CLINICAL PHARMACOLOGY ;GOOD
SIMPLIFIED SUMMARY
Types of receptors
Ligand-gated ion channels
G-protein coupled receptors
Tyrosine kinase/cytokine receptors
Nuclear/steroid hormone receptors
Ligand gated ion channels
Fast signal at synapses
Respond to specific ligands
Ions through impermeable membranes
Selective
e.g. Nicotinic receptors
Ligand-gated ion channels as drug targets
GABA(A) - benzodiazapines and barbituates for sedation
and dec neural activity, ANTAGONIST: Flumazenil
Glutamine receptor - ketamine
GPCR pathways
Stimulatory, inhibitory -> Adenylyl cyclase -> cAMP ->
PKA...
Tyrosine kinase receptors
Enzymes that transfer phosphate groups from ATP to
tyrosine residues on intracellular target proteins
,Mediate growth factors, cytokines, and some hormones
like insulin
Tyrosine kinase receptor example
VEGFRs - angiogenesis during development, VEGFR2
trigger endothelial growth through dimerisation and
autophosphorylation
Protein kinase inhibitors
Imatinib (rationally designed small molecule)
Transtuzimab
Cetuximab
Bevacizumab
Nuclear/Steroid hormone receptors
Activation via dimerisation
Act as transcription factors
Steroid receptor ligands
Glucocorticoids
Progesterone
Estrogen
Mineralocorticoid
Androgen
How do drugs bind to receptors?
Van der Waals
Hydrogen binding
Ionic interactions
Covalent binding
Affinity
The higher the affinity of the drug to the receptor, the
lower the conc needed to produce a level of receptor
occupancy
Efficacy
,Intrinsic activity, between 0-1
Defined by Emax (ability for drug to bind and cause a
change in receptor action
Potency
EC50 is used to measure potency of an agonist, EC50 is
the effective conc to cause 50% of the maximal response
Inc potency = lower EC50
Agonists
Have affinity and efficacy, mimic ligands and activate
receptors (+ve efficacy)
Drugs that elicit maximum response are full agonists
Partial agonists cannot elicit 100% response even at full
receptor occupancy
Inverse agonists
Decrease basal receptor activity (-ve efficacy)
Antagonists
Bind to receptors and have no effect on activity (0 efficacy)
Can be reversible or irreversible (covalent)
(reversible will only shift curve across)
Full Agonist example
Methadone
Partial agonist example
Bupronephrine
Antagonist example
Naloxone
Typical antipsychotics
, Dopamine antagonists
e.g. haloperidol
Atypical antipsychotics
Dopamine and 5HT antagonists (less selective, dec
sedative effects)
e.g. clozapine, quetiapine
Receptor plasticity
Receptor states and populations change over time
This is responsible for changes in drug effectiveness over
time
Desensitisation
Up regulation (antagonist use)
Down regulation (agonist use)
Non-receptor protein targets
Ion channels
Enzymes
Carrier proteins
Ion channels as targets
Voltage-gated
Local anaesthetics, Ca2+ channel blockers
Enzymes as targets
NSAIDs
Statins
Cholinesterase inhibitors (dementia)
Prostanoids effects
Target cyclo-oxygenase, preventing downstream effects ->
inhibition of COX1/2, dec inflamm, fever, pain
SIMPLIFIED SUMMARY
Types of receptors
Ligand-gated ion channels
G-protein coupled receptors
Tyrosine kinase/cytokine receptors
Nuclear/steroid hormone receptors
Ligand gated ion channels
Fast signal at synapses
Respond to specific ligands
Ions through impermeable membranes
Selective
e.g. Nicotinic receptors
Ligand-gated ion channels as drug targets
GABA(A) - benzodiazapines and barbituates for sedation
and dec neural activity, ANTAGONIST: Flumazenil
Glutamine receptor - ketamine
GPCR pathways
Stimulatory, inhibitory -> Adenylyl cyclase -> cAMP ->
PKA...
Tyrosine kinase receptors
Enzymes that transfer phosphate groups from ATP to
tyrosine residues on intracellular target proteins
,Mediate growth factors, cytokines, and some hormones
like insulin
Tyrosine kinase receptor example
VEGFRs - angiogenesis during development, VEGFR2
trigger endothelial growth through dimerisation and
autophosphorylation
Protein kinase inhibitors
Imatinib (rationally designed small molecule)
Transtuzimab
Cetuximab
Bevacizumab
Nuclear/Steroid hormone receptors
Activation via dimerisation
Act as transcription factors
Steroid receptor ligands
Glucocorticoids
Progesterone
Estrogen
Mineralocorticoid
Androgen
How do drugs bind to receptors?
Van der Waals
Hydrogen binding
Ionic interactions
Covalent binding
Affinity
The higher the affinity of the drug to the receptor, the
lower the conc needed to produce a level of receptor
occupancy
Efficacy
,Intrinsic activity, between 0-1
Defined by Emax (ability for drug to bind and cause a
change in receptor action
Potency
EC50 is used to measure potency of an agonist, EC50 is
the effective conc to cause 50% of the maximal response
Inc potency = lower EC50
Agonists
Have affinity and efficacy, mimic ligands and activate
receptors (+ve efficacy)
Drugs that elicit maximum response are full agonists
Partial agonists cannot elicit 100% response even at full
receptor occupancy
Inverse agonists
Decrease basal receptor activity (-ve efficacy)
Antagonists
Bind to receptors and have no effect on activity (0 efficacy)
Can be reversible or irreversible (covalent)
(reversible will only shift curve across)
Full Agonist example
Methadone
Partial agonist example
Bupronephrine
Antagonist example
Naloxone
Typical antipsychotics
, Dopamine antagonists
e.g. haloperidol
Atypical antipsychotics
Dopamine and 5HT antagonists (less selective, dec
sedative effects)
e.g. clozapine, quetiapine
Receptor plasticity
Receptor states and populations change over time
This is responsible for changes in drug effectiveness over
time
Desensitisation
Up regulation (antagonist use)
Down regulation (agonist use)
Non-receptor protein targets
Ion channels
Enzymes
Carrier proteins
Ion channels as targets
Voltage-gated
Local anaesthetics, Ca2+ channel blockers
Enzymes as targets
NSAIDs
Statins
Cholinesterase inhibitors (dementia)
Prostanoids effects
Target cyclo-oxygenase, preventing downstream effects ->
inhibition of COX1/2, dec inflamm, fever, pain
