Pharmacodynamics: Drug Targets

Dr Sufyan Akram

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

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

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

Drug Targets

• Enzymes• Transporter proteins• Ion channels• Receptors

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

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

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+, Ca2+, K+ and Cl− are controlled by the state of the channels

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 Ca2+, or all three. Anion channels would be permeable to Cl−• The molecular structure of the ion channel

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 (Ca2+) antagonists (blockers) were designed to target voltage-gated Ca2+ ion channels• Examples include nifedipine, amlodipine, verapamil

and diltiazem. They are commonly prescribed for angina and hypertension

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

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

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

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

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)

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

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

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

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

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

References

• Naish et al. Medical Sciences (2011)• Chapter 4

• Lippincott Illustrated Reviews: Pharmacology 5th ed (2011)• Chapter 1

Thank you