Introduction to the principles of drug action

Dr. M. Yulis Hamidy, M.Kes., M.Pd.Ked

Basic Pharmacological Concepts

Pharmacology = The study of the interaction between chemicals and a biological system. Pharmacodynamics = study of the biochemical and physiological effects of drugs and their mechanisms of action (the effects of the drug on the body) Pharmacokinetics = deals with absorption, distribution, biotransformation and excretion of drugs (the way the body affects the drug with time)

Pharmacodynamics
Mechanisms of drug action
Non-specific drug action
general anaesthetics, osmotic diuretics, antacids

Alter transport systems

Ca antagonists, local anaesthetics, cardiac glycosides

Alter enzyme function

COX inhibitors, MAO inhibitors, AChE inhibitors

Act on receptors
Synaptic transmitter substances, hormones

Receptors
Proteins Cell membranes Intracellular 4 main types:
Agonist gated transmembrane channels G-protein coupled Nuclear receptors that regulate gene transcription Linked directly to tyrosine kinase

 Agonist gated channels

receptors

 G-protein coupled

receptors

G-protein coupled receptors

 Nuclear receptors that regulate gene transcription

receptors

 Linked directly to tyrosine kinase

Receptor acts as an enzyme

receptors

Transport Systems
Lipid cell membrane
barrier to hydrophyllic molecules transport in /out cell

Ion channels
voltage gated ligand gated

Active transport processes

Na+ pump Noradrenaline transport

Ion channels
Voltage and transmitter gated
Ca2+ channels in heart

Voltage gated
Na+, K+, Ca2+ - same basic structure Subtypes of each exist Examples:
calcium antagonists local anaesthetics anticonvulsants antiarhythmics Ca2+ in VSM & heart Na+ in nerves Na+ Na+
Transport systems

 Voltage gated channels

Transport systems

Active transport processes

transport substances against concentration gradient special carrier molecules require metabolic energy

Sodium Pump
expel Na+ ions Na+/K+ ATPase
cardiac glycosides some diuretics

Noradrenaline transport
tricyclic antidepressants block reuptake
Transport systems

Enzymes
Catalytic proteins that increase the rate of chemical reactions Drug examples
Anticholinesterases Carbonic anhydrase inhibitors Monoamine oxidase inhibitors Cyclo-oxygenase inhibitors

Speed of responses

DRUG RECEPTOR INTERACTIONS

Intermolecular forces
Covalent bonds - two atoms share an electron
- (40-110kcal/mol) - long lasting - desirable?
e.g. Alkylating agents (e.g. anticancer nitrogen mustards)

Ionic bonds - electrostatic attraction between oppositely

charged ions
- much weaker than covalent bonds (10 kcal/mol) - reversible

Hydrogen bonds - electrostatic attraction between hydrogen

atom and electronegative atom
- relatively stable (1-7 kcal/mol) - reversible

Van der Waals bond

- weak bond (0.5 - 1 kcal/mol)

Affinity
measure of how avidly a drug binds to its receptor
Equilibrium constant KD KA concentration of drug that produses 50% of response

Intrinsic activity
Ability of a drug to elicit a response from a receptor

Agonist

= a drug that is able to alter the conformation of a receptor in such a way that it elicits a response in the system

Full

Partial

Antagonist

= a drug that binds to a receptor but does not elicit a response from the system

Competitive

Irreversible

Agonist vs antagonist
K+1
Ag

K-1

Ag

Response

K+1 Ant

R K-1

Ant

Graded dose-responses
One tissue/organ can yield the full response range
Full agonist
Response

Partial agonist

Agonist concentration [A]

Log dose-response curve

Full agonist

Response

Partial agonist

Log concentration [A]

Emax & ED50

Emax
Response

Emax

ED50

ED100

Log concentration [A]

Effect of competitive antagonists

Agonist alone

Response

Increasing concentrations of competitive antagonist

Log [A]

Effect of irreversible antagonists

Agonist alone Low dose

Response

High dose

Log [A]