4.4 SNS Antagonists & False transmitters Flashcards
a1 receptors
- tissues
- functions
- Various (vascular, GI tract etc.)
- Vasoconstriction, relaxation of GI tract
α2 receptors
- tissues
- functions
- Presynaptic terminals, vascular smooth muscle, CNS
- Inhibition of transmitter release, vasoconstriction, CNS actions
β1 receptors
- tissues
- functions
- Heart, GI tract, kidneys
- Increased cardiac rate and force, relaxation of GI tract, renin release from kidneys
β2 receptors
- tissues
- functions
- Bronchi, smooth muscles, liver
- Bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis
β3 receptors
- tissues
- functions
- Adipose tissue
- Lipolysis
what is the selectivity for labetalol?
α1 + β1
what is the selectivity for phenotolamine?
α1 + α2
what is the selectivity for prazosin?
α1
what is the selectivity for propranolol?
β1 + β2
what is the selectivity for atenolol?
β1
Hypertension refers to an increase in blood pressure associated with increased risk of other diseases (sign rather than a disease itself):
• Underlying cause is rarely diagnosed (often primary hypertension)
• Defined by NICE guidelines as a blood pressure of__________________, or diagnosed with an ambulatory blood pressure monitoring (ABPM) daytime average or home blood pressure monitoring (HBPM) average of __________________
• Main contributing elements: blood volume, cardiac output, peripheral vascular tone
140/90 mmHg or higher;
135/85 mmHg or higher
The different β blockers (-olols) may be cardioselective (β1) or non-selective:
Competitive antagonism of the β1 adrenoceptors is responsible for most of the antihypertensive actions (unclear how effective β2 antagonism is):
• CNS effects: reduces sympathetic tone to various tissue targets
• Cardiac effects: reduces ____________ → not in chronic treatment
• Renal effects: reduces _____________ → chronic long-term benefit (due to blocking of the vasoconstrictor effects of angiotensin II)
The common long-term feature in the antihypertensive actions of these β adrenoceptor antagonists is the ____________________:
• Blockade of facilitatory effects of presynaptic β adrenoceptors on NA release may also contribute to the antihypertensive effect
heart rate and cardiac output;
renin production;
reduction in peripheral resistance (due to kidneys and angiotensin)
Why is β blockers dangerous in diabetics?
Use of β blockers masks the symptoms of hypoglycaemia (palpitations and tremors): • Non-selective antagonists are more dangerous in diabetics as they block β2-driven glycogenolysis
• β1-selective agents are advantageous as hepatic glucose release is controlled by β2 receptors
Why can’t β blockers be used in patients with acute/ unstable heart failure?
obstructive lung diseases (e.g. bronchitis) Cardiac failure
Treatment in chronic heart failure leads to reduced mortality:
• Cannot be used in acute/unstable heart failure due to acute negative inotropic effects
why is there bronchoconstriction due to β blockers?
Little importance in the absence of airway disease, but can be dramatic and life-threatening in asthmatic patients/other obstructive lung diseases (e.g. bronchitis)
why is there cold extremities due to β
blockers?
Loss of β-mediated vasodilation in cutaneous vessels
why is there bad dreams due to β blockers?
CNS effects
why is there fatigue due to β blockers?
Reduced cardiac output and muscle perfusion
What are the effects of propranolol?
- Non-selective (β1 + β2)
- At rest: little change in HR, CO, BP *Reduces the effects of exercise/stress on these variables (at rest parasympathetic dominates)
What are the effects of atenolol?
- Cardioselective (β1)
- Mainly antagonises NA effects on the heart (also affects any tissues with β1 receptors)
What are the effects of labetalol?
- Dual-acting (β1 + α1)
- 4:1 selectivity for β1
- Lowers BP via reduced TPR (kidneys – reduced angiotensin; vascular SM – constriction)
- No long-term change in HR/CO → long-term benefit by changing TPR
α blockers can be non-selective (blocks both α1 and α2 receptors), leading to _______________ (α receptors are the main mediators of peripheral resistance):
• Leads to __________________ (reflex response to fall in BP)
• Blood flow through _____________ is increased (dilation in peripheral resistance vessels), but direct effects on vascular smooth muscles of such vascular beds are slight (mainly mediated by β1)
• Side effect: _____________(sympathetic input usually prevents pooling of blood in the legs)
reduced arterial pressure;
increased heart rate and cardiac output;
cutaneous and splanchnic vascular beds;
postural hypotension
What are the effects for Phentolamine?
- Non-selective (α1 + α2)
- Vasodilation in peripheral resistance vessels → fall in BP (α1)
- Concomitant α2 blockade increases NA release → enhances reflex tachycardia
- No longer clinically used (for acute treatment of hypertension in surgery)
- Side effect: Increased GI motility → diarrhoea
What is prazosin used for?
