Adaptations to drugs Flashcards
What are four mechanisms where there is a loss of efficacy of drugs that occur
- change in receptors
- exhaustion of mediators
- increased metabolic degradation of drug
- resistance in target organism
How can phosphorylation lead to loss of efficacy
- phosphorylated receptor (most G protein coupled receptors) = binding site for beta arrestin agonist
- Beta arrestin- intracellular proteins – block interaction with g protein – no second messanger cascade– no efficacy
Why does prolong exposure to agonist lead to gradual decrease in responsiveness (translocation of receptors- down regulation)
- gadual decrease in receptor expression on cell surface
- internalisation of receptors by endocytosis
- depends on receptor being phosphorylated
- adaption to common hormone receptor
How is adrenaline binded to g protein coupled receptor
- g protein coupled receptor + adrenaline –adenylate cyclase– ATP to Camp– protein kinase A – increase force and heartbeat
How is beta adrenoreceptor desensitised by adrenaline with phosphorylation and down regulation
- repeated stim of b AR by adrenaline
- phosphorylation or receptor
- promotes beta arrestin bind- –inhibits receptor to stimulate G protein e– cell response decreases – signals endocytosis of receptor– down regulation
Why might prolongue exposure to antagonist lead to gradual decrease in agonist response
- continuous antagonist block– gradual decrease in receptor expression on cell surface– suddenly super sensitive to agonists
– this is why beta blockers has to have gradual withdrawal – as it can have rebound hypertension
What happens when a GAPA binds to receptor
- GABA binds to GABA a receptor – central receptor pore opens – more cl- ions into neuron– hyperpolarises– decreases neuronal excitability
What does benzodiazepines do when binds to GABAa receptor
- high affinity to GABAa receptor
- increase of Cl- into neuron
- reduces excitability
- depressant effect
– withdrawal of benzodiazepines gradual– down regulation of receptors – sudden cessation (withdrawal syndromme)
What is exhausion of mediator substance and how does anphetamine drug do this
- depletion of essential intermediate substance
- -anphetamine (CNS stimulant) replaces noradrenaline in vesicles in nerve terminals– causes amines to be released from nerve terminals instead of noradrenaline
What must you ensure when administering nitrate coronary vasodialator or to treat angina
- ensure patient seated
as side affects after administration: flushing (reduction in left ventricular work), headache, postural hypotension (reduction in venous return)
What is the mode of action of nitrates
- nitrate groups interact with enzymes and SH grouple– reduce to NO or S- nitrothiol (which is then reduced)– releases nitric oxide
How does potent vasodialators cause smooth muscle relaxation
- nitric oxide = potent vasodilator
- activates guanylyl cyclase– increases cyclic GMP– inhibits CA2+ enetery into cell – causes smooth cell muscle relaxation
How does nitrate tolerance lead to exhaustion of mediators
- repeated administeration – depletes SH groups to make NO
- not problem for GNT angina (chest pain due to reduced blood flow to heart) treatment – half life of 3 mins
— to have tolerance we need prolonge nitrate infusions, prolonge nitrate patches, modified release formulations
What are CYP enzyme inducers and inhibitors
- induction accelerate metabolism – decrease drug efficacy: cigarette smoke
- inhibition decrease drug metabolism – increase toxicity : grapefruit juice, clarithromycin
Why is clarithromycin and wafarin interaction increase anticoagulant effect
- clarithromycin inhibitor of CYP3A4
- warfarin metabolised by several CYP45- enzymes (CYP3A4)
- decreased warfarin metabolism – higher toxicity (increase risk of bleeding)
