Drugs acting on the adrenergic nervous system Flashcards
Adrenergic system makes use of the chemical messengers ______ and ______ .
adrenaline, noradrenaline
________ is the neurotransmitter released by the sympathetic nerves which feed smooth muscle and cardiac muscle
Noradrenaline
Adrenaline is a hormone released along with noradrenaline from the ___________.
adrenal medulla
Adrenaline is a hormone released along with noradrenaline from the ___________.
adrenal medulla
When is adrenaline released?
during times of danger or stress
Both the α and the β-adrenoceptors are what type of receptors?
G-protein-coupled receptors
Adrenergic neurotransmission is responsible for the body’s sympathetic or parasympathetic response?
sympathetic
The blood vessels supplying skeletal muscle have mainly _______ adrenoceptors and are [constricted/dilated] by adrenaline
β2, dilated
What is the function of a1 adrenoreceptors?
- vasoconstriction
- increased peripheral resistance
- increased blood pressure
- increased closure of internal sphincter of the bladder
What are a2 receptors also called?
autoreceptors
What is the function of a2 receptors?
- inhibition of norepinephrine release
- inhibition of acetylcholine release
- inhibition of insulin release
- lowers sympathetic activity
What is the function of B1 adrenoreceptors?
- tachycardia
- increased lipolysis
- increased myocardial contractility
- increased release of renin
What is the function of B2 receptors?
- vasodilation
- decreased peripheral resistance
- bronchodilation
- increased muscle and liver glycogenolysis
- increased release of glucagon
- relaxed uterine smooth muscle
Both adrenaline and noradrenaline act as?
agonists
What is the starting precursor for the synthesis of catecholamines?
tyrosine
L-Tyrosine becomes Levodopa by?
hydroxylation with tyrosine hydroxylase
Levodopa becomes Dopamine by?
decarboxylation with Dopa decarboxylase
What does MAO do?
oxidation
What does COMT do?
methylation
What happens if reuptake of norepinephrine is prevented?
norepinephrine stays longer in the synapse to give a longer duration of adrenergic transmission
How is the excess release of norepinephrine prevented?
by inhibiting the a2-receptors using norepinephrine (negative feedback inhibition)
What is isoprenaline?
a powerful β-stimulant devoid of α-agonist activity
Norepinephrine is active/inactive, and selective/nonselective
active, nonselective
What is the effect of adding isopropyl to noradrenaline?
- increased selectivity for beta receptor because the beta binding site is big enough for isoprenaline
- decreased activity for alpha receptor
Is alpha or beta receptor bigger?
beta receptor
What happens if phenol groups are absent in a compound that binds to B-receptors?
activity drops more significantly for β-receptors than for α-receptors
How does the addition of an α-methyl group affect the α2-receptor selectivity?
it increases α2-receptor selectivity
Effects of a-Methylnoradrenaline?
- lowers adrenergic transmission
- works similarly to an antagonist but is actually an agonist
What does it mean if we design a compound that selectively activated a2 receptors with minimum activity on other receptors?
it means that the compound lowers adrenergic transmission
How is the N-alkyl group affected by a polar functional group such as phenol?
the N-alkyl group results in a dramatic rise in activity and selectivity
If we add an extra bulky functionality to any compound, it will become more selective for which receptor?
beta receptor
What are the advantages of adding a phenol group to the end of an N-alkyl group?
- higher beta selectivity
- more active because of more hydrogen bonding interactions
- higher affinity
Adrenaline is administered with local anaesthetics in order to?
to constrict blood vessels and prolong local anaesthetic activity at the site of injection
Why is vasoconstriction important when administering local anaesthetics?
because it lowers side effects and prevents the local anesthetic from spreading to other parts of the body
What is ephedrine?
- an adrenergic agonist that activates both α− and β-adrenoceptors
- natural product existing as a racemate of the R, S and S, R stereoisomers
What is ephedrine used as?
a vasopressor and cardiac stimulant
Compare ephedrine to adrenaline
it is more lipophilic than adrenaline so it can cross the
blood–brain barrier and act as a stimulant
Why do ephedrine and pseudoephedrine have lower affinity to alpha and beta receptors?
because they don’t have catechols; this results in them having less activity
What is Pseudoephedrine?
- adrenergic agonist
- the S,S diastereomer of ephedrine.
What is pseudoephedrine used as?
nasal decongestant
Ephedrine and pseudoephedrine are __________ agents.
mixed-action adrenergic
What does a mixed-action adrenergic agonist do?
it can switch on the alpha and beta receptors
What is dobutamine?
β1-agonist
What is dobutamine used for?
treatment of cardiogenic shock
What is clonidine?
a selective α2-agonist
What is clonidine used for?
treatment of hypertension
How does clonidine work?
by decreasing the release of norepinephrine
What is oxymetazoline?
selective α1-agonist
What is xylometazoline?
selective α1-agonist
Both oxymetazoline and xylometazoline act as?
vasoconstrictors
Both oxymetazoline and xylometazoline are used in the treatment of?
nasal congestion and bloodshot eyes
Compare dobutamine to adrenaline/noradrenaline
dobutamine is structurally similar to adrenaline/noradrenaline except it has an extension
What is phenylephrine?
a selective α1-adrenergic receptor agonist
What is phenylephrine used as?
decongestant
What is the consequence of lacking one OH group in the case of phenylephrine?
less active, lower affinity
What is the difference between phenylephrine and norepinephrine?
