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CVS > Week 5 > Flashcards

Week 5 Flashcards

1
Q

The autonomic nervous system a reminder

A

Three key divisions:
-sympathetic (thoracolumbar)
-parasympathetic (Craniosacral)
-enteric (the gut)- an important reservoir for blood

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2
Q

Effects of sympathetic stimulation

A

Cardiovascular;
-increased heart rate and contractility B1
-vasoconstriction a1 and a2
-some vasodilation B2
-regulations of renin release for volume control b1

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3
Q

Perivascular nerves

A

In adventitia of blood vessels
Neurotransmitter is release in this outer layer and it diffuses towards the smooth muscle cells to cause its effect

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4
Q

Drugs that act at receptors

A

The availability of sub-type selective drugs means that many drugs that act at adrenoceptors are clinically useful
Receptors subtypes are relatively distinct cellular locations which also allows for specific targeting

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5
Q

Adrenoceptors subtypes

A

Alpha :
A1 and a2 ————— vascular
A1: a1A, a1B, a1D
A2: a2A, a2B

Beta:
B1- cardiac tends to activate Gs pathway
B2- vascular
B3

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6
Q

Selective agonists and antagonists: with CV relevance

A

Agonist. Antagonist
A1: Phenylnephrine, midodrine. Doxazosin
A2: Clonidine.
B1: Dobutamine Metoprolol
B2: Salbutamol

Midodrine: a prodrug, the active drug being desglymidodrine

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7
Q

B-adrenoceptor activation: effects on the heart

A

Increased heart rate (positive chronotropic effect)
Increased contractility rate (positive inotropic effect)
Increased automaticity
Fast relaxation and recovery (lusitropic effect)

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8
Q

B-adrenoceptor activation: intracellular pathways

A

Binding of agonist to B1 receptor will activate Gs signalling pathway (mediated by AC through cAMP and PKA)
A beta agonist like isoprenaline (ISO) or adrenaline
PKA has multiple targets:
- increased ICa,L current (Ca2+ channel) for greater Ca2+ entry
-increased Ik for faster repolarisation
-increased Na+/K+ ATPase activity increased If (funny current) for positive chronotropy
-increased SR Ca2+ uptake (via phospholamban inhibition of SERCA). This allows cardiomyocytes to remove Ca2+ more quickly allowing for faster relaxation
-increased Ca2+ sensitivity of contractile apparatus within cells

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9
Q

Clinical uses of agonists

A

Adrenaline (b/a agonist):
-the most important drug
Used to treat:
-asystole, ventricular fibrillation and other severe arrhythmias
-anaphylaxis- during anaphylaxis you get major vasodilation around body so a1 agonist helpful
-when injected locally, causes vasoconstriction; commonly used in a mixture with local anaesthetics
Dobutamine:
-b1 agonist
-used to treat cardiogenic shock by providing “inotropic support”

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10
Q

A1 adrenoceptors activation in smooth muscle: intracellular pathways

A

Classical pathway: a1 adrenoceptors coupled to Gq-> activation IP3-> IP3 mediated Ca2+ release from SR-> contraction
Alternative pathway: through PKC, through rho-kinase

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11
Q

Phenylephrine a1 agonist

A

Vasoconstriction
One of the many potential ingredients of sudafed
Used to treat nasal congestion

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12
Q

Midodrine (prodrug for a1 agonist)

A

Prodrug: a compound that after administration is metabolised into a pharmacologically active drug
Causes: vasoconstriction, with venoconstriction (increased capacitance) probably being more important
Used to treat:
-postural hypotension in autonomic failure, it causes tonic a1 mediated vasoconstriction which keeps up total peripheral resistance.therefore more of blood is shunted centrally which means they are more able to cope with postural change
-postural hypotension is also treated with a Mineralocorticoid to increase circulating volume (fludrocortisone)

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13
Q

Droxidopa

A

Prodrug for noradrenaline (by analogy with dopa for dopamine)
Used for the short term treatment of postural hypotension in autonomic failure

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14
Q

alpha2-adrenoceptor agonists

A

Clonidine: centrally acting anti hypertensive, acts by decreasing sympathetic drive
Brimonidine: direct transcutaneous vasoconstriction for rosacea (cutaneous vasodilation-redness)

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15
Q

Clinical uses of antagonists

A

Doxazosin: a1
-causes vasodilation by opposing resting tone
-used to treat: hypertension, Raynauds syndrome (inappropriate or excessive cutaneous vasoconstriction)
“B blockers” eg propranolol (B1/B2), metoprolol (b1), atenolol (B1):
-negative chronotropic actions
-negative inotropic actions
-inhibits automaticity
-hence decrease the work done by the heart: decreases HR, decreases contractility, decreases automaticity
-Anti-platelet aggregation
-used to treat: angina, heart failure, cardiac arrythmias (antidysrhythmic drugs), hypertension

