Basic Concepts of Pharmacology in Drug Development (ATA 2012)

by R. A (Bob) Lyon, Section Head R&D Proctor and Gamble

The objective of the talk was to outline the process of drug development, the principles underlying this process and some of the associated terminology and techniques.

Drugs are exogenous substances that bring about a change in biological function through a chemical interaction with the endogenous mechanisms within the body.

The overall flow of drug development is as follows

Identification of a target mechanism in the body which brings about a desired alteration in biological function (e.g. 5HT1A (serotonin) receptor activation, alleviating anxiety)

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Screening of numerous compounds in vitro to try to identify compounds having the desired effect and narrow down to a single “lead compound” which has the best and “cleanest" effect (low toxicity and other, possibly undesirable, effects)

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Various animal studies, examining the specific and general pharmacology of the lead substance, and its safety (toxicity, mutagenicity, effect on reproduction, etc.)

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Phase I (preclinical) studies on humans, typically healthy, investigating safety (adverse effects), tolerance (dosage) and pharmacokinetics (absorption, distribution, metabolism, excretion)

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Phase II clinical studies on small numbers of target subjects to investigate efficacy (proof of concept - effect on target, e.g. anti-anxiety) safety, and dose-effect relationships in this population

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Phase III large scale clinical studies on the target population

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Submission to the regulatory authorities

After approval (possibly with contingencies)↓

Phase IV

This process typically takes of the order of 10 years, and costs of the order of $500 million

Principles of drug action

Drugs largely work by interacting with signalling between cells. In the talk this was illustrated by signalling at the synapse between neurons.

There are various possible targets for this interaction, which include:

a direct effect at the cell level to stimulate or block the release of a chemical substance such as a hormone, neurotransmitter or enzyme (e.g. releasing agents);

activation or blocking of the receptors for such chemical substances, provoking the receptor to produce a response by mimicking the natural substance (agonist); or blocking or altering the receptor so that the natural substance cannot produce a response (antagonist)

activation or blocking of a transporter substance, to enable a substance, or nerve impulse, etc., to reach its target, or stop it from so doing.

activation or inhibition of an enzyme, by altering the molecule to make it more or less active, or by mimicking a natural substrate and blocking active sites

stimulation or repression at gene level, to activate or inhibit expression of an enzyme

There are numerous possibilities, and the molecular mechanisms are exceedingly complex.

Expressing drug dose/response (in vitro)

Agonists can be full agonists, giving a 100% response, or partial agonists, giving less than a 100% response. The effect of an agonist is typically expressed as ED₅₀ or EC₅₀ - the dose or concentration giving a 50% effect. The maximum effect is E_max. For measuring dose [D] vs. effect, log[D] vs. (E/E_max) is generally used, which gives a sigmoidal curve.

The dose-response is an expression of the affinity of the agonist for the receptor or receptor occupancy.

Potency expresses dose/effect - i.e. is related to EC₅₀; in general, high potency is preferred since a lower dose is likely to generate less side-effects

Antagonists do not have intrinsic activity but shift the effect of an agonist. Antagonism can be competitive, when binding to a receptor is reversible and the antagonist competes with the agonist, or non-competitive, when the antagonist binds irreversibly or alters the receptor. Competitive antagonism increases EC₅₀, and it may be possible to achieve a maximal effect with more agonist. Non-competitive antagonism on the other hand lowers E_max, because fewer receptors are available.

The remarks on competitive and non-competitive antagonism also broadly apply to competitive and non-competitive inhibition of enzymes, except that in this case competition is between an inhibitor which can reversibly bind to an active site on the enzyme, and a natural substrate.

Effectiveness of course needs to be weighed against safety. One index of this is the therapeutic index, which

ED₅₀ for a therapeutic effect/ED₅₀ for a lethal effect

Measuring drug-receptor interaction

Radioligand binding was introduced as a method for studying receptor interactions. by radiolabelling drugs (ligands) to study affinity for receptors by comparison with the same or different unlabelled ligands.

Drugs of Abuse: A Pharmacological Perspective

R. A (Bob) Lyon, Section Head R&D Proctor and Gamble

Outline of drug action in the central nervous system

The talk began by outlining the functioning of the central nervous system, wherein the neuron bodies emit electrical signals along the dendrites to the terminal branches to release neurotransmitters into the synapse to communicate between nerve cells, etc., and the various levels at which drugs can affect this process, before the synapse (presynaptic) by affecting firing, synthesis storage and release of the neurotransmitters, or inhibiting their re-uptake so that their effect persists for longer, or after the synapse (post-synaptic), by interacting with their receptors to potentiate or block their effects on their target.

They can stimulate, or mimic the action of natural substances (agonists, e.g. serotoninergic drugs such as LSD, which are 5HT-2A agonists) or block this action (antagonists such as Naloxone, an opioid antagonist).