Phenylephrine has only one OH while norepinephrine has two
Isoprenaline shows some selectivity for what receptors?
β-receptors (both 1 and 2)
What was the disadvantage of using isoprenaline?
it showed no selectivity between the different subtypes of β-receptors so it also activated the β1-receptors of the heart, leading to unwanted cardiovascular effects
How can selectivity between different types of β-receptors be obtained?
- by introducing alkyl substituents to the side chain linking the aromatic ring and the amine
- varying the alkyl substituents on the nitrogen
What is isoetharine?
β2-agonist
What is the disadvantage of isoetharine?
it was short lasting because the COMT enzyme methylates the catechol and makes it inactive
Why is isoetharine more selective for B2?
because the ethyl fits a pocket in the binding site of B2 receptor but has no place in the B1 receptor
What is salbutamol?
β2-agonist
Compare salbutamol and isoetharine
- CH2 was added between methyl and OH to make salbutamol to protect it from COMT
- salbutamol has the same potency as isoprenaline, but is 2000 times less active on the heart and is more selective for B2
How long is the duration of action of salbutamol?
4 hours
Is salbutamol taken up by transport proteins or metabolized by COMT?
no
Which enantiomer of salbutamol is more active?
R enantiomer
What is levalbuterol?
the pure R enantiomer of salbutamol
B2 agonist
Can COMT methylate R-Salbutamol?
no because it is not a catechol anymore
What is salmefamol?
B2 agonist
Compare salmefamol to salbutamol
salmefamol is 1.5 times more active than salbutamol and has a longer duration of action (6 hours)
Advantages of R-Salmefamol extension
- more hydrogen bonding
- higher affinity
- higher lipophilicity
Why does salmefamol have a longer duration of action?
it is more lipophilic so it binds more strongly with albumin in plasma
What is the duration of action of salmefamol?
6 hours
Is salmefamol or salbutamol more suitable for treating noctural asthma?
neither
What is salmeterol?
B2 agonist that has twice the potency of salbutamol and an extended action
What is the duration of action of salmeterol?
12 hours
R-Salmeterol is a bioisostere for?
catechol
Is R-Salmeterol a COMT substrate?
no
What is the most important use for a1?
nasal decongestion by vasoconstriction
What is a2 agonist used for?
vasodilation
treatment of hypertension
lowering sympathetic stimulation
What is carvedilol?
antagonist at both the α and β adrenoceptors
What is labetalol?
antagonist at both the α and β adrenoceptors
What are carvedilol and labetalol both used as?
antihypertensives
What is carvedilol used for?
treatment of cardiac failure
What are a1-antagonists used to treat?
hypertension or to control urinary output
What is prazosin?
the first α1-selective antagonist
What is the problem with prazosin?
it is short acting
Why are doxazosin and terazosin better than prazosin?
because they are given as once-daily doses
What drugs have been used for the treatment of benign prostatic hyperplasia?
doxazosin and terazosin
______ are being considered as antidepressants
α2–antagonists
What is mirtazepine?
α2–antagonist
antidepressant agent which increases noradrenaline and serotonin levels
What was chosen as the lead compound to design β-blockers?
isoprenaline
What is pronethalol?
β-blocker that is a partial agonist
What was the first β-blocker to be used clinically for angina, arrhythmia, and high blood pressure?
pronethalol
What is propranolol?
pure β-antagonist
What has greater activity - pronethalol or propranolol?
propranolol
What has greater activity - pronethalol or propranolol?
propranolol
Which enantiomer of propranolol is the active form?
S-enantiomer although propranolol is used clinically as a racemate
What is the importance of having an isopropyl?
increased B-receptor selectivity
What is the first non-selective β-antagonist?
propranolol
All B1 selective substituents are on ______ position.
para
What is more potent, practolol or propranolol?
propranolol
What is more potent, practolol or propranolol?
propranolol
What is practolol?
a selective cardiac β1-antagonist which does not block vascular or bronchial β2 -receptors
Why is practolol much safer than propranolol for asthmatic patients?
because it is more polar and has fewer CNS effects
All second-generation beta blockers are?
hydrogen bond acceptors
Are first generation beta blockers selective?
no
Are second generation beta blockers selective?
yes
What is esmolol?
second generation B-blocker that has rapid onset of action
Why is esmolol short-acting?
it contains ester that is easily hydrolyzed
What is esmolol used for?
it is administered if the heart starts to beat too rapidly, especially during surgical procedures
α-methyltyrosine inhibits?
tyrosine hydroxylase (regulatory enzyme for catecholamine biosynthesis)
_______ is sometimes used clinically to treat tumour cells which overproduce catecholamines (e.g., Pheochromocytoma)
α-methyltyrosine
____________ are used as a way of downregulating the adrenergic system
false transmitters
Are false transmitters more or less active than noradrenaline?
less
Is a-Methylnoradrenaline a neurotransmitter?
no
__________ was once prescribed as an antihypertensive agent, but it has serious side effects (e.g. depression). Therefore, it is no longer used.
reserpine
