Drugs & The CVS - The Heart Flashcards by Rama Jha

3 different mechanisms regulating HR?

Ica (T or L)

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If?

Hyperpolarisation-activated cyclic nucleotide-gated (HCN) channels
•’funny’ channels
• predominantly a Na+ channel (initates depolarisation)
• switches on during hyperpolarisation
• utilises cAMP

BUT not enough on its own to initiate FULL depolarisation

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Ica (T or L)?

Transient T-type Ca2+ channel
OR
Long-lasting L-type

• mediates fast calcium influx

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Ik?

Potassium channels

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What is Phase 4 during HR regulation in SA Node?

ONENOTE!!

Spontaneous depolarisation (pacemaker potential) that triggers the AP

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SN and PSN effect on HR?

SN
• INCREASES cAMP
SO
• INCREASES If & Ica

PSN
• DECREASES cAMP
SO
• INCREASES Ik

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How is contractility regulated?

B1-receptor stimulation activates AC which creates cAMP which activates PKA - 2 main actions:
• phosphorylates proteins in the myofibril
• induces CICR in the SR (via stimulating Ca2+ influx into SR via. RyR)

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Where does the majority of Ca2+ come from in the cardiac muscle?

75% - from CICR (aka SR)

25% - from the outside

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How is Ca2+ then removed for contractility regulation?

Either
• pumped back into the SR (via. ATPase Ca2+ channel)
• removed via. Na/Ca exchanger (w. the help of Na/K ATPase)

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What influences myocardial oxygen supply?

PRIMARILY
• coronary blood flow
(pathologically more important)

AND also
• arterial O2 supply

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What regulates myocardial oxygen demand?

Myocyte contraction - primary determinant

increased HR = increased contractions
increased afterload = increased force of contraction
increased preload = small increase in force of contractions

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Drugs influencing HR?

• BETA-BLOCKERS (predominantly B1)
- decrease If & Ica

• CA2+ ANTAGONISTS
- decrease Ica

• IVABRADINE

decrease If
less pronounced as Ca2+ is the main driver

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Drugs influencing contractility?

• BETA-BLOCKERS

decreases contractility
reduces phosphorylation & cross-bridge formation

• CALCIUM ANTAGONISTS

decreases Ica
stops further entry of Ca2+ into myofibrils

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What are the two classes of calcium antagonists?

RATE SLOWING
• CARDIAC & VSM action
• Phenylakylamines - e.g. Verapamil
• Benzothiazepines e.g Diltiazem

NON-RATE SLOWING
• VSM action - more potent!
• Dihtdropyridines e.g. amlodipine

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What can occur with non-rate slowing calcium antagonists?

Have NO effect on the heart (just VSM)
BUT
the profound vasoDILATION produced can lead to REFLEX TACHYCARDIA

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Drugs influencing myocardial O2 supply/demand?

• ORGANIC NITRATES

DIRECTLY supply NO
increases cGMP = stimulates K+ channel opening = relaxation
can stimulate K+ channel directly as well!

• POTASSIUM CHANNEL OPENERS

stimulates hyperpolarisation (ability of coronary arteries to contract is impaired)
-VE feedback on Ca2+ channels

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Ultimately what do organic nitrates & potassium channel openers affect?

INCREASE coronary blood flow!

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What 2 different effects of nitrates/potassium openers influence preload & afterload?

DECREASE preload/afterload (demand)
AND
INCREASE O2 supply (increase blood supply)

VASOdilation = decreased afterload
VENOdilation = decreased preload

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Classically what is angina defined as?

Classic mismatch between myocardial O2 supply & demand!

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How can the drugs be used than for angina treatment?

Beta-blocker OR CCA
• background treatment
• e.g. Ivabradine - more specific
Nitrate
• symptomatic treatment (i.e. exercise)
Other
• e.g. K-channel openers if intolerant to other drugs

What aspects of the myocardial O2 supply and demand do the drugs affect?

Ivabradine
• HR

Beta-blocker
• HR
• Contractility

CCB
• HR
• Contractility

Nitrate & K-channel opener
• Coronary blood flow
• Preload
• Afterload

What are possible criteria should be aware of if on beta-blockers?

Worsening HF
• CO reduction & increased vascular resistance can affect it for the worst!

Bradycardia
• if heart block, decreased conduction through AV node so can worsen it

MAINLY due to B2 as are vasoDILATORS so are blocking that!

What can be used to lessen the 2 big beta-blocker side-effect?

Pindolol (non-selective)
• has ISA

Carvedilol (mixed B&A-blockers)
• A1 blockade gives additional vasoDILATOR properties!!

Other possible SEs of beta-blockers in relation to certain conditions?