The language of drugs (Reference USA)

Drugs can be used for medical or non-medical (“recreational”) purposes Medical drugs are classified broadly as over the counter (OTC) or prescription (Rx, ethical), there is also a further category of “behind the counter” for OTC substances which can be used as starting materials for illegal drugs (eg. pseudoephededrine, a nasal decongestant which can be used to make methamphetamine.

Potential drugs of abuse are “scheduled”, ranging from Schedule 1, with no known medical use and high degree of danger from abuse (e.g. heroin and LSD), to Schedule 5 medical use and low abuse potential (e.g. codeine, an opiate). Benzodiazepine and amphetamines are 3-4, and cocaine is 2, because of medical use in eye surgery.

Designer drugs are synthetic drugs employing chemical modification to avoid scheduling. Until identified and scheduled, they remain legal; however, since they are not subject to any conventional approval process, they are potentially extremely unsafe.

Route of administration, how the drug is administered e.g. orally, nasally, by smoking, intravenously, rectally vaginally, etc.

Drug delivery device - the device used to administer the drug, e.g. sugar cube, pipe, syringe, cup

Addiction: psychological craving

Dependence: a physico-chemical need for the drug for well-being

Withdrawal: what happens after cessation in dependants

Tolerance: the need for more in order to get the same effect

Classes of drugs of abuse

Central nervous stimulants - include, caffeine, nicotine, amphetamine, cocaine, and “bath salts”. effects include high energy/focus and decreased need for sleep.

Caffeine: adenosine receptor antagonist, side-effects diuresis, nervousness, rapid tolerance, addictive, leads to dependence (withdrawal effects)

Nicotine: nicotinic receptor agonist; side effects increased blood pressure and heart rate; rapid tolerance, addictive, leads to dependence (one of most addictive)

Amphetamines (illegal synthetics) increase dopamine and norepinephrine release and block reuptake; side effects increased BP and heart rate, psychosis and long term psychological changes (schedule 2)

Cocaine: snorted, smoked or injected in increasing order of effect. Increases dopamine release and reuptake; side effects increased BP and heart rate (potentially lethal) (schedule 2 -use as anesthetic in eye surgery)

“Bath salts”: designer drugs (mephedrone, methylenedioxypyrovalerone, etc., Ivory Wave, Vanilla Sky, etc.). Cheap high, effects similar to amphetamine; side effects include paranoia, hallucinations and suicidal tendencies. Schedule 1

Central nervous system depressants: include alcohol, opiates/opioids, barbiturates, benzodiazepine; effects, relaxation, analgesia, sedation

Alcohol (ethanol): affects acetylcholine,, GABA (γ-aminobutyric acid) and NMDA (N-methyl-D-aspartate) exact mechanism not fully understood; general depressive effect with dose response from relaxation to death; side effects foetal alcohol syndrome, alcoholism, liver disease; tolerance, addictive, leads to dependence. Warning as to the potentially dangerous effects of combining with a stimulant such as caffeine and guaraná (e.g. Four Loko).

Opiates/opioids: e.g. morphine, codeine, thebane; µ opioid receptor agonists; side effects include constipation; highly addictive/dependency creating (withdrawal)

Barbiturates and benzodiazepines: GABA receptor agonists; anxiolytics and hypnotics (librium, valium, rohypnol)

Psychedelics: principal effects are enhancement or modification of reality

Marijuana: mildly hallucinogenic, contains delta 9-THC and >60 other cannabinoids which act as cannabinoid 1 and 2 receptor agonists; effects include euphoria, laughter and relaxation; side-effects, anxiety, coughing and paranoia

K2, Spice and THC are more potent and more addictive

LSD, psilocybin, mescaline, DMT, dimethoxytryptamine (santo daime); serotonin 5HT2A agonists; effect (8-12 hr) is alteration of experience, vivid colours, the setting determines the trip; side effects include weakness, jaw clenching and increased heart rate; rapid dependence, no dependence or addiction; potential applications to enhance spirituality in terminal patients

Ecstasy, (N-methyl)-3,4-methylenedioxyamphetamine), MDMA; adrenaline uptake inhibitor, serotonin 5HT2A agonist

Dissociative: e.g. PCP (phencyclidine), ketamine and dextromethorphan; NMDA antagonists, altering distribution of glutamate, associated with out of body experience/detachment.

PCP is addictive and associated with psychotic side effects; ketamine is used as an animal tranquilizer, and can lead amnesia, depression and breathing problems at high doses. Dextromethorphan is an OTC cough suppressant which causes similar effects at high doses

Saliva divinorum, κ-opioid agonist, can induce dissociative effects and “visions, used in Mexican native religion.

Delirants: alkaloids atropine and scopolamine are (competitive) muscarinic cholinergic antagonists, associated with tachycardia and hyperthermia.