l15 pharm

what is the main focus of PD module lecture 4?

enzymes, transporters, and ion channels as molecular drug targets, and how drugs interact with them

what are the major protein drug target classes?

receptors, enzymes, ion channels, and transporters

what is potency?

potency is how much drug is needed to produce a response

what is efficacy?

efficacy is the maximum response a drug can produce

how do you rank drugs by potency on a log concentration-response curve?

the curve further left is more potent because less drug is needed

how do you rank drugs by efficacy on a concentration-response curve?

the curve with the higher maximum plateau has higher efficacy

can drugs be equally potent but have different efficacies?

yes, drugs can need similar concentrations but produce different maximum responses

can a drug be very potent but low efficacy?

yes, it may work at low concentration but only produce a small maximum response

what is the main learning objective of this lecture?

to describe the key function of enzymes, transporters, and ion channels, and how drugs interact with them

what are ion channels?

ion channels are pore-forming protein complexes that allow ions to flow across cell membranes

why do ions need channels to cross membranes?

ions are charged and cannot easily cross the hydrophobic lipid membrane by themselves

what does hydrophobic mean?

hydrophobic means water-repelling or lipid-loving

what are examples of ions that move through ion channels?

Na⁺, K⁺, Ca²⁺, and Cl⁻

what does an ion channel do when it is open?

it allows specific ions to move across the membrane

what does an ion channel do when it is closed?

it prevents ions from moving through

what is gating?

gating is the stimulus or mechanism that opens or closes an ion channel

how are ion channels usually classified?

by gating, meaning what opens the channel

what is a ligand-gated ion channel?

an ion channel that opens when a ligand binds

why are ligand-gated ion channels also receptors?

because ligand binding causes the channel to open and produces a cellular response

what is a voltage-gated ion channel?

an ion channel that opens in response to changes in membrane potential

what is membrane potential?

the electrical difference across the cell membrane

what are second messenger-gated channels?

channels that open or close in response to intracellular or extracellular signalling molecules

what is a channelopathy?

a disorder caused by abnormal ion channel function

what can cause channelopathies?

genetic mutations or autoimmune attack on ion channels

what are examples of genetic channelopathies?

cystic fibrosis, long QT syndrome, and short QT syndrome

what are examples of autoimmune ion channel/receptor disorders?

myasthenia gravis and possibly multiple sclerosis

why is myasthenia gravis related to ion channels?

the immune system attacks nicotinic acetylcholine receptors, which are ligand-gated ion channels at the neuromuscular junction

how can drugs interact with ion channels?

they can act as blockers or modulators

what does an ion channel blocker do?

it blocks ion movement/permeation through the channel

what does permeation mean?

permeation means movement of ions through the channel

what does an ion channel modulator do?

it increases or decreases the probability that the channel opens

what is the simple difference between a blocker and modulator?

a blocker blocks the channel pore, while a modulator changes how likely the channel is to open

what type of ion channel can local anaesthetics block?

voltage-gated sodium channels

what is an example of a local anaesthetic that blocks Na⁺ channels?

lignocaine

why do local anaesthetics reduce pain?

they block sodium channels in sensory nerves, preventing pain signals/action potentials from travelling

what are examples of anti-epileptics that block sodium channels?

phenytoin and carbamazepine

why can sodium channel blockers be anti-epileptic?

they reduce excessive neuronal firing by limiting action potentials

what are action potentials?

electrical signals in nerves and muscles

what is amlodipine?

a calcium channel blocker used for high blood pressure and coronary artery disease

how does blocking calcium channels help high blood pressure?

it reduces calcium entry into vascular smooth muscle, causing relaxation and lower blood pressure

what are sulfonylureas?

drugs that block ATP-sensitive potassium channels, used in type 2 diabetes

what are examples of sulfonylurea-like drugs listed in the lecture?

repaglinide and nateglinide

how can blocking ATP-sensitive K⁺ channels help diabetes?

it helps trigger insulin release from pancreatic beta cells

what is an enzyme?

an enzyme is a biological catalyst that speeds up a specific chemical reaction

what is a catalyst?

a substance that speeds up a reaction without being used up

what is a substrate?

the molecule an enzyme acts on

what is a product?

the molecule formed by an enzyme-catalysed reaction

what is an enzyme-substrate complex?

the temporary complex formed when a substrate binds to an enzyme

why are enzymes important drug targets?

