BASIC PHARMACOLOGICAL PRINCIPLES Drugs are exogenous molecules that mimic or block the action of endogenous molecules or systems.

Many types of pharmacological receptors: Physiological receptors: endogenous proteins that are the receptors for endogenous chemical signalling compounds such as hormones or neurotransmitters. Many drugs bind to such receptors. Other proteins such as enzymes, ion channels: drugs may bind to specific sites on proteins and prevent them from doing their job or, less commonly, they may stimulate them e.g. an ion channel in a membrane may be 'blocked' or it may be opened. Nucleic acids: drugs may bind to regulatory sites on nucleic acids to influence gene expression or protein synthesis. The bound drug may activate the receptor to provoke a response i.e. the drug is an agonist The bound drug may prevent the receptor from being activated i.e. the drug is an antagonist The type of binding site and the nature of the interaction(covalent-permanent or ionicreversible) of the drug with its binding site on the receptor determine the primary effects of the drug ___________________________________________________________________________ Pharmacodynamics: what a drug does to an organism - the sum of all of the actions of a drug Pharmacokinetics: what the organism does to the drug - absorption, distribution, metabolism and excretion (ADME)

Drug Discovery in the Pharmaceutical Industry

Drug Development in the Pharmaceutical Industry CLINICAL TRIALS 0

Phase 0 : first-in human trial using subtherapeutic dosing in human subjects. Can include tests on humanized animals or tissues

I
Small scale :involving 20 to 80 healthy volunteers

II
Medium scale : involving about 100 to 300 patient volunteers

III
Large scale :involving about 1000 to 3000 patient volunteers

IV
Post registration studies

safety Side effects Dose finding

safety Side effects effectiveness

safety Side effects effectiveness

comparison with current available medicines

Different populations Long-term safety

1 0

y e a r s

___________________________________________________________________________

The concentration-response relationship

Rectangular hyperbola

Symmetrical sigmoid

100%

100%

Drug concentration

Log Drug concentration

The maximal effect (Emax): Indicates the maximum response a drug can produce, i.e. the top of the concentration response curve The EC50: Molar conc. of a drug that produces 50% of the maximum response

There are three main types of pharmacological experiments: experiments in vitro experiments in vivo experiments ex vivo A tissue or organ is removed from an animal that has been treated with a drug, and the effects that drug has had on organ function are tested in vitro concentrations are expressed in Moles per litre i.e. Molar (M) 1 Mole of a drug contains 6.02 x 1023 drug molecules and weighs the molecular mass, in grams A 1 Molar solution contains 1 Mole of a drug dissolved in 1 litre of solvent Most importantly, a 1 Molar solution of drug X will contain the same number of drug molecules as a 1 Molar solution of drug Y ___________________________________________________________________________ RECEPTORS Receptors are protein macromolecules usually inserted across the lipid bilayer of the cell 2 main functions: Recognition/detection Transduction They interact with, or bind specific chemicals e.g.hormones or neurotransmitters; specificity Receptors are classified with respect to the drugs they bind eg nicotinic acetylcholine receptors

100%

Response

0%

AFFINITY is a measure of how strongly the drug binds to the receptor. Both agonists and antagonists have affinity for their receptor. Quantified by the Kd value (drug conc needed for 50% receptor occupancy a lowerd Kd corresponds to higher affinity) EFFICACY is a measure of the ability of a drug, once bound to the receptor to initiate a response (the response could be molecular, cellular, tissue, systemic or therapeutic, though defined historically at the tissue level). Full agonists have high efficacy, partial agonists have low efficacy, competitive antagonists have zero efficacy) POTENCY is a measure of the conc range of a drug over which it is effective. Quantified by EC50 a lower EC50 corresponds to a higher potency (related to affinity but not identical eg high amplification in the intracellular signalling pathways often results in a 50% maximum response being reached with much less than 50% occupation of the receptors, so EC50 is often smaller than Kd) Agonists: affinity AND efficacy whereas Antagonists: affinity BUT NO efficacy

100%

Response

0% Two main types of agonists So agonists bind to the receptor (have affinity) and activate it (have efficacy) Naturally occurring neurotransmitters and hormones are agonists e.g. adrenaline Agonists can be either partial agonists or full agonists Full agonists have high efficacy and as a result are very effective at producing a biological response Partial agonists have low efficacy and are therefore less effective Forms of antagonism Chemical - use one drug to chemically inactivate another Pharmacokinetic - one drug alters the way the body deals with another Physiological - two drugs act to produce opposing effects so canceling each other Competitive antagonists compete with the agonist for the same site on the receptor molecule, but dont activate it i.e. have affinity but zero efficacy Can be reversible or irreversible Non-competitive antagonists act at a different site on the receptor or another molecule closely associated with it Can be reversible or irreversible Reversible antagonists: Their effects can be overcome by increasing theconcentration of the agonist Reversible competitive antagonists produce a parallel shift to the right of the AGONIST log concentration- response curve

The pA2 of an antagonist: The affinity of a reversible competitive antagonist is quantified using its pA2. This is the negative logarithm of the concentration of antagonist that necessitates

that you double the agonist concentration to produce the same response (i.e. dose ratio = 2.0)

Bioassay Determining the relative potency of different drugs is a key role of the pharmacologist A bioassay is any techniques where the potency of a drug is determined by measuring the biological response it produces Pharmacologists have developed hundreds of different bioassays, ranging form cells in culture to clinical trials in humans to look at different aspects if drug response Bioassays underpin the development of new drugs in the pharmaceutical industry

Therapeutic index = LD50/ED50 LD50 = lethal dose in 50% of population ED50 = Effective dose in 50% of the population

Not used anymore

___________________________________________________________________________ Schild Plot

log (dose ratio -1) = log (antagonist concentration) log KB Construct a graph of log dose ratio-1 (x-axis) against log antagonist (y-axis)