MECHANISMS OF DRUG ACTION

DEFINITIONS
PHARMACODYNAMICS: In general terms it is
what the drug does to the body.
- It refers to drug action mechanisms and its
effects.
- Central to drug action and effects is the
receptor.
 RECEPTORS
• The component of the cell or organism which
interacts with a drug to produce the observed
therapeutic and toxic effects.
• Receptor important for development of drugs
and therapeutic decisions in clinical practice.
• 1. They largely determine the quantitative
relations between dose or drug concentration
and the pharmacologic effects.
• Affinity for the drug determines the dose
required
• Number of receptors may limit maximal effect
• 2. They are responsible for selectivity of drug
action
• The molecular size, shape and electrical
charge of drug determines whether it will bind
to receptor and with what affinity
• Small changes can cause changes of
therapeutic response and toxic effects
• 3. They mediate the action of both agonists
and antagonists
• Agonists, antagonists- pure and constitutive
• Receptors are unique
• Known and unknown
 RECEPTORS
• Drug-receptor complex – For drug action to
take place, it must bind to receptor
• Different bond types formed – ionic,
hydrogen, Van Der Waals, covalent
• Specificity of shape and electrical charge
determines selectivity
• Affinity
 Types
• They are basically protein molecules
• Enzymes e.g. acetyl cholinesterase-for
edrophonium, dihydrofolate reductase for
methotrexate, pyrimethamine
• Transport proteins e.g. Na/K ATPase- for
digoxin
• Structural proteins e.g. tubulin for colchicine,
vincristine
• Regulatory proteins - for endogenous proteins
like hormones, neurotransmitters, autacoids.
They mediate the actions of many of the most
useful therapeutics agents
 RESPONSES PRODUCED
• Agonists – produce a response
• Antagonists- oppose the action of agonists
• Types of drug antagonism:
• Chemical
• Functional
• Competitive- equilibrium, non-equilibrium
• Non-competitive
• Partial agonists
 RECEPTOR EFFECTOR COUPLING
• Coupling def.= binding /effector systems
• Coupling efficiency determined by
• Initial conformational change
• Transduction mechanism
• Spare receptors e.g. cardiac beta
adrenoceptors
• Spareness may be temporal or in number
 DOSE RESPONSE RELATIONSHIPS
• Dose response curves
• Quantal relationships – quantal dose response
curve, cumulative frequency curve
• Therapeutic index – LD50/ED50
• Protective index - TD50/ED50
• GRADED RESPONSES
• Graded response curves
• Potency= ED50a/ED50b
• Efficacy- rate and degree of response
• Affinity
• k1 k3
• A+R ↔ AR → Response
• k2
• Affinity = K1/k2
• Efficacy = k3
• Affinity is one of the determinants of potency
• Efficacy contributes to both potency and
maximum effect of drug.
 TRANSDUCTION MECHANISMS FOR
ENDOGENOUS REGULATORS
• 1. Intracellular receptors
• 2. Protein kinases- Tyrosine kinase receptors
• Serine kinase receptors, guanylyl cyclase
linked receptors
• 3. Cytokine receptors
• 4. Ion channel associated receptors
• 5. G-protein linked receptors
 INTRACELLULAR RECEPTORS
• 3 DOMAINS - ligand binding domain, effector
domain, and a regulator domain
• Steroid hormones, thyroid hormones, vitamin
D, retinoids
 TYROSINE KINASE RECEPTORS
• Peptide hormones regulating growth and
differentiation and development e.g.
• Insulin, epidermal growth factor, platelet
derived growth factor, lymphokines like TGF-α
• PHOSPHORYLATE tyrosine residues activating
or deactivating the molecules. Dimerization.
• Targets are regulatory proteins, enzymes,
structural proteins
• They are composed of:
• Extracellular hormone binding domain
• Catalytic intracellular domain
• Short hydrophobic amino acid residues
crossing plasma membrane
 OTHER KINASE RECEPTORS
• SERINE KINASE receptors - Similar to tyrosine
kinase receptors. Phosphorylates serine
residues
• THREONINE KINASE receptors –
Phosphorylates threonine residues
• GUANILYL CYCLASE linked receptors – CGMP is
produced E.g ANP, which regulates blood
volume and vascular tone.
 CYTOKINE RECEPTORS
• Like tyrosine kinase receptors but more
complex
• Growth hormone, erythropoietin, interferons
• Janus kinase family of proteins(JAKS)
• STATS( signal transduction and activators of
transcription)
• Dimerization occurs
ION CHANNEL ASSOCIATED RECEPTORS
• The binding of a ligand causes conformational
change which opens up ion channels.
• Typically used by neurotransmitters.
• Channels opened up are those of – Na, K, Ca
 G-PROTEIN LINKED RECEPTORS
• Biogenic amines, eicosanoids, many peptide
hormones, muscurinic Ach receptors, 5HT,
Epinephrine/nor-epinephrine
• Extracellular ligand binding receptor
• Transmembrane protein
• G-protein
• Effecter protein
• Second messenger
 SECOND MESSENGERS
• CAMP
• CGMP
• IP3
• DAG
• Ca
 G-proteins
• 1.Gs
• 2. Gi
• 3. Golf
• 4. Go
• 5. Gq
• 6. Gt
 DRUG RECEPTOR ACTION WITHOUT
RECEPTORS
• 1.Neutralization- antacids
• 2.Osmotic effect – mannitol
• 3.Acidification and alkalinisation- NaHCO3,
NHCl4
• 4.Bulk forming agents laxatives, mgSO4
• 5. Counterfeit incoorporation mechanisms-
Antivirals, cytotoxics- purine and pyrimidine
analogues
• 6. Chelation- penicillamine, dimercaprol,
ferroxamine
FACTORS DETERMINING DRUG EFFECTS
• 1. Age
• 2. sex
• 3.Route of drug administration
• 4.Medication errors and patient compliance
• 5.Placebo effects
• 6. Tolerance –genetics
• 7. Physiological variables
• 8. Pathological factors
• 9. Genetic factors