HLTH6120 & NQCG3111:

Introduction to
Pharmacology 1
Pharmacodynamics
Dr David Voegeli.

Defining the Terms.

Pharmacodynamics:
In simple terms is the study of what a drug does to
the body i.e. How it works!
Pharmacokinetics:
Is the study of what the body does to a drug i.e.
How the drug is handled.

Targets for drug action.

Most drugs work by initially binding to a protein.
Many of these proteins are involved in physiological
regulation.
Common protein targets include:
Enzymes

Carrier molecules
Ion channels

Receptors
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Protein Synthesis

Basic amino acid structure

Levels of protein structure

Functions of cell membrane

proteins.

Enzymes as
pharmacological targets.

Enzymes
A protein (or protein-based molecule) that acts as a catalyst
to speed up a chemical reaction. Acts on specific substances
known as substrates.
Drug / enzyme interactions may involve:
Substrate analogues
False substrates
Conversion of pro-drugs
Accounts for a large number of drug actions.
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Enzymes - Substrate analogues

Similar molecular shape to normal substrate.
Usually work via competitive inhibition of enzyme.
May be reversible (neostigmine) or irreversible (aspirin).
Reversible inhibitors bind to enzyme via weak non-covalent
bonds (e.g. hydrogen bonds, ionic bonds) and can easily be
removed. Fairly non-specific.
Irreversible inhibitors covalently modify enzyme binding
site and tend to be fairly specific in action.
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Enzymes - False substrates

Again often similar molecular shape to normal substrate.
Drug molecule behaves like normal substrate and is acted
upon by the target enzyme to produce an abnormal product
that disrupts the normal pathway.
E.g. Methyldopa, Fluorouracil, Aromatase inhibitors (e.g.
Exemestane).

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Carrier proteins as
pharmacological targets.

Carrier Molecules
The movement of substances across the cell membrane
often requires a carrier molecule (e.g. ions, glucose, amino
acids).
Carrier specific for particular molecule (shape).
Some drugs can target these carriers and block transport.
E.g. PPIs, cardiac glycosides, TCAs

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Omeprazole as an example of carrier inhibition.

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Ion Channels as
pharmacological targets.

Ion Channels
Over 100 types of ion channel.
Important in systems that
require rapid responses e.g. NS,
renal, CVS.
Drugs either block or modulate
channels.
E.g. local anaesthetics,
amiloride, diltiazem, nicorandil,
benzodiazepines.

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Receptors as
pharmacological targets.

Receptors
Highly complex area of pharmacology.
Involves knowledge of receptor superfamilies, subtypes,
and downstream cell signalling.
4 receptor superfamilies:
Ionotropic (ligand-gated channels)

Metabotropic (G-protein coupled)

Kinase-linked

Nuclear.
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Rang et al, 2002

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Rang et al, 2002

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Agonists and Antagonists.

Rang et al, 2002

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Ionotropic receptors
Examples include:
Nicotinic ACh (nAChR)
GABAA
5HT3
Generally similar structure.

Involved in very fast transmission e.g. neurotransmitters,

synapses.

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Structure of Nicotinic ACh Receptor.

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Metabotropic (G-protein coupled)

Examples include:
Muscarinic ACh (mAChR)
Adrenoceptors ( & )

Dopamine receptors
Opioid receptors
5HT receptors

Purine receptors
Receptors in special senses
Actions can be fairly complex.

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G Protein Coupled Receptors.

Rang et al, 2002

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Metabotropic (G-protein coupled) cont.

Called G-Proteins due to association with guanine
nucleotides (GTP, GDP).
Can interact with large variety of receptors and effectors.

Generally causes amplification of signal.

Utilises system of second messenger effector systems:

e.g.

adenylate cyclase/cAMP
phospholipase C/inositol phosphate

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G-Proteins and second messengers.

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Kinase-linked receptors
Examples include:
Insulin receptors
Growth hormone receptors
Cytokine receptors
Involves tyrosine-kinase & guanylate cyclase.

Two important pathways:

Ras/Raf/MAP kinase cell division & growth

Jak/Stat cytokines, inflammation.

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Nuclear (or intracellular) receptors

Examples include:
Steroid receptors
Thyroid hormone receptors
Vitamin D
Retinoic acid

Able to regulate DNA transcription (turn genes on or off)

and influence protein expression.
Powerful!!
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Nuclear receptors cont.

These receptors are intracellular proteins.
Ligands must enter cell to bind.
Pattern of gene activation depends on cell type and nature
of ligand.
Effects diverse and slow onset due to altered protein
expression.

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Desensitisation & Tachyphylaxis.

Effect of a drug often diminishes when repeatedly
administered.
Tachyphylaxis = rapidly decreasing response to drug.
Various causes:
Change in receptors;
Loss of receptors;
Exhaustion of mediators;
Increased metabolic degradation

Physiological adaptation

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Tachyphyaxis examples
Nitrate therapy
Some drugs of abuse (cocaine)
? Medium-acting bronchodilators.

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Summary and conclusion.

Summary of drug targets.

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Final Questions.

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Further Reading.
Chapters 1 & 2 Neal M. (2009) Medical pharmacology at a
glance. Blackwell, London.
Chapters 1,2,3 & 4 in Rang H, Dale M, Ritter J, Flower R,
Henderson G. (2011) Pharmacology. Churchill Livingstone,
London.

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