Mechanisms of drug action Flashcards
Types of drug antagonism
- Receptor blockade
- Physiological antagonism
- Chemical antagonism
- Pharmacokinetic antagonism
Drug antagonism (receptor blockade)
- 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
Drug antagonism (physiological antagonism)
- 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
Drug antagonism (chemical antagonism)
- 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)
Drug tolerance
Gradual decrease in responsiveness to drug with repeated administration over days or weeks (eg: benzodiazepines used in epilepsy tx)
Drug tolerance cellular mechanism causes (pharmacokinetic factors)
- increased rate of drug metabolism when given repeatedly over time period
- eg: barbiturates, alcohol
Drug tolerance cellular mechanism causes (loss of receptors)
- 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
Drug tolerance cellular mechanism causes (change in receptors)
- 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
Drug tolerance cellular mechanism causes (exhaustion of mediator stores)
- Amphetamine (central stimulant causing euphoria)
- Mediator of Amphetamine is noradrenaline in central endogenous terminals
Drug tolerance cellular mechanism causes (physiological adaption)
- homeostatic responses lead to tolerance to drug side effects
- eg: antihypertensives
Receptor families
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
Ion channel-linked receptors
- otherwise known as ionotropic receptors
- fast response (milliseconds)
- located in membrane
- effector: channel
- direct coupling
- examples include nAChR, GABAa
G-protein-coupled receptors
- 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
Kinase-linked receptors
- 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
Intracellular steroid type receptors
- 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)
Drug antagonism (pharmacokinetic antagonism)
- 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)
Type 1 receptor structure
-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
Type 2 receptor structure
- metabotropic
- 1 unit (no subunits)
- 7 transmembrane domains (alpha helices)
Type 3 receptor structure
- 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
Type 4 receptor structure
- 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)
Use dependency in receptor blockade
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)
Receptor up-regulation
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Drug antagonism
Drug can reduce response of another drug
