(PM3B) Adrenergic Therapeutics Flashcards
What are the stages in catecholamine synthesis?
(1) Tyrosine converted to DOPA via tyrosine hydroxyls
(2) DOPA converted to dopamine via DOPA decarboxylase
(3) Dopamine converted to noradrenaline via dopamine ß-hydroxylase
(4) Noradrenaline converted to adrenaline via phenylethanolamine N-methyltransferase
What molecule provides negative feedback in catecholamine synthesis?
Noradrenaline
Where is noradrenaline released?
ALL post-ganglionic sympathetic fibres
Where is adrenaline released?
Adrenal gland
On which molecule does noradrenaline provide negative feedback on, in catecholamine synthesis?
Tyrosine hydroxylase
Where does noradrenaline bind?
Either alpha/beta adrenoceptors
What are the adrenoceptor subtypes?
(1) alpha-1
(2) alpha-2
(3) beta-1
(4) beta-2
(5) beta-3
What subtypes of alpha-1 adrenoceptor are there?
(1) alpha-1A
(2) alpha-1B
(3) alpha-1D
What subtypes of alpha-2 adrenoceptor are there?
(1) alpha-2A/D
(2) alpha-1B
(3) alpha-1C
Where are alpha-1 adrenoceptors located?
Smooth muscle
Where are alpha-2 adrenoceptors located?
(1) Smooth muscle
(2) Nerve terminals
Where are beta-1 adrenoceptors located?
Heart
Where are beta-2 adrenoceptors located?
(1) Smooth muscle
(2) Heart
(3) Skeletal muscle
(4) Nerve terminals
Where are beta-3 adrenoceptors located?
(1) Skeletal muscle
(2) Fat
What is the function of alpha-1 adrenoceptors?
(1) Vasoconstriction
(2) Contraction – relax GIT
(3) Glycogenolysis
What is the function of alpha-2 adrenoceptors?
(1) Contraction
(2) Inhibition of neurotransmitter release
What is the function of beta-1 adrenoceptors?
Increase cardiac rate + force
What is the function of beta-2 adrenoceptors?
(1) Vasodilation
(2) Bronchodilation
What is the function of beta-3 adrenoceptors?
(1) Thermogenesis
(2) Lipolysis
Which G protein does the alpha-1 adrenoceptor act on?
G-alpha-q
Which G protein does the alpha-2 adrenoceptor act on?
G-alpha-i/o
Which G protein does the beta-1 adrenoceptor act on?
G-alpha-s
Which G protein does the beta-2 adrenoceptor act on?
G-alpha-s
Which G protein does the beta-3 adrenoceptor act on?
G-alpha-s
What is the response of alpha-1 adrenoceptor binding?
Increased IP3
What is the response of alpha-2 adrenoceptor binding?
Decreased cAMP
What is the response of beta-1 adrenoceptor binding?
Increased cAMP
What is the response of beta-2 adrenoceptor binding?
Increased cAMP
What is the response of beta-3 adrenoceptor binding?
Increased cAMP
For which adrenoceptor subtype does noradrenaline have the greatest potency?
alpha-1
For which adrenoceptor subtype does noradrenaline have the poorest potency?
beta-2
beta-3
What are some selective agonists of alpha-1 adrenoceptors?
(1) Phenylephrine
(2) Methoxamine
What are some selective agonists of alpha-2 adrenoceptors?
(1) Clonidine
(2) Brimonidine
What are some selective agonists of beta-1 adrenoceptors?
(1) Dobutamine
(2) Xamoterol
What are some selective agonists of beta-2 adrenoceptors?
(1) Salbutamol
(2) Terbutaline
(3) Ritodrine
What are some selective agonists of beta-3 adrenoceptors?
Mirabegron
What are some selective agonists of alpha-1 adrenoceptors?
(1) Doxacin
(2) Terazosin
What are some selective agonists of alpha-2 adrenoceptors?
(1) Yohimbine
(2) Idazoxan
What are some selective agonists of beta-1 adrenoceptors?
(1) Atenolol
(2) Metoprolol
(3) Bexatolol
What are some selective agonists of beta-2 adrenoceptors?
Butoxamine
What are some selective agonists of beta-3 adrenoceptors?
None/ unknown
Where is tyrosine hydroxylase found?
ONLY in noradrenergic neurones
What are the stages of adrenergic transmission?
(1) Tyrosine converted to noradrenaline
(2) Noradrenaline packaged into vesicles
(3) Noradrenaline vesicles move into synaptic cleft via exocytosis
(4) Noradrenaline binds to postsynaptic cell receptors/ uptake 1 transport system/ uptake 2 transport system/ alpha-2 adrenoceptor on presynaptic membrane
What is given in event of cardiac arrest? Why?
Adrenaline
1 in 10000 dilution
IV
Causes vasoconstriction via alpha-1 and beta adrenoceptor stimulation
What is given in event of cardiogenic shock?
ß1-selective adrenoceptor agonist
Dobutamine
Increased cardiac output
What is given to treat asthma?
ß2-selective agonists
e. g. salbutamol/ terbutaline (short-acting)
e. g. salmeterol/ formoterol (long-acting)
What is given to treat an overactive bladder (incontinence), with specific regard to adrenergic transmission?
ß3-selective agonist
Mirabegron
Only when anti-muscarinic drugs are ineffective/ contraindicated
What effects does the adrenaline in an EpiPen have on the adrenergic receptors during anaphylaxis?
