Introduction to the principles of drug action Dr. M. Yulis Hamidy, M.Kes., M.Pd.Ked
Feb 24, 2016
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