Post on 24-Feb-2016
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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