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16
Q

Carvedilol

A

Mixed B and a adrenoceptor antagonist
Also inhibits a particular cardiac K+ channel leading to a V-W class 3 antidysrhythmic action
Uses:heart failure

Why are they useful:
-B blockers themselves are used in heart failure to decrease cardiac workload
-many people with heart failure also have hypertension so blocking the a adrenoceptor can help drop pressure and by dropping TPR you decrease afterload which can be helpful in heart failure

17
Q

Why do B-blockers decrease BP

A

They decrease cardiac output especially during exercise, stress etc
-may lead to “resetting” of baroreceptors (in the context of hypertension)
B1 receptors in kidney lead to renin release:
-renin leads to production of angiotensins (hence vasoconstriction and fluid retention which would increase BP)
Inhibit the trophic effects of catecholamines in the heart (and hence inhibit cardiac hypertrophy associated with both hypertension and heart failure)

18
Q

Cardiovascular effects of parasympathetic stimulation

A

Heart:
-negative chronotropic action through action at the Sinoatrial node
-slow AV node conduction
-little effect on myocardial contractility but evidence for vagal modulation of ventricular rhythm

Blood vessels:
-limited vasodilation, because limited innervation, despite widespread endothelial mAChRs
-complicated by muscarinic receptor-induced release of NO from endothelial cells

19
Q

Muscarinic signalling pathways in the heart

A

The muscarinic receptors are the main receptors on the heart mediating effects of ACh
They’re mostly M2 receptors
The two main M2-mediated signalling pathways:
-direct G-protein mediated activation of KACh channel, this can cause Hyperpolarisation of cardiomyocytes
-inhibition of adenylate cyclase (ADC)- opposing PKA-mediated actions on a range of channels. This means many of the actions of muscarinic receptor activation are opposite to those mediated by B-adrenoceptor activation

20
Q

Cardiovascular uses muscarinic antagonists

A

Atropine
Cardiac effects: block cardiac M2 receptors
Other effects (block all muscarinic receptors): decreased secretions (mouth, airways, gut), bronchodilation, constipation, urinary retention, pupillary dilation, confusion/hallucinations
BNF uses: bradycardia following MI with hypotension, excessive bradycardia with beta blocker use, intra-operative bradycardia

21
Q

Other sympathetic pathways targeted by drugs

A

Synthesis, release and recycling of noradrenaline
-synthesis of NA and packaging into vesicles
-NA exocytosis and its reuptake by NAT back into cytoplasm
-NA breakdown by MAO
-NA uptake into other cell types through other transporters and its degradation in other cells

22
Q

Drugs affecting reuptake

A

Uptake 1:
-neuronal uptake of NAd
-mediated by NAT (noradrenaline transporter)
-is a secondary active transporter (requiring Na+ and Cl-)
-blocked by cocaine and the tricyclic antidepressants eg imipramine
-causes pro-arrhythmic effects of drugs such as cocaine
-this is because if we have NA exocytosed and we block NAT you lead to accumulation of NA in extracellular space
-therefore you get amplification of sympathetic drive- increase activity of cardiomyocytes including their automaticity (tendency to generate spontaneous rhythms) if this is excessive leads to arrythmia

Uptake 2;
-non neuronal

23
Q

Drugs affecting metabolism

A

Monoamine oxidase MAO:
-blocker are the MAOIs (MAO inhibitors) eg phenelzine, iproniazid
- 2 main subtypes: MAOA and MAOB. selegiline is a selective MAOB inhibitor
-strongly interact with other drugs targeting noradrenergic signalling
Side effects in periphery: by stopping breaking down of NA in periphery you can amplify noradrenergic signalling

24
Q

Methyldopa

A

First line for the treatment of hypertension in pregnancy
Mixed mechanisms of action: DOPA decarboxylase inhibition (so less peripheral NAd) and converted by dopamine B-hydroxylase to a-methylnorepinephrine, an a2-adrenoceptor agonist acts on brain which drops central sympathetic drive

25
Q

Drugs affecting release from sympathetic nerve terminals

A

Indirectly acting sympathomimetic amines:
-eg tyramine, ephedrine, amphetamine
-tyramine is found in many foods (eg cheese), which can cause an increase in blood pressure, particularly in conjunction with MAO inhibitors
-cause reversal of noradrenaline transport through NET and so cause release
By entering in nerve terminals via NAT they can cause reversal of this transporter for NA transport so NA pushed out when they enter so by displacing NA from nerve terminals in heart they indirectly cause the NA to activate those receptors in the heart so have actions that mimic SNS