(1) Bronchodilation via ß2 adrenoceptor
(2) Increased BP via alpha-1 adrenoceptor
What is the treatment of glaucoma using adrenoceptor agonists?
Adrenaline/ brimonidine/ apraclonidine
- selective alpha2-agonists
- used to reduce intraocular pressure
- used when ß-blockers are inappropriate
What is local anaesthesia using adrenoceptor agonists?
Adrenaline
- prolongs LA action
- e.g. lidocaine in dental procedures
- e.g. bupivacaine in spinal anaesthesia
What is the use of adrenoceptor agonists in labour?
ß2-selective agonists
e.g. ritodrine/ salbutamol
Smooth muscle relaxant
Inhibit sympathetic-induced contraction of uterus
Prevention of premature labour from 24-33 weeks
How long can ß2-selective agonists prolong premature labour for?
Maximum 48 hours
Which ß2-selective agonists can prolong premature labour for?
(1) Ritodrine
(2) Salbutamol
How many weeks gestation is considered premature?
24-33 weeks
What are the effects of alpha-adrenoceptor antagonists on blood pressure?
Doxazosin/ terazosin
Cause vasodilation
Decrease arterial BP
Not first line
Treatment of hypertension
What are the effects of alpha-adrenoceptor antagonists on benign prostatic hyperplasia?
alpha-1A adrenoceptor selective antagonists
- e.g. alfuzosin/ indoramin/ tamsulosin
Relaxes smooth muscle in bladder + prostate
Treats enlargement of prostate + improves urinary retention
What are the cardiovascular effects of beta-adrenoceptor antagonists?
Non-selective = propranolol/ timolol
ß1-selective = metoprolol/ atenolol
Important drugs in the treatment of:
- angina
- MI
- dysrhythmia
- heart failure
- hypertension
What are the effects of beta-adrenoceptor antagonists on glaucoma?
Topical ß-blocker
Betaxolol – ß1-selective
Act to reduce production of aqueous humour
- reduce intraocular pressure
can also use carteolol/ timolol eye drops
What are the effects of beta-adrenoceptor antagonists on migraines?
Propranolol/ metaprolol
Migraine prophylaxis
What are some side-effects of beta-adrenoceptor antagonists?
(1) Cardiac depression/ bradycardia
(2) Fatigue + tiredness
(3) Cold extremities – reduced blood flow
Can cardioselective beta-adrenoceptor antagonists be taken in a patient with asthma or COPD?
No
Contraindicated
What are some contraindications for beta-adrenoceptor antagonists?
(1) Cardioselective beta-blockers in patients with asthma or COPD
(2) Eye drops used for glaucoma for patients with cardiovascular disease
(3) Patients prone to hypoglycaemia
- ß2-receptors control glucose release from the liver
(4) Liver disease
Give an example of an adrenoceptor partial agonist.
Clonidine
What is clonidine?
alpha-2 partial agonist
Used in treatment of hypertension
What is the mechanism of action of clonidine?
(1) Activation of alpha-2 adrenoceptor
(2) Causes negative feedback on noradrenaline release in presynaptic membrane
(3) Down-regulation of noradrenaline reduce alpha-1-mediated vasoconstriction
What is the mechanism of action of alpha-2 partial agonists?
(1) Activation of alpha-2 adrenoceptor
(2) Causes negative feedback on noradrenaline release in presynaptic membrane
(3) Down-regulation of noradrenaline reduce alpha-1-mediated vasoconstriction
Give two examples of indirect sympathomimetics that are used therapeutically as nasal decongestants.
(1) Ephedrine
(2) Pseudoephedrine
What is the mechanism of action of ephedrine?
(1) Acts as substrate for uptake transport system in presynaptic membrane
(2) Leads to noradrenaline release
(3) Causes vasoconstriction
(4) Reduces nasal blood flow + oedema (congestion)
What is the mechanism of action of pseudoephedrine?
(1) Acts as substrate for uptake transport system in presynaptic membrane
(2) Leads to noradrenaline release
(3) Causes vasoconstriction
(4) Reduces nasal blood flow + oedema (congestion)
What is the mechanism of action of indirect sympathomimetics?
(1) Acts as substrate for uptake transport system in presynaptic membrane
(2) Leads to noradrenaline release
(3) Causes vasoconstriction
(4) Reduces nasal blood flow + oedema (congestion)
Other than ephedrine and pseudoephedrine, name substrates of uptake transport system 1 in the presynaptic membrane.
(1) Tyramine
(2) Amphetamine
When are substrates of uptake transport system 1 used therapeutically?
(1) Narcolepsy
(2) ADHD
(3) Appetite suppression
What other actions do substrates of uptake transport system 1 have therapeutically?
Pyschoactive agents
e.g. cocaine/ tricyclic antidepressants
Treatment of depression
What are the enzymes responsible for catecholamine metabolism (breakdown)?
(1) Monoamine oxidase (MAO)
- MAO-A
- MAO-B
- found in mitochondria in sympathetic nerve terminals/ liver/ intestinal epithelium
(2) Catechol-O-methyl-transferase (COMT)
What is the significance of COMT and MAO?
Enzymes
Responsible for catecholamine metabolism (breakdown)
What is an MAOI?
Monoamine oxidase inhibitor
What are some therapeutic uses of MAOIs?
(1) Anti-depressant
- e.g. phenelzine
- if SSRIs/ TCAs are ineffective
(2) Parkinson’s disease
- MAO-B selective
- prevention of dopamine breakdown
- slows disease progression
- e.g. selegiline/ rasagiline
