Pharmacodynamics: Drug-Pharmacodynamics: Drug-Receptor InteractionsReceptor Interactions

Drug ReceptorsDrug ReceptorsReceptor:

Synonym: Target moleculeMacromolecule (or macromolecular complex)

which binds agonists with high structural selectivity with the consequence that a characteristic effect occurs

Or site of drug action responsible for the pharmacological effect

The component of the organism with which the chemical agent was presumed to interact.

Receptors can be any functional macromelecular component of the organism

Drug Binding SitesDrug Binding Sites (Receptors and Acceptors)Binding Site

Specific and SaturableReceptor

Binding Site + EffectAcceptor

Binding Site + no Effect

Types of BindingTypes of BindingReversible

ionic attraction, hydrogen bonds, Van der Waals interactions

Slowly reversible/irreversiblehigh affinity non-covalent binding, covalent binding

Specific receptors and Non-Specific receptors and Non-specific drug targetsspecific drug targetsNon-specific drug targetsNon-specific drug targets

- Water- H+ ion, HO- ion- Metal ions as relatively specific

receptors

Specific Receptors Specific Receptors (drug receptors)- Enzymes- Membrane sterols / proteins- DNA

Differences between Differences between Specific Receptors and Non-specific Specific Receptors and Non-specific Drug TargetsDrug Targets

Specific Specific receptors receptors are stereoselectivecan be selectively

blocked by antagonist drugs

are occupied at nanomolar or micromolar concentrations

LigandsLigands (Receptor binding (Receptor binding molecules)molecules)Drugs or endogenous compounds binding to

receptors are described as Ligands.

Ligands are classified into 2 groupsAgonistAgonist: molecule that binds to receptor and

produces similar response to that of the endogenous ligand.Partial agonist: agonist that produce partial

effect.AntagonistAntagonist: molecule that binds to a receptor, but

does not cause a response.Competitive: reversible or weak bindingNon-competitive: non-reversible or strong

binding

LigandsLigands (Agonist and (Agonist and Antagonist)Antagonist)

Affinity and EfficacyAffinity and EfficacyAffinity: the attraction of the drug for the receptor.high affinity: low concentrations bind

low affinity: high concentrations bind

no affinity: does not bindEfficacy: the intrinsic activity

Max. effect efficacy = 1Min. effect efficacy = 0

Agonist and AntagonistAgonist and AntagonistAffinity Efficacy

Agonist yes highPartial agonist yes lowAntagonist

Competitive low-medium noNon-competitive high no

Classifications of Drug Classifications of Drug ReceptorsReceptors

Drug classification can be based on several things

Classified byGeneral characteristicsLocationConsequence of interactionSecondary chemical messenger involved in the transduction pathway

Classifications of Drug ReceptorsClassifications of Drug ReceptorsBased on General Based on General characteristicscharacteristicsBased on general characteristics, drug

receptors can be classified into 4 groups

Classical Receptors Or Physiological receptors

Uptake carriers or Transport proteins

Ion channels Enzymes

Classifications of Drug Classifications of Drug ReceptorsReceptorsBased on LocationBased on Location

Example 1 Receptors of the nervous systemPost-synaptic receptor: In postsynaptic cells, neurotransmitter

receptors receive signals that trigger an electrical signal, by regulating the activity of ion channels.

Pre-synaptic receptor: On presynaptic cells the binding of a neurotransmitter to a specific receptor provides feedback and mediates excessive neurotransmitter release.

Example 2 Receptors that are on the surface and inside the cellsCell-surface receptor

Ion-channel-linked receptorsG-protein-linked receptorsEnzyme-linked receptors

Intracellular receptor

Classifications of Drug Classifications of Drug ReceptorsReceptorsBased on Consequence of Based on Consequence of InteractionInteractionStimulation or Inhibition

Of an enzymeOf an organ activity

Stimulate or Inhibit heart contractilityContraction or Relaxation of muscle

Classifications of Drug Classifications of Drug ReceptorsReceptorsBased on Secondary Based on Secondary MessengersMessengers

Secondary messengers of the signal transduction processes are in different kinds and can be used to classify the receptors connected to them.

Drug

Receptors

Effector or Target

Cyclic AMPCyclic GMPPhosphoinositolArachidonic acidCalcium ion

Drug-Receptor InteractionDrug-Receptor InteractionStructure specificStereo-selectiveLock and key mechanism

Drug + Receptor

Drug-receptor complex

Response

Transduction pathways

Affinity

Potency

Efficacy

Receptor-mediated Mechanism of Receptor-mediated Mechanism of ActionAction

drugs beneficial effectcaused by the drugs ability to

interact with the receptor and change in physiologicalor biochemicalor pathological processes

Then termed mechanism of drug action

Intermediate MessengersIntermediate Messengers or Second MessengersSecond Messengers

Activation of a receptor may initiate a series of events mediated by intermediate messengers.

Signal transduction Drug Binding Site Effect intermediate

messengerse.g. cyclic AMP

Mechanism of actionMechanism of action Classical ReceptorsClassical ReceptorsDrug actions on Classical receptors

are based on types of LigandsAgonist -> StimulationAntagonist -> Inhibition

Neurotransmitter norepinephrine (NE) receptor

actionHormones

angiotensin receptor actionLocal hormones

histamine receptor action

Mechanism of actionMechanism of action Uptake CarriersUptake Carriers

Uptake carriers or Transport proteins can have a role in regulation of drug action

Example: Norepinephrine (NE) action

NE

NE release from nerve

Receptors

Neurotransmission

Uptake carrier

Reuptake

Rapid inactivation

Decrease NE action

Drug

Uptake inactivation

More NE

Increase NE action

X

Nerve Cell

Mechanism of actionMechanism of action Ion ChannelsIon Channels

drug - ion channel

enhances /inhibits action

e.g. Ca++ channel blocker (verapamil)

Mechanism of actionMechanism of action EnzymesEnzymesdrug-enzyme interaction

inhibition of enzyme activity

• Neostigmine inhibits acetyl cholinesterase

• increased acetyl choline• Aspirin inhibits cyclooxygenase

• decreased prostaglandins

Inhibition of Enzyme ActivityInhibition of Enzyme Activity - NeostigmineNeostigmine

Mechanism of of action:anti-cholinesteraseInhibits activity of acetyl-cholinesterase

Effects: increase Acetylcholine (ACh) levels in the synapse.

Clinical use: treatment of myasthenia gravis

Action of NeostigmineAction of Neostigmine

SkeletalSkeletal MuscleMuscle

Somatic Nervous Somatic Nervous System (voluntary)System (voluntary)

AChACh

AChEAChE

acetateacetate cholinecholine

Nicotinic AChreceptor

N

N

N

N

NNeostigmine

Inhibition of Enzyme ActivityInhibition of Enzyme Activity AspirinAspirin

Mechanism of action: cyclo-oxygenase inhibitor Pharmacological effects: prostaglandin release

pain and fever

Clinical use: treatment of pain and fever

Inflammation Inflammation and COXand COX

Infection

Arachidonic Acid (released from cell membrane)

Prostaglandins

Pain Fever

Cyclooxygenase (COX)Cyclooxygenase (COX)

Action of AspirinAction of AspirinInfection

Arachidonic Acid (released from cell membrane)

Prostaglandins

Pain Fever

CyclooxygenaseCyclooxygenase

Aspirin