Introduction: principles of drug action

Medical pharmacology is the science of chemicals that interact with the human body. These interactions are divided into two classes:

• pharmacodynamics   Effects of the drug on the body

• pharmacokinetics  way the body affects the drug with time.

A few drugs  act by virtue of their physicochemical properties, and this is called non‐specific drug action. Some drugs act as inhibitors for certain transport systems  or enzymes. However, most drugs produce their effects by acting on specific protein molecules, located in the cell membrane. These proteins are called receptors, and respond to endogenous chemicals in the body.

These chemicals are either synaptic transmitter substances or hormones. For example, acetylcholine is a transmitter substance released from motor nerve endings, it activates receptors in skeletal muscle, initiating a sequence of events that results in contraction of the muscle. Chemicals (e.g. acetylcholine) that activate receptors and produce a response are called agonists. Some drugs, called antagonists, combine with receptors, but do not activate them. Antagonists reduce the transmitter substance combining with the receptor and reduce or block its action.

The activation of receptors by an agonist or hormone is coupled to the physiological or biochemical responses by transduction mechanisms that often  involve molecules called ‘second messengers’.

The interaction between a drug and binding site of the receptor depends on the complementarity of ‘fit’ of the two

molecules. The closer the fit and the greater the number of bonds, the stronger will be the attractive forces between them, and the higher the affinity of the drug for the receptor. 

The ability of drug to combine with one type of receptor is called specificity. No drug is truly specific but

many have selective action on one type of receptor. Drugs are prescribed to produce a therapeutic effect, but they often produce additional unwanted effects that range from  trivial ( slight nausea) to the fatal (aplastic anaemia).

Receptors

These are protein molecules that are activated by transmitters or hormones. Many receptors have been cloned and their amino acid sequences determined. The four main types of receptor are.

1 Agonist (ligand)‐gated ion channels are made up of protein subunits (e.g. nicotinic receptor, γ‐aminobutyric acid (GABA) receptor.

2 G‐protein‐coupled receptors form family of receptors with seven membrane spanning helices. 

3 Nuclear receptors for steroid hormones and thyroid hormones are present in the cell nucleus and regulate transcription and thus protein synthesis.

4 Kinase‐linked receptors are surface receptors that possess intrinsic tyrosine kinase activity. They include receptors for insulin, cytokines and growth factors

Transmitter substances are chemicals released from nerve terminals, diffuse across the synaptic cleft and bind to the receptors. This binding activates receptors by changing their conformation and triggers a sequence of postsynaptic events resulting in, muscle contraction or glandular  secretion. Following its release, the transmitter is inactivated by either enzymic degradation (acetylcholine) or reuptake (norepinephrine noradrenaline, GABA). Many drugs act by  reducing or enhancing synaptic transmission.

Hormones are chemicals released into bloodstream they produce  physiological effects on tissues possessing specific hormone receptors. Drugs may interact with the endocrine system by inhibiting (antithyroid drugs, or increasing (oral antidiabetic agents, hormone release. Drugs interact with hormone receptors, which may be activated steroidal antiinflammatory drug or blocked (oestrogen antagonists). Local hormones (autacoids) histamine, serotonin (5‐hydroxytryptamine, 5HT), kinins and prostaglandins, are released in pathological processes. The effects of histamine can sometimes be blocked with antihistamines, and drugs that block prostaglandin synthesis (aspirin) are widely used as anti‐inflammatory agents

Transport systems

Lipid cell membrane provides barrier against the transport of hydrophilic molecules into or out of the cell.

Ion channels are selective pores in the membrane, allow the ready transfer of ions down their electrochemical gradient. open closed state of these channels is controlled by the membrane potential (voltage‐gated channels) or by transmitter substances (ligand‐gated channels). Some channels (Ca2+ channels in the heart) are both voltage and transmitter gated. Voltage‐gated channels for sodium, potassium and calcium have the same basic structure, and subtypes exist for each different channel. Important examples of drugs that act on voltage‐gated channels are calcium‐channel blockers, which block L‐type calcium channels in vascular smooth muscle and the heart, and local anaesthetics, which block sodium channels in nerves. Some anticonvulsants and some antiarrhythmic drugs also block Na+ channels. No clinically useful drug acts primarily on voltage‐gated K+ channels, but oral antidiabetic drugs act on a different type of K+ channel that is regulated by intracellular adenosine triphosphate (ATP).

Active transport processes are used to transfer substances against their concentration gradients. They utilize special carrier molecules in the membrane and require metabolic energy. Two examples are.

1 Sodium pump.  expels Na+ ions from inside the cell by a mechanism that derives energy from ATP and involves  adenosine triphosphatase. The carrier is linked to the transfer of K+ ions into the cell. The cardiac glycosides  act by inhibiting the Na+/K+‐ATPase. Na+ and Cl− transport processes in the kidney are inhibited by some diuretics.

2 Norepinephrine transport. The tricyclic antidepressants prolong the action of norepinephrine by blocking its reuptake into central nerve terminals.

Enzymes

These are catalytic proteins increase the rate of chemical reactions in the body. Drugs that act by inhibiting enzymes include: anticho‐linesterases, which enhance the action of acetylcholine  carbonic anhydrase inhibitors, which are diuretics i.e. increase urine flow monoamine oxidase inhibitors, which are antidepressants and inhibitors of cyclo‐oxygenase e.g. aspirin.

Second messengers

chemicals whose intracellular concentration increases/decreases in response to receptor activation by agonists, which trigger processes result in a cellular response. The second messengers are: 

Ca2+ ions, 

cyclic adenosine monophosphate,

inositol‐1,4,5‐ trisphosphate and 

diacylglycerol. 

cAMP is formed from ATP by the enzyme adenylyl cyclase when, for example, β‐adrenoceptors are stimulated. The cAMP activates an enzyme protein kinase A, which phosphorylates a protein and leads to a physiological effect. InsP3 and DG are formed from membrane phosphatidylinositol 4,5‐bisphosphate by activation of a phospholipase C. Both messengers can activate kinases, but InsP3 does  indirectly by mobilizing intracellular calcium stores.

G-proteins

G‐protein‐coupled receptors are linked to their responses by a family of regulatory guanosine triphosphate binding proteins. receptor agonist complex induces  conformational change in the G‐protein. The αGTP complex dissociates from the G‐protein and activates (or inhibits) the membrane enzyme or channel. The signal to the enzyme or channel ends because αGTP has intrinsic GTPase activity and turns itself off by hydrolysing the GTP to guanosine diphosphate (GDP). αGDP then reassociates with the βγ G‐protein subunits.