UMP2005 pharmacology of the sympathetic nervous system

Question 1

what type of receptor are adrenoreceptors?

Answer 1

• GPCRs
• g protein coupled receptors

Question 2

what are the subtypes of adrenoreceptors?

Answer 2

• alpha 1 and 2
• Beta 1,2,3x

Question 3

what is the pathway of alpha 1 adrenoreceptors?

Answer 3

• coupled with Gq protein
• causes stimulation of phospholipase C which stimulates IP3/DAG which Ca release causing muscle contraction

Question 4

what is the pathway of alpha 2 adrenoreceptors?

Answer 4

• coupled to Gi protein
• inhibits adenyl cyclase which decreases levels of cAMP causing decreased contraction/excitability

Question 5

what is the pathway of beta-adrenoreceptors?

Answer 5

• 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

Question 6

give an example of a non-selective competitive irreversible alpha adrenoreceptor antagonist

Answer 6

• phenoxybenzamine
  (used in treatment of paroxysmal hypertension and sweating resulting from pheochromocytoma)

Question 7

give an example of a non-selective competitive reversible alpha adrenoreceptor antagonist

Answer 7

• phentolamine
  (used to reverse the effects of an anesthetic medicine in soft tissues, such as the lips and tongue)

Question 8

give some examples of selective alpha 1 adrenoreceptor competitive reversible antagonists

Answer 8

• 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)

Question 9

give some examples of selective alpha 2 adrenoreceptor competitive reversible antagonists

Answer 9

• 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)

Question 10

give some therapeutic uses of a1 adrenoreceptor antagonists

Answer 10

• hypertension
• phaeochromocytoma
• benign prostatic hyperplasia

Question 11

how do alpha 1 antagonists work against hypertension?

Answer 11

• prevent noradrenaline from stimulating a1 receptors to constrict, so with the antagonist the blood vessels dilate to decrease blood pressure

Question 12

what happens when alpha 1 adrenoreceptors are blocked?

Answer 12

• 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

Question 13

how do alpha 1 antagonists work against benign prostatic hyperplasia?

Answer 13

• 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

Question 14

give 2 examples of non-selective Beta adrenoreceptor antagonists

Answer 14

• 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)

Question 15

give some examples of selective Beta 1 adrenoreceptor antagonists

Answer 15

• atenolol
  (treat hypertension and arrhythmia)
• bisoprolol
  (treat hypertension and heart failure)
• metoprolol
  (treat hypertension and arrhythmia)

Question 16

what are Beta-adrenoreceptor antagonists with intrinsic sympathomimetic activity and give some examples?

Answer 16

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)

Question 17

how do beta blockers work?

Answer 17

• block the effect of adrenaline on organs and tissues like the heart
• this will slow the heart down and thus also decrease blood pressure

Question 18

give 2 examples of combined alpha 1 and beta 1 antagonists

Answer 18

• carvedilol
  (treat hypertension and prevent heart disease)
• labetatol
  (treat hypertension especially in pregnancy and emergency)

Question 19

give an example of a combined Beta 1 antagonist and Beta 3 agonist

Answer 19

• 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

Question 20

give some uses of beta adrenoreceptor antagonists

Answer 20

• treat hypertension, heart failure, angina, arrhythmias, myocardial infarction, thyrotoxicosis, anxiety, migraine, glaucoma

Question 21

what is the differences between lipid and water soluble beta blockers?

Answer 21

• 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

Question 22

what are some unwanted side effects of Beta blockers?

Answer 22

• fatigue, bradycardia, cold extremities, hypoglycaemia, sleep disturbance and nightmares

Question 23

what are some contradictions of beta blockers

Answer 23

• can cause bronchospasm = avoid in asthma patients
• can cause hypoglycaemia = avoid in diabetic patients
• also avoid in AV block and severe peripheral vascular disease

Question 24

why should beta blockers be avoided in some type 1 diabetic patients?

Answer 24

• 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

Question 25

why should beta blockers be avoided in some type 2 diabetic patients?

Answer 25

- 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

Question 26

what is the link between adrenoreceptors and hyperlipidaemia?

Answer 26

- 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

Question 27

what does it mean that some beta blockers are inverse agonists?

Answer 27

- 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

Question 28

describe the beta adrenoreceptor arrestin/GRK pathway

Answer 28

- 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)

Question 29

describe how some beta blockers are biased agonists for the GRK/Arrestin pathway

Answer 29

- 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

Question 30

what are the 3 ways you can interfere with adrenoreceptor stimulation with pre-synaptic processes?

Answer 30

- synthesis - storage -release

Question 31

give some examples of drugs used to inhibit the synthesis of catecholamines (to reduce adrenoreceptor stimulation)

Answer 31

- 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

Question 32

describe the process of recycling noradrenaline in the presynaptic terminal

Answer 32

- 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

Question 33

what is VMAT2 used for in presynaptic nerve terminals?

Answer 33

- uptake of NA into vesicles

Question 34

how does reserpine work?

Answer 34

- inhibits VMAT2 which allows NA to be uptaken into vesicles in the presynaptic nerve terminal - so less NA is released