Mechanisms of drug action

Question 1

Types of drug antagonism

Answer 1

• Receptor blockade
• Physiological antagonism
• Chemical antagonism
• Pharmacokinetic antagonism

Question 2

Drug antagonism (receptor blockade)

Answer 2

• binding of antagonist to receptor to prevent binding of agonist (blocking of receptor prevents agonist action)
• includes competitive and irreversible inhibition
• ‘Use dependency’ of ion channel blockers/irreversible antagonists (eg: local anaesthetics)->speed of blocker response depends on how active the tissue is

Question 3

Drug antagonism (physiological antagonism)

Answer 3

• Drugs act on different receptors which leads to opposite effects in same tissue
• example includes noradrenaline which increases blood pressure (vasoconstriction) and histamine which reduces blood pressure (vasodilation)=opposite effects on vessel diameter so antagonise each others actions

Question 4

Drug antagonism (chemical antagonism)

Answer 4

• drug interaction in solution=one drug negates effect of other
• less common on therapeutics
• example includes dimercaprol (chelating agent which forms heavy metal ion complexes to reduce toxicity if heavy metal/lead poisoning->complex for reasonably excreted by kidney)

Question 5

Drug tolerance

Answer 5

Gradual decrease in responsiveness to drug with repeated administration over days or weeks (eg: benzodiazepines used in epilepsy tx)

Question 6

Drug tolerance cellular mechanism causes (pharmacokinetic factors)

Answer 6

• increased rate of drug metabolism when given repeatedly over time period
• eg: barbiturates, alcohol

Question 7

Drug tolerance cellular mechanism causes (loss of receptors)

Answer 7

• receptor removal from membrane by membrane endocytosis
• repeated stimulation by agonist leads to cell endocytosing receptors (receptors enclosed in vesicles inside cell) so fewer are available on cell surface-> receptor ‘down-regulation’
• examples include beta-adrenoceptors

Question 8

Drug tolerance cellular mechanism causes (change in receptors)

Answer 8

• receptor densensitization from continued receptor stimulation over long time period (number on cell surface does not change, just structural change)
• involved conformational change
• example includes nAChR at neuromuscular junctions

Question 9

Drug tolerance cellular mechanism causes (exhaustion of mediator stores)

Answer 9

• Amphetamine (central stimulant causing euphoria)

- Mediator of Amphetamine is noradrenaline in central endogenous terminals

Question 10

Drug tolerance cellular mechanism causes (physiological adaption)

Answer 10

• homeostatic responses lead to tolerance to drug side effects
• eg: antihypertensives

Question 11

Receptor families

Answer 11

4 types based on molecular structure and signal transduction systems

• Type 1: ion channel-linked receptors
• Type 2: G-protein-coupled receptors
• Type 3: Kinase-linked receptors
• Type 4: Intracellular steroid type receptors

Question 12

Ion channel-linked receptors

Answer 12

• otherwise known as ionotropic receptors
• fast response (milliseconds)
• located in membrane
• effector: channel
• direct coupling
• examples include nAChR, GABAa

Question 13

G-protein-coupled receptors

Answer 13

• otherwise known as metabotropic receptors
• slower response than ion channel-linked receptors (seconds) as has to bind to G-protein first
• located in membrane
• effector: enzyme or channel
• G-protein coupling
• examples include beta1-adrenoceptors (heart) and mAChR

Question 14

Kinase-linked receptors

Answer 14

• located in membrane
• takes minutes (very slow response)
• result in intracellular protein phosphorylation
• effector: enzyme
• direct coupling
• examples include insulin receptor, growth factor and cytokine receptors etc

Question 15

Intracellular steroid type receptors

Answer 15

• otherwise known as nuclear receptors
• located intracellularly in nucleus (drug/hormone needs access to inside of cell to find receptor)
• takes hours (long response)
• regulates gene transcription
• effector: gene transcription
• coupling via DNA
• examples include steroid/thyroid receptors (activated by steroids and thyroid hormones)

Question 16

Drug antagonism (pharmacokinetic antagonism)

Answer 16

• one drug (antagonist) reduces concentration of active drug at site of action (co-administration effects)
• drug can do this by: reducing absorption of another drug, increasing metabolism of another drug or increasing excretion of another drug
• clinically important interaction (aware of interference during drug administration)
• example includes barbiturates (anti-epileptics which result in quicker enzyme metabolism of other drugs if same enzyme involved in their metabolism=possibly higher dose of other drug in co-administration if knowledge of rapid metabolism)

Question 17

Type 1 receptor structure

Answer 17

-4/5 subunits
-transmembrane sections (otherwise known as alpha helices=each subunit composed of 4 transmembrane segments=DEFINING FEATURE)
-alpha helices provide channel lining
external binding domain

Question 18

Type 2 receptor structure

Answer 18

• metabotropic
• 1 unit (no subunits)
• 7 transmembrane domains (alpha helices)

Question 19

Type 3 receptor structure

Answer 19

• kinase linked
• 1 transmembrane domain (alpha helix)
• large intracellular domain
• intracellular loops where catalytic doman is (often tyrosine kinase linked)->outside binding leads to activation inside

Question 20

Type 4 receptor structure

Answer 20

• found in nucleus
• binding domain for agonist to stimulate the receptor
• receptor stimulation unfolds receptor to expose DNA binding domain
• DNA binding domain (zinc fingers=fingers of protein containing zinc atoms)

Question 21

Use dependency in receptor blockade

Answer 21

the more active the tissue on which the drug is acting (more tissue is used), the more effective this ion channel blocker will be (will produce a more complete blocker response more rapidly)

Question 22

Receptor up-regulation

Answer 22

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Question 23

Drug antagonism

Answer 23

Drug can reduce response of another drug