UMP2005 pharmacology of the sympathetic nervous system Flashcards
what type of receptor are adrenoreceptors?
- GPCRs
- g protein coupled receptors
what are the subtypes of adrenoreceptors?
- alpha 1 and 2
- Beta 1,2,3x
what is the pathway of alpha 1 adrenoreceptors?
- coupled with Gq protein
- causes stimulation of phospholipase C which stimulates IP3/DAG which Ca release causing muscle contraction
what is the pathway of alpha 2 adrenoreceptors?
- coupled to Gi protein
- inhibits adenyl cyclase which decreases levels of cAMP causing decreased contraction/excitability
what is the pathway of beta-adrenoreceptors?
- B 1 = coupled to Gs protein = stimulates adenyl cyclase, increasing cAMP, causing contraction/excitability
- B2/3 = coupled to either Gs or Gi so either stimulate or inhibit adenyl cyclase
give an example of a non-selective competitive irreversible alpha adrenoreceptor antagonist
- phenoxybenzamine
(used in treatment of paroxysmal hypertension and sweating resulting from pheochromocytoma)
give an example of a non-selective competitive reversible alpha adrenoreceptor antagonist
- phentolamine
(used to reverse the effects of an anesthetic medicine in soft tissues, such as the lips and tongue)
give some examples of selective alpha 1 adrenoreceptor competitive reversible antagonists
- prazosin
(manage and treat hypertension, benign prostatic hyperplasia, PTSD-associated nightmares, and the Raynaud phenomenon) - doxazosin
( treat symptoms of benign prostatic hyperplasia and hypertension) - tamsulosin
(treat symptomatic benign prostatic hyperplasia and chronic prostatitis and to help with the passage of kidney stones)
give some examples of selective alpha 2 adrenoreceptor competitive reversible antagonists
- yohimbine
(used in veterinary medicine to reverse the effects of xylazine in dogs and deer and used to treat erectile dysfunction) - idazoxan
(trials for mental illnesses and neurodegeneration) - atipamezole
(reversal of the sedative and analgesic effects of dexmedetomidine and medetomidine in dogs)
give some therapeutic uses of a1 adrenoreceptor antagonists
- hypertension
- phaeochromocytoma
- benign prostatic hyperplasia
how do alpha 1 antagonists work against hypertension?
- prevent noradrenaline from stimulating a1 receptors to constrict, so with the antagonist the blood vessels dilate to decrease blood pressure
what happens when alpha 1 adrenoreceptors are blocked?
- decrease blood pressure (vasodilation)
- postural hypotension = dizziness
- failure of ejaculation
- miosis ( pupils constrict )
- baroreceptor reflex can cause tachycardia and renin cause sodium and water retention
how do alpha 1 antagonists work against benign prostatic hyperplasia?
- they block receptors from noradrenaline to constrict
- so the antagonists relax the prostatic smooth muscle
- helps reduce constriction on urethra, help urine flow more easily
give 2 examples of non-selective Beta adrenoreceptor antagonists
- propranolol
( treat high blood pressure and other heart problems, but it can also help with the physical signs of anxiety, like sweating and shaking) - timolol
(treat and manage open-angle glaucoma and ocular hypertension)
give some examples of selective Beta 1 adrenoreceptor antagonists
- atenolol
(treat hypertension and arrhythmia) - bisoprolol
(treat hypertension and heart failure) - metoprolol
(treat hypertension and arrhythmia)
what are Beta-adrenoreceptor antagonists with intrinsic sympathomimetic activity and give some examples?
beta-blockers that are able to stimulate beta-adrenergic receptors (agonist effect) and to oppose the stimulating effects of catecholamines (antagonist effect) in a competitive way
- pindolol
(treat hypertension)
- oxprenolol
(treat hypertension and arrhythmia)
how do beta blockers work?