- Highly selective (α1)
- Vasodilation → fall in BP
- Less tachycardia than non-selective antagonists as drugs do not increase NA release (no α2)
- CO decreases → fall in venous pressure (dilation of capacitance vessels) → does not affect cardiac function appreciably
- Modestly decreased LDL, increased HDL
- Not the drug of choice (only in extreme cases → hypertension in ICU)
- Side effect: Postural hypotension (drastic hypotensive effect not well tolerated)
Methyldopa is a false transmitter used as an antihypertensive agent → taken up by noradrenergic neurones, decarboxylated and hydroxylated to form the false transmitter α-methyl-noradrenaline:
• α-methyl-noradrenaline is not deaminated by _________ → tends to accumulate in larger quantities than NA → displaces NA from synaptic vesicles
• Released in the same way as NA but:
o Less active than NA on α1 adrenoceptors → _____________
o More active on presynaptic α2 adrenoceptors → _______________ (reduces transmitter release below normal levels)
• CNS effects: _____________
Uses
- Maintenance of renal and CNS blood flow: widely used in hypertensive patients with renal insufficiency or cerebrovascular disease
- Foetal effects: _________________ → used in hypertensive pregnant women
Side effects
- Dry mouth, sedation, orthostatic hypotension, male sexual dysfunction
MAO;
less effective at causing vasoconstriction;
autoinhibitory feedback mechanism operates more strongly;
stimulates brainstem vasopressor centre to inhibit sympathetic outflow;
no adverse effects on foetus despite crossing blood-brain barrier
Cardiac arrhythmias are abnormal/irregular heartbeats, which account for 350000 deaths in the USA alone, commonly caused by __________________
• Electrical conductance is much slower through the damaged tissue due to abnormal electrical circuits (causes arrhythmias)
• Can be treated using _______________
myocardial ischaemia;
class II anti-arrhythmics (β antagonists)
How does class II anti-arrhythmics (β antagonists) affects the SA node?
Affect the pacemaker current which regulates heartbeat activity:
• Increased sympathetic drive to the heart via β1 receptors can precipitate or aggravate arrhythmias (especially after MI due to increased sympathetic tone)
How does class II anti-arrhythmics (β antagonists) affect the SA node
AV conductance depends critically on sympathetic activity: • AV nodal refractory period increased (-ve dromotropy) by β adrenoceptor antagonists → slows the ventricular rate
Propranolol is a non-selective β antagonist Class II drug with its effects mainly attributed to _______________
• Helps to reduce mortality of patients with myocardial infarction
• Particularly successful in treating arrhythmias during ________________
β1 antagonism:
exercise or mental stress
Angina is pain that occurs when the ______________________, often localised at the chest, arm, and neck (starting at the chest and radiating distally):
• Often brought on or exacerbated by exertion or excitement
• Mainly caused by ____________ (laying down of fatty deposits in coronary vessels) → narrows the blood vessels (especially in the junctions) → reduced O2 delivery
oxygen supply to the myocardium is insufficient for its needs;
atherosclerosis
What is the characteristic of stable angina?
Pain on exertion → increased demand on heart due to fixed narrowing of the coronary vessels (e.g. atheromas)
What is the characteristic of unstable angina?
Pain with less and less exertion (culminates with pain at rest):
• Platelet-fibrin thrombus associated with ruptured atheromatous plaque (without complete vascular occlusion) → risk of infarction
What is the characteristic of variant (Prinzmetal) aginaa
Occurs at rest due to coronary artery vasospasm associated with atheromatous disease:
• Presents with ECG changes (e.g. ST elevation) but no clinical sign of myocardial infarction (e.g. cTn elevation)
Why β blockers are used to treat angina
reducing myocardial oxygen demand via decreasing HR, SBP, and cardiac contractile activity:
What are the side effects of β blockers
- Fatigue, insomnia, dizziness
- Sexual dysfunction
- Bronchospasm, bradycardia, heart block, hypotension, decreased myocardial contractility
What are the contraindications of beta blockers?
- Bradycardia (HR < 55 beats/min)
- Bronchospasm
- Hypotension (SBP < 90 mmHg)
- AV block or severe congestive
Glaucoma occurs due to an increased intraocular pressure due to the poor drainage of aqueous humour (between cornea and lens):
• Aqueous humour is formed by the ________________ → if drainage channels become blocked, build-up of aqueous humour occurs → increased IOP
• If left untreated, this permanently _________________
AQUEOUS HUMOUR
The aqueous humour is produced by blood vessels in the ciliary body via ________________ (activity controlled by adrenoceptors on ciliary body surface):
• Flows into the posterior chamber → through the pupil → anterior chamber
• Drain into the trabecular network → __________________
• Production of aqueous humour is indirectly related to blood pressure and blood flow in the ciliary body
TREATMENT
• β antagonists can be used to treat glaucoma, either using non-selective (e.g. carteolol hydrochloride, levobunolol hydrochloride, timolol maleate) or β1-selective (e.g. betaxolol hydrochloride) agents:
• Reduce the___________________ by blocking the receptors on the ciliary body → blocks the effects of circulating adrenaline
ciliary body;
damages the optic nerve and causes blindness;
carbonic anhydrase;
veins and canal of Schlemm;
rate of aqueous humour formation
What are other uses of β antagonists
- anxiety states: Controlling somatic symptoms associated with sympathetic over-reactivity (e.g. palpitations, tremors)
- migraine prophylaxis: Maintaining blood flow in the brain
- benign essential tremor: Reduces sympathetic effects on muscle spindles