ALWAYS want to know if patient is either
 • asthmatic 
OR
 • diabetic
BEFORE giving beta-blockers

as can lead to
• bronchoconstriction
• hypoglycaemia (masks the early warning sign of this)
• cold extremities

Why does beta-blocker use lead to cold extremities?

Cold extremities/worsening of peripheral artery disease LOSS of B2-receptor mediated cutaneous vasodilation in extremities

Other general SEs of beta-blocker use?

``` Fatigue Impotence (sexual dysfunction) Depression CNS effects (lipophilic agents) • e.g. nightmares ``` ALTHOUGH RCTs question the validity of these

SEs of CCBs in relation to B-blockers?

Said to be 'safer' than b-blockers

SEs of Verapamil?

CCB - rate-limiting Bradycardia & AV-block • heart Ca2+ channels blockers Constipation • gut Ca2+ channels blocked

SEs of Dihydropyridines?

CCB - non-rate limiting Ankle oedema • vasodilation means more capillary pressure in extremities Headache/flushing • due to vasodilation Palpitations • reflex SNS adrenergic activation due to vasodilation

SEs of K+-opening channels/nitrates?

Ankle oedema • vasodilation means more capillary pressure in extremities Headache/flushing • due to vasodilation

What are the aims of rhythm disturbance treatment?

Reduce sudden death Alleviate symptoms PREVENT STROKE!!

Simple classification of arrhythmias?

Based on site of origin • Supraventricular (above ventricles) - e.g. Amiodarone, Verapamil • Ventricular - e.g. Flecainide, Lidocaine • Complex (supra + ventricular) - e.g. Disopyramide

What is the Vaughan Williams Classification and what is interesting about it?

Classification of anti-arrhythmic drugs separated into 4 areas: • Class 1 = Na+-channel blockade • Class 2 = Beta-blockers • Class 3 = K+-channel blockade (prolong repolarisation) • Class 4 = Ca2+-channel blockade Classification is of LIMITED clinical significance due to the significance of cross-overs in rhythm disturbance

Potential selective anti-arrhythmic drugs?

* Adenosine * Verapamil * Amiodarone * Digoxin

MOA of Adenosine?

Activates A1 receptors in the SA & AV node •Gi protein activation = reduces AC conversion of ATP to cAMP • = decreased cAMP = decreased ionotropic & chronotropic effect Also causes relaxation in VSMCs by increasing cAMP instead (Gs-protein)

Use of Adenosine?

Targets SVT!! • IV-given • short-action (thus safer than Verapamil) • Class IV drug

Use of Verapamil?

Reduces ventricular responsiveness to atrial arrythmias

MOA of Verapamil?

Blocks VGCC • depresses SA firing and subsequent AV node conduction Class IV drug

Uses of Amiodarone?

SVT & VT • due to RE-ENTRY (onenote for explanation!!)

MOA of Amiodarone?

Complex but probably invovles multiple ion-channel block • most likely prolongs hyperpolarisation which reduces chance of re-entry Class I, II, III & IV • SO limited clinical importance

Adverse effects of Amiodarone?

Accumulation in body (t1/2 10-100days) Skin rashes (photosensitive) Hypo OR hyper-thryoidism Pulmonary fibrosis

What 2 broad affects does Digoxin have on?

1. INHIBITS NA+/K+ ATPase | 2. Central vagal stimulation

What effect does Digoxin have on inotropy in regards to (1)?

``` Inhibits Na+/K+ ATPase • increases IC Ca2+ • reversal of Na+/Ca2+ exchanger • Na efflux & Ca influx • POSITIVE INOTROPIC EFFECT ``` Ca2+ struggles to leave the cardiac muscle so remains for longer = contraction becomes STRONGER

What effect does Digoxin have on inotropy in regards to (2)?

Central vagal stimulation • increases refractory period AND • reduced rate of conduction through the AV node SO slows the HR down!

What is the double whammy of Digoxin?

Improving rhythm control of the heart WHILST ALSO improving CO (by increasing contractility)

Uses of Digoxin?

In atrial fibrillation & flutter leads to a rapid ventricular rate that can • impair ventricular filling (due to reduced filling time) & • reduce CO Digoxin via. vagal stimulation reduces the conduction of electrical impulses within the AV node • fewer impulses reach the ventricles and ventricular rate falls

SEs of digoxin?

Dysrhythmias | e.g. AV conduction block, ectopic pacemaker activity

Why does hypokalaemia (usually due to diruetic use) lower threshold for digoxin toxicity?

Digoxin is a K+-receptor competitive antagonist SO low blook K+ means less competition and so the effect of digoxin are enhanced (onenote for more info!)

Digoxin?

Cardiac glycoside