1. BIOLOGICAL ACTION OF DRUGS ON MEMBRANES
UNIVERSITY OF LUSAKA
BIOLOGICAL ACTION OF DRUGS ON MEMBRANES

2. HOW DRUGS ACT
Molecular pharmacology has advanced rapidly in recent years. This new knowledge is not only changing our understanding of drug action, it is also opening up many new therapeutic possibilities

3. HOW DRUGS ACT
First, we consider the types of target proteins on which drugs act. Next, we describe the main families of receptors and ion channels . Finally, we discuss the various forms of receptor-effector linkage (signal transduction mechanisms) through which receptors are coupled

4. HOW DRUGS ACT
The relationship between the molecular structure of a receptor and its functional linkage to a particular type of effector system is a principal theme.

5. HOW DRUGS ACT
We go into more detail than is necessary for understanding today's pharmacology at a basic level, intending that students can, if without losing the thread; however, we are confident that tomorrow's pharmacology will rest solidly on the advances in cellular and molecular biology that are discussed here.

6. TARGETS FOR DRUG ACTION
The protein targets for drug action are:
ion channels
enzymes
carrier molecules (transporters)

7. RECEPTORS
Receptors are the chemical messengers being the various hormones and transmitters. Many therapeutically useful drugs act, either as agonists or antagonists, on receptors

8. ION CHANNELS
Some ion channels (known as ligand-gated ion channels or ionotropic receptors) incorporate a receptor and open only when the receptor is occupied by an agonist; others are gated by different mechanisms, voltage-gated ion channels being particularly important. In general, drugs can affect ion channel function by interacting either with the receptor site of ligand-gated channels, or with other parts of the channel molecule.

9. ION CHANNELS
The interaction can be indirect, involving a G-protein and other intermediaries or direct, where the drug itself binds to the channel protein and alters its function. In the simplest case, exemplified by the action of local anaesthetics on the voltage-gated sodium channel, the drug molecule plugs the channel physically blocking ion permeation.

10. ENZYMES
Many drugs are targeted on enzymes . Often, the drug molecule is a substrate analogue that acts as a competitive inhibitor of the enzyme (e.g. captopril, acting on angiotensin-converting enzyme; in other cases, the binding is irreversible and non-competitive (e.g. aspirin, acting on cyclo-oxygenase

11. ENZYMES
Drugs may also act as false substrates, where the drug molecule undergoes chemical transformation to form an abnormal product that subverts the normal metabolic pathway. An example is the anticancer drug fluorouracil, which replaces uracil as an intermediate in purine biosynthesis but cannot be converted into thymidylate, thus blocking DNA synthesis

12. CARRIER MOLECULES
The transport of ions and small organic molecules across cell membranes generally requires a carrier protein, because the permeating molecules are often too polar (i.e. insufficiently lipid-soluble) to penetrate lipid membranes on their own

13. CARRIER MOLECULES
There are many examples of such carriers , including those responsible for the transport of glucose and amino acids into cells, the transport of ions and many organic molecules by the renal tubule, the transport of Na+ and Ca2+ out of cells, and the uptake of neurotransmitter precursors (such as choline) or of neurotransmitters themselves (such as noradrenaline, 5-hydroxytryptamine [5-HT], glutamate, and peptides) by nerve terminals

14. RECEPTOR PROTEINS
These substances, known as α-toxins. The best known is α-bungarotoxin, the main component of the venom of the Malayan banded krait (Bungarus multicinctus).

15. RECEPTORS & DISEASE
Increasing understanding of receptor function in molecular terms has revealed a number of disease states directly linked to receptor malfunction. The principal mechanisms involved are:
autoantibodies directed against receptor proteins
mutations in genes encoding receptors and proteins involved in signal transduction.

16. RECEPTOR & DISEASE
An example of the former is myasthenia gravis (, a disease of the neuromuscular junction due to autoantibodies that inactivate nicotinic acetylcholine receptors. Autoantibodies can also mimic the effects of agonists, as in many cases of thyroid hypersecretion, caused by activation of thyrotropin receptors

17. RECEPTOR & DISEASE
Activating antibodies have also been discovered in patients with severe hypertension (α-adrenoceptors), cardiomyopathy (β-adrenoceptors), and certain forms of epilepsy and neurodegenerative disorder (glutamate receptors)

18. RECEPTOR & DISEASE
Adrenoceptor polymorphisms are common in humans, and recent studies suggest that certain mutations of the β2-adrenoceptor, although they do not directly cause disease, are associated with a reduced efficacy of β-adrenoceptor agonists in treating asthma and a poor prognosis in patients with cardiac failure

19. RECEPTOR & DISEASE
Mutations in G-proteins can also cause disease. For example, mutations of a particular Gα subunit cause one form of hypoparathyroidism, while mutations of a Gβ subunit result in hypertension.

20. THE END
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