- block the effect of adrenaline on organs and tissues like the heart
- this will slow the heart down and thus also decrease blood pressure
give 2 examples of combined alpha 1 and beta 1 antagonists
- carvedilol
(treat hypertension and prevent heart disease) - labetatol
(treat hypertension especially in pregnancy and emergency)
give an example of a combined Beta 1 antagonist and Beta 3 agonist
- nebivolol
- treat hypertension and heart failure
-induces nitric oxide production from endothelium and myocardium via activation of beta(3)-adrenergic receptors, which improves blood flow
give some uses of beta adrenoreceptor antagonists
- treat hypertension, heart failure, angina, arrhythmias, myocardial infarction, thyrotoxicosis, anxiety, migraine, glaucoma
what is the differences between lipid and water soluble beta blockers?
- lipid soluble = liver metabolised, shorter half life
- water soluble = excreted by kidnyes, longer half life
- lipid soluble antagonists may have more CNS side effects but may be better for anxiety and migraine
what are some unwanted side effects of Beta blockers?
- fatigue, bradycardia, cold extremities, hypoglycaemia, sleep disturbance and nightmares
what are some contradictions of beta blockers
- can cause bronchospasm = avoid in asthma patients
- can cause hypoglycaemia = avoid in diabetic patients
- also avoid in AV block and severe peripheral vascular disease
why should beta blockers be avoided in some type 1 diabetic patients?
- they may exacerbate hypoglycaemia in insulin dependent diabetes (mostly type 1)
- as it blocks Beta-2 mediated glucose release from the liver and also sympathetic responses to hypoglycaemia
why should beta blockers be avoided in some type 2 diabetic patients?
- mechanism not clear but non-selective, non-vasodilating, Beta blockers may reduce skeletal muscle blood flow and so insulin dependent glucose uptake
- Carvedilol and nebicolol have better glycaemic control as they are selective beta and alpha-1 blockers
what is the link between adrenoreceptors and hyperlipidaemia?
- beta blockers may increase blood triglycerides and decrease HDL (except carvedilol which may reduce triglycerides and LDL)
- alpha blockers like doxazosin may reduce blood triglycerides, increase HDL and decrease LDL
what does it mean that some beta blockers are inverse agonists?
- some beta blockers display some spontaneous activity
- metoprolol shown to be a very good inverse agonist on beta blockers
- they can reduce cAMP and cardiac contractility below basal levels
- as they can act through both Gs and Gi which oppose each other
describe the beta adrenoreceptor arrestin/GRK pathway
- Beta 1 and 2 adrenorecpeotrs linked to Gs coupled protein, stimulates adenyl cyclase which increases cAMP
- this causes arrestin to activate and GRK to phosphorylate
- however, as arrestin binds to the GPCR it desensitized, blocking the signalling pathway
(Beta 3 have no GRK phosphorylation sites so much less desensitization)
describe how some beta blockers are biased agonists for the GRK/Arrestin pathway
- carvedilol and nebivolol can stimulate GRK phosphorylation of Beta 1 and 2 adrenoreceptors and stimulate arrestin binding and ERK1/2 kinase activity (basically blocking signalling pathway)
- this is thought to be cardio protective which may be useful in some patients
what are the 3 ways you can interfere with adrenoreceptor stimulation with pre-synaptic processes?
- synthesis
- storage
-release
give some examples of drugs used to inhibit the synthesis of catecholamines (to reduce adrenoreceptor stimulation)
- a-methytyrosine = block tyrosine hydroxylase which converts L-tyrosine into L-DOPA
- disulfiram = blocks dopamine B-hydroxylase which converts dopamine into noradrenaline
- a-methyldopa = competitive inhibitor of dopa decarboxylase which converts L-DOPA into dopamine
describe the process of recycling noradrenaline in the presynaptic terminal
- NA is taken back into the presynaptic nerve terminal by NA transporter
- then MAO breaks down excess NA
- NA is then uptaken into vesicles by VMAT2
what is VMAT2 used for in presynaptic nerve terminals?
- uptake of NA into vesicles
how does reserpine work?
- inhibits VMAT2 which allows NA to be uptaken into vesicles in the presynaptic nerve terminal
- so less NA is released
