Cardiovasualar Durgs Lecture 1 Flashcards
how angina occurs
when one or more of the coronary arteries becomes narrowed or blocked, usually by atherosclerosis
adrenoreceptors
receptors that mediate central and peripheral actions of the neurotransmitter noradrenaline and the hormone and neurotransmitter adrenaline
where adrenoreceptors are found
in nearly all peripheral tissues and on many neuronal populations within the central nervous system
what roles do noradrenaline and adrenaline play
- blood pressure
- heart rate and force
- airway reactivity
activating alpha-adrenoreceptors
generally contracts smooth muscle, except in the gut
activating beta-1 receptors
contracts cardiac muscle
- predominate in the heart
activating beta-2 receptors
relaxes smooth muscle
- predominate in the airways
beta-blockers
used predominately in treatment of hypertension, angina and cardiac arrhythmias
how beta-blockers work
they prevent catecholamines from accessing the beta-adrenergic receptor sites in the heart and other organs
they prevent catecholamines from accessing the beta-adrenergic receptor sites in the heart and other organs
- decreased heart rate and force of contraction
- decreased renin secretion
Structure-Activity Relationship of beta-blockers
see lecture notes for structure
alcohol group
- R-enantiomer of NA is more active than S
- indicates that secondary alcohol is involved in H-bonding
- compounds lacking hydroxyl group have greatly reduced interaction, but still posses some activity
- alcohol group is important, but not essential
amine group
- normally protonated and ionised at physiological pH
- ^important since replacing it with carbon results in large drop in activity
- activity affected by number of substituents
- primary and secondary amines have good adrenergic activity
- tertiary and quaternary ammonium salts don’t
both phenol substituents
- can be replaced by other groups capable of interacting with binding site of hydrogen bonding
- particularly true for the meta phenol group
alkyl substitution
- alkyl substitution on the side chain linking the aromatic ring to the amine decreases activity
- may be a steric effect which blocks h-bonding to the alcohol or prevents molecule adopting active conformation
isoprenaline
- non-selective beta-agonist
dichloroisoprenaline
- partial agonist
- overall acts as an antagonist
pronethalol
- replaces di-chloro substitution with aromatic ring
- partial agonist, but overall beta blocker
- first beta-blocker to be used clinically
propanolol
- produced by experimenting with length of chain between aromatic ring and the amine
- was a pure antagonist with 10-20x greater activity than pronethalol
synthesis of aryloxypropanolamines
- nucleophilic substitution by the phenol, chemoselective for alkyl halide
- nucleophilic substitution by the amine, regioselective for less substituted part of epoxide
- synthesis allows variation of aromatic rings and N-substituents
- racemic products formed
first generation beta-blockers
- branched, bulky N-alkyl substituents are good for beta-antagonist activity
- variation of aromatic ring system possible
- substitution on side chain methylene group increases stability but lowers activity
- alcohol group on side chain essential for activity
- replacing ether oxygen is detrimental
- n-alkyl substituents longer than isopropyl or t-butyl are less effective but extension with n-arylethyl is beneficial (-CHMe-CH2-Ph)
- AMINE MUST BE SECONDARY
what receptors do first generation beta-blockers act on
- both beta-1 and beta-2 receptors
- can’t be used with asthmatic patients
second generation beta-blockers
- beta-1 selective
- addition of another side chain on para-position
- substitution has to be in para for beta-1 selectivity, as another hydrogen bond is formed which isn’t possible with beta-2
third generation beta-blockers
- inlude n-arylakyl group
- extra vasodilating properties through blockade of alpha-adrenergic receptors
- they have massive extensions after the amide group
3rd generation beta blockers: labetalol, carvedilol and bucindolol
cause vasodilation through blockage of alpha-1 receptors
3rd generation beta blockers: nebivolol
causes vasodilation by endothelium-derived NO
why is carvedilol an exception to 3rd generation beta-blockers
why is carvedilol an exception to 3rd generation beta-blockers
beta-blockers on hypertension
- they decrease blood pressure by reducing cardiac output
- acute treatment with beta-blockers not effective in reducing arterial pressure due to compensatory increase in systemic vascular resistance
beta-blockers on angina
- antiangial effects attributed to cardiodepressant and hypotensive actions
- by reducing heart rate, force and arterial pressure, they reduce work of heart and oxygen demand
- improves oxygen supply/demand ratio, which can relieve anginal pain
beta-blockers on arrhythmias
- antiarrhythmic properties related to beta-blockers ability to inhibit sympathetic influences on cardiac electrical activity
- sympathetic nerves increase SA node firing
kind of heart failure that most patients have
systolic dysfunction
systolic dysfunction
contractile function of the heart is depressed
beta-blockers on systolic dysfunction
- some specific beta-blockers improve cardiac function and reduce mortality
- may be related to blockade of excessive chronic sympathetic influences on the heart, which are known to be harmful to the failing heart
- however, precise mechanism is poorly understood
beta-blocker side effects
- dizziness
- tiredness
- slow heartbeat
thing to note with beta-blockers
lipophilic beta-blockers can cross the BBB, so they have been associated with a low incidence of CNS side effects