blocking or modifying enzymes changes the amount of product made, which can produce therapeutic effects

how do most enzyme-targeting drugs act?

most act as competitive inhibitors

what is a competitive enzyme inhibitor?

a drug that competes with the substrate for the enzyme’s active site

what is the active site of an enzyme?

the site where the normal substrate binds and the reaction occurs

what happens when a competitive inhibitor occupies the active site?

the substrate cannot bind, so the reaction is reduced

what is captopril?

a competitive inhibitor of angiotensin converting enzyme, ACE

what enzyme does captopril inhibit?

angiotensin converting enzyme, ACE

what is the substrate for ACE in the captopril example?

angiotensin I

what is the product of ACE activity?

angiotensin II

what does angiotensin II do generally?

it helps increase blood pressure

how does captopril lower blood pressure?

it inhibits ACE, reducing angiotensin II production

what is a non-competitive enzyme inhibitor?

a drug that binds to a site different from the substrate binding site and reduces enzyme activity

how can non-competitive inhibitors work?

they can bind elsewhere, change enzyme shape, block cofactor binding, or prevent substrate interaction

what is a cofactor or co-enzyme?

a helper molecule needed for some enzyme reactions

what enzyme does aspirin inhibit?

cyclooxygenase, COX

what is the substrate for COX?

arachidonic acid

what is the product listed for COX in the lecture?

prostaglandin H₂

how does aspirin inhibit COX?

it binds to COX and changes its function/shape so arachidonic acid cannot be processed properly

what are prostaglandins involved in?

pain, inflammation, and fever

why can aspirin reduce pain, fever, and inflammation?

it reduces prostaglandin production by inhibiting COX

what is a false substrate?

a drug that an enzyme mistakes for the normal substrate, leading to an abnormal product

what is a prodrug?

a drug given in inactive or less active form that enzymes convert into an active drug

what is L-dopa an example of?

a prodrug used in Parkinson’s disease

what is L-dopa converted into?

dopamine

why is L-dopa used instead of dopamine in Parkinson’s disease?

L-dopa crosses the blood-brain barrier better than dopamine and can be converted into dopamine in the brain

what is carbidopa?

a peripherally restricted inhibitor that prevents L-dopa metabolism outside the brain

why is carbidopa given with L-dopa?

it reduces peripheral conversion of L-dopa, allowing more L-dopa to reach the brain

what does peripherally restricted mean?

it acts mainly outside the brain

what is methyldopa an example of?

a false substrate used in hypertension

what does methyldopa eventually act as?

an alpha-2 receptor agonist

what is a transporter?

a membrane protein that moves ions or small molecules across membranes

how is a transporter different from an ion channel?

a channel forms a pore, while a transporter binds and moves molecules across by changing shape

where are transporters important in pharmacology?

renal tubules, intestinal epithelium, blood-brain barrier, nerve terminals, and cell membranes

how do drugs usually act on transporters?

they usually inhibit transporters

what happens when a transporter is inhibited?

the transported molecule is no longer moved normally, so it may accumulate or decrease in certain places

what is serotonin also called?

5-hydroxytryptamine or 5-HT

what is serotonin?

an important neurotransmitter

what functions is serotonin involved in?

sleep, appetite, memory, sexual behaviour, neuroendocrine function, and mood

what amino acid is serotonin made from?

tryptophan

what is the synthesis pathway for serotonin?

tryptophan → 5-HTP → 5-HT

where is serotonin stored before release?

in vesicles

what triggers serotonin release from nerve terminals?

an action potential causing calcium entry

why are voltage-dependent calcium channels important in neurotransmitter release?

Ca²⁺ entry triggers vesicle fusion and neurotransmitter release

what determines the extent and duration of serotonin receptor activation?

reuptake of serotonin from the synapse

what is SERT?

the serotonin reuptake transporter

what does SERT normally do?

it transports serotonin back into the presynaptic neuron

what happens if SERT is blocked?

more serotonin remains in the synapse, increasing/prolonging receptor activation

what drugs block SERT?

SSRIs such as fluoxetine

what is fluoxetine?

an SSRI that blocks serotonin reuptake

what does SSRI stand for?

selective serotonin reuptake inhibitor

what does VMAT2 do?

VMAT2 packages monoamine neurotransmitters like serotonin into vesicles

what blocks VMAT2?

reserpine