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)

PharmacodynamicsMechanisms of drug action

– Non-specific drug action

general anaesthetics, osmotic diuretics, antacids

– Alter transport systemsCa antagonists, local anaesthetics, cardiac glycosides

– Alter enzyme functionCOX inhibitors, MAO inhibitors, AChE inhibitors

– Act on receptorsSynaptic transmitter substances, hormones

Receptors Cell membranes

Intracellular

4 main types:• Agonist gated transmembrane channels• G-protein coupled • Nuclear receptors that regulate gene

transcription• Linked directly to tyrosine kinase

Proteins

• Agonist gated channels

receptors

• G-protein coupled

receptors

G-protein coupled receptors

receptors

• Nuclear receptors that regulate gene transcription

• 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 structureSubtypes of each existExamples:

calcium antagonists Ca2+ in VSM & heartlocal anaesthetics Na+ in nervesanticonvulsants Na+

antiarhythmics 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 glycosidessome diuretics

• Noradrenaline transporttricyclic 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 INTERACTIONSIntermolecular 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 Waal’s bond - weak bond (0.5 - 1 kcal/mol)

Affinitymeasure of how avidly a drug binds to its

receptor– Equilibrium constant KD

– KA concentration of drug that produses 50% of response

Intrinsic activityAbility 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

AgK+1

K-1

Ag

AntK+1

K-1

+

+

Response

Ant

R

R

Graded dose-responses

Full agonist

Partial agonist

Agonist concentration [A]

Res

pons

eOne tissue/organ can yield the full response range

Log concentration [A]

Res

pons

eFull agonist

Partial agonist

Log dose-response curve

•Emax & ED50

Log concentration [A]

Res

pons

e

Emax

½ Emax

ED50 ED100

I I I I I I I I

Effect of competitive antagonists

Log [A]

Res

pons

e

Increasing concentrationsof competitive antagonist

Agonist alone

Effect of irreversible antagonists

Log [A]

Res

pons

e

Agonist alone Low dose

High dose