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

2. 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
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3. 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
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4. Introduction Basically, we could have Side Effects Adverse effects
Hypersensitivity reactions
Idiosyncrasies
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5. 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
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6. 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)
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7. 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
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8. 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.
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9. 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.
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10. 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.
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11. 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.
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12. 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)
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13. Popoola Temidayo B.Pharm, M.Sc, FPCPharm
New Drug Development
Popoola Temidayo B.Pharm, M.Sc, FPCPharm
12/2/2018

14. 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
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16. 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
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17. 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
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18. 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
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19. 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
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20. 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)
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22. 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
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23. 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.
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25. 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 ( ) 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
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26. Clinical Development
Phase III studies are the definitive double-blind randomized, multi-centred trials on 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
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28. 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
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29. Post-Marketing Surveillance
It also evaluates potential issues such as
use of the drug in comorbid states
Drug interactions
Hypersensitivity or Idosyncrasies
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