e.g. bone marrow depression with chloramphenicol) 12/2/2018

Popoola Temidayo B.Pharm, M.Sc, FPCPharm New Drug Development Popoola Temidayo B.Pharm, M.Sc, FPCPharm 12/2/2018

Introduction Most of modern pharmacology is based on drugs that came from the laboratories of pharmaceutical companies, without which neither the practice of therapeutics nor the science of pharmacology would be appreciated The reverse is also true 12/2/2018

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Drug discovery Candidate molecules are chosen on the basis of their pharmacological properties In the past, drug discovery schemes were based on measuring complex responses in vivo. Now, it is started with a defined protein target, so the first step is target identification. E.g. Development of ARBs 12/2/2018

Drug discovery When the biochemical target has been decided the next step is to find lead compounds Cloning of the target protein Screen thousands to millions of compounds against the cloned protein is established assays (robots used) You could also do predictive computer based assays (Bioinformatics)- lead optimization 12/2/2018

Drug discovery In resource limited settings e.g. Nigeria, scientists still work from measuring complex responses in vivo. Historically, natural products, derived mainly from fungal and plant sources, have proved to be a fruitful source of new therapeutic agents. Familiar examples include penicillin, streptomycin and many other antibiotics, vinca alkaloids, taxol, ciclosporin and rapamycin 12/2/2018

Drug discovery The main disadvantage of natural products as lead compounds is that they are often complex molecules that are difficult to synthesize or modify; consequently lead optimization may be difficult, and commercial production very expensive 12/2/2018

Drug discovery In lead optimization, the aim (usually) is to increase the potency of the compound on its target, and to optimize it with respect to other properties, such as selectivity, metabolic stability, etc. Pharmacological profiling involves a broader range of assays on different test systems in vivo (animal models mimicking aspects of the clinical condition) 12/2/2018

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Pre-Clinical Development Involves Pharmacological testing, to check that the drug does not produce any potentially hazardous or serious unwanted effects Initial toxicological testing, to eliminate genotoxicity, histological and biochemical evidence of tissue damage and to determine the maximum non-toxic dose 12/2/2018

Pre-Clinical Development Pharmacokinetic screening: studies on the absorption, metabolism, distribution and elimination (ADME studies) in laboratory animals. Chemical and pharmaceutical development: to assess the possibility of large-scale synthesis, the stability of the compound under various conditions, and to develop a formulation suitable for clinical studies. 12/2/2018

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Clinical Development Phase I trials are performed on a small group (20-80) of normal healthy volunteers Phase II studies are performed on groups of patients (100-300) and are designed to test for efficacy (including dose required) in clinical situations phase II trials examine whether or not the initial hypothesis was correct 12/2/2018

Clinical Development Phase III studies are the definitive double-blind randomized, multi-centred trials on 1000-3000 patients compares the new drug with commonly used alternatives. These trials are extremely costly, difficult to organize and often take years to complete, particularly if the treatment is designed to retard the progression of a chronic disease 12/2/2018

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Post-Marketing Surveillance At the end of phase III, the drug will be submitted to the relevant regulatory authority for licensing (Marketing approval) Phase IV studies comprise the obligatory postmarketing surveillance detects any rare or long-term adverse effects resulting from the use of the drug in a clinical setting in many thousands of patients 12/2/2018

Post-Marketing Surveillance It also evaluates potential issues such as use of the drug in comorbid states Drug interactions Hypersensitivity or Idosyncrasies 12/2/2018