Pharmacodynamics

Basic physiological concepts in pharmacodynamics

1. Pharmacodynamics: Drug Targets Dr Sufyan Akram

2. Pharmacodynamics Pharmacodynamics is about how drugs work on living organisms; the qualitative and quantitative study of the biochemical and physiological effects of drugs on the body. Qualitative studies investigate the mechanisms of the action of drugs and endogenous molecules

3. Pharmacodynamics Quantitative studies allow comparison of the relationship between drug concentration and effect Quantitative studies include the measurement of drug effects at varying concentrations and this information is useful for estimating drug potency and efficacy

4. Potency vs Efficacy Potency is amount of a drug that is needed to produce a given effect Potency is determined by affinity of drug for receptor and number of receptors available Efficacy is the maximum effect that a drug can produce, regardless of dose

5. Drug Targets Enzymes Transporter proteins Ion channels Receptors

6. ENZYMES Drugs may target enzymes as: Inhibitors – when normal enzyme action is inhibited Reversible (e.g. anticholinesterase drugs such as neostigmine) Irreversible (e.g. cyclo-oxygenase (COX) inhibitors such as aspirin) False substrates – when an abnormal metabolite is produced E.g. Fluorouracil , an anti-cancer drug, acts as a false substrate by replacing uracil in normal purine biosynthesis Pro-drugs – when an inactive precursor is converted to an active drug by enzyme action

7. CARRIER PROTEINS Carrier proteins, or transporters, transfer ions and small molecules that are not sufficiently lipid soluble, across the cell membrane ATP-dependent transporters, also called pumps, are the sites of action of a number of therapeutic agents Transport-mediated responses are slower than ion-channel-mediated ones

8. ION CHANNELS Ions cannot penetrate the lipid cell membrane and need ion channels to facilitate their diffusion across the membranes. Ion channels are large protein complexes that span the cell membrane The intracellular concentration of important ions such as Na + , Ca 2+ , K + and Cl − are controlled by the state of the channels

9. ION CHANNELS Ion channels are classified according to: Their gating properties – many drugs target ion channels to exert a therapeutic effect by changing the status of the channel (i.e. open or closed ) Voltage-gated – when the ion channel opens or closes in response to a change in the transmembrane electrochemical gradient Ligand-gated – when ion channels change status in response to the binding of a ligand to a receptor site incorporated into the channel structure Their selectivity for specific ions , for example, cation channels are selectively permeable to Na + , K + , or Ca 2+ , or all three. Anion channels would be permeable to Cl − The molecular structure of the ion channel

10. ION CHANNELS Voltage-gated channels are therapeutically the more important ion channels Voltage-gated channels are made up of four subunits: an α subunit, a large glycoprotein (MW 270 000), and smaller β, γ and δ glycoprotein subunits Calcium channel (Ca 2+ ) antagonists (blockers) were designed to target voltage-gated Ca 2+ ion channels Examples include nifedipine , amlodipine, verapamil and diltiazem . They are commonly prescribed for angina and hypertension

11. RECEPTORS The majority of receptors targeted by drugs are transmembrane proteins involved in chemical signalling in cells. As most water soluble drugs (ligands) do not cross cell membranes, they have to exert their intracellular effect from an extracellular location Ligands that activate receptors to send signals across the cell membrane are known as first messengers: they activate an intracellular second messenger system that causes changes in cell function

12. RECEPTORS A ligand is called a receptor agonist when it binds to a specific receptor, activates it and produces a cellular response. When a ligand binds to the receptor and produces no effect & prevents the binding of an agonist, it is a receptor antagonist Binding is usually rapidly reversible If the binding is covalent, the duration of the ligand–receptor association may be prolonged, if not irreversible The effect of irreversible binding can only be overcome, in the long term, by the synthesis of new receptors to replace those bound to the ligand

13. RECEPTORS The number of receptors present in any cell is not static. There is a high turnover of receptors as they are continually formed and removed from the cell membrane The number of receptors may be increased ( up-regulation ) or decreased ( down-regulation ) by drugs or disease

14. Receptor Classification Type 1: Ionotropic receptors also termed ligand-gated Type 2: G protein-coupled receptors (GPCR ) Type 3: Enzyme-linked receptors Type 4: Intracellular receptors

15. 1. Ionotropic receptors (ligand-gated) These are membrane receptors coupled directly to an ion channel and are receptors on which ‘fast’ transmitters act. The tissue response occurs in a few milliseconds Important examples include: Nicotinic receptors (stimulated by acetylcholine) γ- amino-butyric acid A receptor ( GABAA-R) Glycine receptor ( Gly -R)

16. 2. G protein-coupled receptors (GPCR) G proteins are so called because they interact with the guanine nucleotides GTP and GDP. The intracellular effector system is the second messenger. The response to receptor activation occurs in 100 ms or seconds Three types that selectively produce different second messengers in the cell: Gs increases cAMP by activating the enzyme adenylate cyclase Gi (also Go) inhibits adenylate cyclase Gq (also G12) activates phospholipase C

17. Protein Kinases As a general rule, the protein kinases produced by the second messenger system have a central role in signal transduction. They control a number of different aspects of cell function, including: Enzymes, transport proteins Muscle contraction, to increase rate and force of cardiac muscle contraction, increase gut motility and secretion Energy metabolism via modulation of neurotransmitter release Ion transport via action on ion channels, particularly Ca2+ channels Cell division and differentiation Cytokine synthesis

18. 3. Enzyme-linked receptors These are membrane receptors that incorporate an intracellular protein kinase domain (usually Tyrosine Kinase) within their structure. Tissue response occurs in minutes The peptides that are ligands for this type of receptor are hormones that promote cell growth and proliferation: They include insulin, insulin-like growth factor, platelet-derived growth factor, cytokines, leptin and atrial natriuretic peptide These receptors are the focus of much research as drug targets for the treatment of cancers, obesity and disordered immunity and inflammation

19. 4. Intracellular receptors These are receptors that regulate gene transcription and are located either in the cell cytoplasm or within the nucleus. The response to these receptors occurs in hours to days They act on DNA to regulate the expression of specific genes to: Alter the genetic expression of enzymes Alter the genetic expression of cytokines Alter the genetic expression of receptor proteins Most steroid hormone analogues use these receptors

20. In Summary… Understanding drug targets allows us to develop drugs that are more specific, effective and with less side effects However, most drugs are not entirely specific in selecting the binding sites, giving rise to side effects if the drug binds to regulatory proteins that are not specific targets For example, tricyclic antidepressant drugs are noted for producing the side effects of dry mouth and urine retention because they block receptors other than the monoamine transporters for which they were designed

21. References Naish et al . Medical Sciences (2011) Chapter 4 Lippincott Illustrated Reviews: Pharmacology 5 th ed (2011) Chapter 1

22. Thank you