Pharmacodynamics Department Of Pharmacology

Tolerance: Decreased response to a drug following repeated administration though the dose is constant. Acute tolerance: develops very fast E.g. Tachyphylaxis to ephedrine Chronic tolerance: develops over a period of time and may be of two types based on the mechanism of development: Pharmacodynamic tolerance (cellular adaptation) – Morphine Pharmacokinetic tolerance (dispositional) – Carbamazepine Both Pharmacodynamic & Pharmacokinetic – Alcohol

Pharmacodynamic (cellular adaptation) tolerance – Eg. Alcohol, Morphine - Chronic exposure to a drug leads to  Response though the dose & plasma concentration remain the same as the cellular response is decreased. Pharmacokinetic (dispositional) tolerance – E.g. Carbamazepine, Alcohol - Chronic exposure to drug leads to  Response due to  in plasma concentration of the drug due to enhanced enzyme activity & metabolism of the drug.

Pharmacogenetics Genetic variation in enzyme activity leading to altered metabolism of drugs. (either absence of an enzyme or presence of an abnormal enzyme) usually inherited. Scoline apnea – Scoline is a skeletal muscle relaxant metabolized by pseudocholinesterase in plasma. In some people an abnormal pseudocholinesterase is present which does not metabolize scoline resulting in prolonged action of scoline. As a result, respiratory muscle paralysis and apnea occurs. Isoniazid (antitubercular drug) – undergoes acetylation. Some are slow acetylators & some are fast acetylators – Slow acetylators may develop toxicity while Fast acetylators s may experience treatment failures.

Polypharmacy is defined as the concomitant use of five or more drugs in the treatment of diseases, suggesting indiscriminate, unscientific, or excessive drugs per prescription. Undesirable consequences of polypharmacy are increase in adverse drug reactions drug interactions Patient non-compliance

Polypharmacy

Compliance: Is the extent to which the patient obliges the treatment instructions. Non-compliance is one of the major causes of treatment failure. Polypharmacy and complicated regimens increase the incidence of noncompliance. Non-compliance can be decreased by Countering above factors and by effective communication with the patient.

Essential Drugs - are those required to meet most of the common medical problems of majority of the population. Eg. WHO essential drug list Rational Drug Therapy (RDT) (WHO def.) requires that patients receive medicines appropriate to their clinical needs, in doses that meet their own individual requirements, for an adequate period of time, & at the lowest cost to them and to the community. It aims at improving the way the drugs are prescribed, dispensed & used.

New Drug Development Learning objectives: 1.Approaches to new drug discovery 2.Drug screening 3.Preclinical safety and toxicity testing 4.Evaluations in humans 5.Clinical trials ( Phase 1 – 4 )

New Drug Development Drug development is a long and expensive journey undertaken primarily by the pharmaceutical industry Drug development may take from 10 – 15 years. Only 10% or less may reach to the level of prescribing Need for clinical testing of compounds Experimental results from animals cannot be extrapolated to humans because Some actions may not be similar – Clomiphen contraceptive in rats & ovulation inducing agent in humans Some ADRs may not be seen in animals – Thalidomide tragedy

New Drug Development Preclinical Studies - tissues and whole animals Review Clinical Studies ● Phase I : healthy volunteers (20-50) - PK, PD ● Phase II : patients (50-300) - PK, PD, dose-ranging, safety ● Phase III : patients ( ) - formal clinical trial, efficacy, safety Granting of Product Licence ● Phase IV : post-marketing surveillance(1000s) studies, for adverse drug reactions etc. Developing & launching a new drug - £100M and 10 to 15 yrs

Approaches to new drug discovery 1.Identification of new drug target 2.Rational drug design based on biological mechanism,drug and receptor structure 3.Chemical modification of known molecule 4.Screening of natural products,previously discovered chemicals 5.Biotechnology and cloning genes to produce peptides and proteins 6.Combination of known drugs to obtain additive or synergistic effect

Drug screening tests ; are done to define the pharmacologic profile of the drug at molecular, cellular,system, organ and organism level. Number of tests are according to the therapeutic goal. Whole animal studies are done to determine the drug effect on organ system and disease models.

Abuse potential studies : are done for those drugs with the possibility of physical dependence. The desired result of these screening procedure is called a lead compound i.e., a leading candidate for a successful new drug. Tolerance tests : are done for drugs that need long- term administration.

Preclinical safety and toxicity testing The goals of preclinical toxicity studies are : 1)To identify human toxicities. 2)For designing tests to further define toxic mechanisms. 3)To predict the specific and most relevant toxicities to be monitored in clinical trials.

Type of safety tests are ; a.Acute toxicity b.Sub acute toxicity c.Chronic toxicity d.Effect on reproductive performance e.Carcinogenic potential f.Mutagenic potential g.Investigative toxicology h.Quantitative estimates like no-effect dose, minimum lethal dose, median lethal dose

Evaluation in humans Is conducted in accordance with stringent guidelines. Design and execution of a good clinical trial require interdisciplinary personals like basic scientists, clinical pharmacologists, clinician specialist,statisticians,etc. Three major confounding factors need to avoid in making study design are ;  The variable natural history of most diseases.  The presence of other disease and risk factors.  Subject and observer bias.

Clinical trials : A notice of Claimed Investigational Exemption for a New Drug must be filed with FDA including : 1)Information on composition and source of the drug. 2)Chemical and manufacturing information. 3)All data from animal studies. 4)Proposed clinical plans and protocols. 5)Name and credentials of clinician who will conduct 6)A compilation of key data relevant to study the

drug in man made available to investigators and their institutional review boards. Phase 1 – The effects of a drug as a function of dosage are established in a small number of healthy volunteers. Goal is to find the maximum tolerated dose but it is designed to avoid severe toxicity. Phase 2 – the study is done in patients with target disease to determine its efficacy. Usually done in special clinical centers and often single blind. A broader range of toxicities may be seen.

Phase 3 – the drug is studied in much larger group of patients to further establish safety and efficacy. Frequently use double-blind and crossover techniques. Certain toxic effects may become apparent during this phase. If phase 3 results meet expectations, application is made for permission to market the new agent. New Drug Application is submitted to FDA.

Phase 4 – begins once FDA’a approval to marketing Is obtained. Continue monitoring the safety of new drug under actual conditions of use in large no. of patients. Careful and complete reporting of adverse reactions and toxicity is important.

From Laboratory to Patient: The Complex Pathway of Biopharmaceutical R&D Source: Pharmaceutical Industry Profile, 2005, PhRMA Drug DiscoveryPre-ClinicalClinical TrialsFDA Review Large-Scale Manufacturing/ Phase IV 5 Years1.5 Years6 Years2 Years NDA Submitted IND Submitted 5 Compounds Average time in stage 1 FDA Approved Drug 250 Compounds 10,000 Compounds

New Drug Evaluation Who? Why? Phase 4 New Drug Application Review

Objectives for self study – Lecture 4 Factors modifying drug action: Age, weight, gender, physiological states (pregnancy, lactation), other diseases, liver and kidney impairment, Concurrent drug administration (Additive effect, synergism, Drug antagonism), Pharmacogenetics, Tolerance Polypharmacy Compliance Essential drugs Rational drug therapy (RDT) Clinical Pharmacology