For drugs which will be registered, human clinical trials must demonstrate safety and efficacy. Clinical trials collect also information about adverse drug reactions.
Clinical trials generally go through several phases:
- phase 1 – small number of healthy human volunteers (normally 20- 80) to determine safety and tolerability
- phase 2 – small number of patients (normally 100-300) to determine efficacy (compared with existing drugs or placebo) and detailed dosage information
- phase 3 – full scale multicentre randomised double blinded controlled clinical trial (normally 1000-3000) where investigational new drug is compared to established therapy or placebo
- phase 4 – obligatory post marketing surveillance to detect any rare or long-term adverse effects
Pharmacokinetics, what the body does to the drug, and Pharmacodynamics, what the drug does to the body, are now manipulable through molecular genomics.
Pharmacodynamics
The study of the mechanism of drug action on living tissue, i.e., the response of tissues to specific chemical agents at various sites in the body.
What the drug does to the body
While some drugs work by direct chemical or physical action, most drug mechanisms of action relate to their interaction with proteins functioning as either:
- Receptors
- Carrier molecules (Transporters)
- Ion channels
- Enzymes
Drug receptor selectivity for a binding site confers specificity for that drug action, mimicking or opposing the effect of the natural ligand. But because of some system near-redundancy, complete selectivity is difficult to achieve, even with modern targeted drugs. This incomplete specificity is a major reason for the adverse effects of drugs.
Protein (polypeptide) receptors are designated according to type as:
- Ligand-gated ion channels: fast-acting, coupled directly to ion channels to effect a change in the resting membrane potential e.g., nicotinic ACh receptor; GABAA receptor
- G-protein coupled receptors: coupled to various second messengers (for signal amplification) such as cAMP via membrane-bound G-proteins: e.g., muscarinic ACh receptors; adrenergic receptors
- Tyrosine kinase linked receptors: directly linked to kinases which cause phosphorylation and activation of enzymatic and regulatory intracellular proteins: e.g., insulin receptor, receptors for cytokines and various growth factors
- TK receptors today are important targets for cancer therapies
- Nuclear receptors: receptors located inside the cell (not on the cell membrane): e.g., steroid hormones and drugs, thyroid hormones, vitamin D
There are other receptor types too: e.g., nitric oxide receptors.
The physiological response of any drug is directly proportional to receptor occupancy, itself dependent on the drug concentration and drug affinity. Most drugs produce their effect through reversible non-covalent binding to target molecules, transposed through the electrostatic forces of stronger ionic and also hydrogen bonds and the weaker van der Waal forces. Rarely, the drug will be of a type that can bind irreversibly to its target via strong covalent bonds.
Compounds that bind to activate the receptor are termed agonists, as they mimic the action of the endogenous ligand. Full agonists produce a maximal response equivalent to biding by the natural ligand while partial agonists are those drugs that can produce only a sub-maximal response. Compounds that bind but do not activate the receptor are termed antagonists, that nature conferred to them by virtue of the fact that they stop the natural ligand from acting at that binding site. This is known as competitive antagonism. A non-competitive form of antagonism occurs where the drug acts on a site different to that of the natural binding site for the ligand, as seen with allosteric regulation of enzymes.
The reduced effect from exposure to a drug over time reflects a certain tolerance (tachyphylaxis) from either receptor down-regulation, fade, or desensitisation (decrease in absolute numbers of receptors). An up-regulation can also be seen in receptor types that have been exposed to antagonism.