26
Q

How can drugs affect the heart

A

Directly: rate/rhythm, force of contraction
Indirectly: vasculature: state, health can influence how heart functions. Blood volume and composition

27
Q

Why do we need drugs that affect rate/rhythm

A

Arrhythmias:
-disorders of rate or rhythm. Abnormal generation/conduction of cardiac action potentials
-causes of arrhythmia, pathology, drug induced, congenital
-types: origin and effect on HR e.g. ventricular tachycardia

Management not cure
-non pharmacological interventions

28
Q

How do antiarrhythmic drugs work

A

Classification: class I, II, III, IV. Bases on impact on ion flux
Class I:
-e.g lidocaine (local anaesthetic, targets voltage gated Na channels), flecainide
-voltage gated Na channel blockers
-subtypes 1A, 1B, 1C subtle difference
-increase refractory period reducing general excitability of cardiac myocytes

Class II:
-beta blockers
-e.g metoprolol
-block B1 receptors
-decrease sympathetic effect on cardiac myocytes

Class III:
-e.g amiodarone, sotalol
-prolongation of action potential
-K+ channel block- those usually involved in repolarisation- primary mechanism?
-prolong plateau phase

Class IV:
-eg verapamil
-calcium channel blockers L type
-found in muscle cells determine intracellular calcium levels
-decrease rate of depolarisation particularly AV
-slow conduction
Relative cardioselectivity: given option, drugs primarily bind to L type calcium channels on cardaic myocytes

29
Q

How do antiarrhythmic drugs work non-classified drugs

A

Adenosine:
-lots receptors on SA and AV node
-K+ channels opens
-Hyperpolarisation, further from threshold, delay before the next action potential
-increased refractory period, nodal conduction slowed
- caffeine is an adenosine receptor antagonist, reverse effect, depolarised, faster rise to the threshold more AP

Cardiac glycosides:
-eg digoxin
-acts on CNS?, increases vagal activity
-decreases AV conduction rate
-decrease ventricular rate

30
Q

General side effects of antiarrhythmic drugs

A

Can cause arrhythmias if you misdiagnose type of arrhythmia
-negative inotropic action, impact force of contraction

31
Q

Drug choice

A

Type of arrhythmia
Patient factors:
-cause of arrhythmia
-comorbidities
—drug interactions
-many metabolised by liver enzymes, commonly used, leads to up regulation of enzymes interference with metabolism
-ion balance, renal compromise

32
Q

Why might we need drugs to affect force of contraction

A

-anaphylaxis- massive reduction in BP
-heart failure:
Cardiac output is insufficient for the metabolic needs of the body
Force contraction normally determined by many factors:
-intracellular Ca2+, any factor impacting this can impact force of contraction

33
Q

How can drugs work to increase contractility

A

Inotropic drugs:
- positive inotropic increasing intracellular Ca2+
3 classes of drugs:
-sympathomimetics mimic action of sympathetic nervous system
-cardiac glycosides
-phosphodiesterase inhibitors

34
Q

Cardiac glycosides

A

Eg digoxin
Mechanism of action;
-partial inhibition of Na+/K+ ATPase
-increases intracellular sodium and reduces electrochemical gradient, activity only driven by the gradient
-so then less activity of the Na/Ca exchanger which is critical for normal cardiac myocyte function.
Less sodium moving in because less of a gradient
-less removal of calcium so intracellular calcium increases and accumulates causing a positive inotropic effect

35
Q

side effects of cardiac glycosides

A

Ionic disturbance:
-increase excitability
-arrhythmias
-neurological disturbance
-GIT, affect smooth muscle function
Gynaecomastia:
-breast growth, similar part of molecule as oestrogen fools receptors thinking its oestrogen

36
Q

Clinical use for digoxin

A

Subset of heart failure patients, individual dose tailoring
Drug interactions
-can be combined with diuretics, decrease in potassium (hypokalaemic) this increase digoxins affect and can increase adverse effects
-since potassium binds to same place on Na+/K+ ATPase as digoxin

37
Q

Phospodiesterase inhibitors

A

E.g Milrinone, enoximone
-phosphodiesterase leads to cAMP/ cGMP breakdown
-so PDE inhibition increases cAMP and cGMP
-this increases Ca2+ intracellularly, increases force if contraction, positive inotropy
PDE type 3- heart
Adverse effects: increase excitability-> arrhythmias
Clinically used for emergencies only, short half life so has to given very often

38
Q

Other drugs for cardiac failure

A

Decrease heart rate:
-beta blockers
-ivabradine- pacemaker current inhibitor in SAN, used in angina and heart failure
Diuretics decrease blood volume
Vasodilators increase systemic volume
ACE inhibitors

CVS (10 decks)

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