4.4 SNS Antagonists & False transmitters

Question 1

a1 receptors

• tissues
• functions

Answer 1

• Various (vascular, GI tract etc.)

- Vasoconstriction, relaxation of GI tract

Question 2

α2 receptors

• tissues
• functions

Answer 2

• Presynaptic terminals, vascular smooth muscle, CNS

- Inhibition of transmitter release, vasoconstriction, CNS actions

Question 3

β1 receptors

• tissues
• functions

Answer 3

• Heart, GI tract, kidneys

- Increased cardiac rate and force, relaxation of GI tract, renin release from kidneys

Question 4

β2 receptors

• tissues
• functions

Answer 4

• Bronchi, smooth muscles, liver

- Bronchodilation, vasodilation, relaxation of visceral smooth muscle, hepatic glycogenolysis

Question 5

β3 receptors

• tissues
• functions

Answer 5

• Adipose tissue

- Lipolysis

Question 6

what is the selectivity for labetalol?

Answer 6

α1 + β1

Question 7

what is the selectivity for phenotolamine?

Answer 7

α1 + α2

Question 8

what is the selectivity for prazosin?

Answer 8

α1

Question 9

what is the selectivity for propranolol?

Answer 9

β1 + β2

Question 10

what is the selectivity for atenolol?

Answer 10

β1

Question 11

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

Answer 11

140/90 mmHg or higher;

135/85 mmHg or higher

Question 12

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

Answer 12

heart rate and cardiac output;

renin production;

reduction in peripheral resistance (due to kidneys and angiotensin)

Question 13

Why is β blockers dangerous in diabetics?

Answer 13

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

Question 14

Why can’t β blockers be used in patients with acute/ unstable heart failure?

Answer 14

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

Question 15

why is there bronchoconstriction due to β blockers?

Answer 15

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)

Question 16

why is there cold extremities due to β

blockers?

Answer 16

Loss of β-mediated vasodilation in cutaneous vessels

Question 17

why is there bad dreams due to β blockers?

Answer 17

CNS effects

Question 18

why is there fatigue due to β blockers?

Answer 18

Reduced cardiac output and muscle perfusion

Question 19

What are the effects of propranolol?

Answer 19

• 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)

Question 20

What are the effects of atenolol?

Answer 20

• Cardioselective (β1)

- Mainly antagonises NA effects on the heart (also affects any tissues with β1 receptors)

Question 21

What are the effects of labetalol?

Answer 21

• 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

Question 22

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)

Answer 22

reduced arterial pressure;

increased heart rate and cardiac output;

cutaneous and splanchnic vascular beds;

postural hypotension

Question 23

What are the effects for Phentolamine?

Answer 23

• 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

Question 24

What is prazosin used for?

Answer 24

• 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)

Question 25

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

Answer 25

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

Question 26

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 _______________

Answer 26

myocardial ischaemia; class II anti-arrhythmics (β antagonists)

Question 27

How does class II anti-arrhythmics (β antagonists) affects the SA node?

Answer 27

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)

Question 28

How does class II anti-arrhythmics (β antagonists) affect the SA node

Answer 28

AV conductance depends critically on sympathetic activity: • AV nodal refractory period increased (-ve dromotropy) by β adrenoceptor antagonists → slows the ventricular rate

Question 29

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 ________________

Answer 29

β1 antagonism: exercise or mental stress

Question 30

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

Answer 30

oxygen supply to the myocardium is insufficient for its needs; atherosclerosis

Question 31

What is the characteristic of stable angina?

Answer 31

Pain on exertion → increased demand on heart due to fixed narrowing of the coronary vessels (e.g. atheromas)

Question 32

What is the characteristic of unstable angina?

Answer 32

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

Question 33

What is the characteristic of variant (Prinzmetal) aginaa

Answer 33

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)

Question 34

Why β blockers are used to treat angina

Answer 34

reducing myocardial oxygen demand via decreasing HR, SBP, and cardiac contractile activity:

Question 35

What are the side effects of β blockers

Answer 35

* Fatigue, insomnia, dizziness * Sexual dysfunction * Bronchospasm, bradycardia, heart block, hypotension, decreased myocardial contractility

Question 36

What are the contraindications of beta blockers?

Answer 36

* Bradycardia (HR < 55 beats/min) * Bronchospasm * Hypotension (SBP < 90 mmHg) * AV block or severe congestive

Question 37

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

Answer 37

ciliary body; damages the optic nerve and causes blindness; carbonic anhydrase; veins and canal of Schlemm; rate of aqueous humour formation

Question 38

What are other uses of β antagonists

Answer 38

- 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