Drugs & The CVS - The Heart Flashcards
3 different mechanisms regulating HR?
If
Ica (T or L)
Ik
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
Ica (T or L)?
Transient T-type Ca2+ channel
OR
Long-lasting L-type
• mediates fast calcium influx
Ik?
Potassium channels
What is Phase 4 during HR regulation in SA Node?
ONENOTE!!
Spontaneous depolarisation (pacemaker potential) that triggers the AP
SN and PSN effect on HR?
SN
• INCREASES cAMP
SO
• INCREASES If & Ica
PSN
• DECREASES cAMP
SO
• INCREASES Ik
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)
Where does the majority of Ca2+ come from in the cardiac muscle?
75% - from CICR (aka SR)
25% - from the outside
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)
What influences myocardial oxygen supply?
PRIMARILY
• coronary blood flow
(pathologically more important)
AND also
• arterial O2 supply
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
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
Drugs influencing contractility?
• BETA-BLOCKERS
- decreases contractility
- reduces phosphorylation & cross-bridge formation
• CALCIUM ANTAGONISTS
- decreases Ica
- stops further entry of Ca2+ into myofibrils
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
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
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
Ultimately what do organic nitrates & potassium channel openers affect?
INCREASE coronary blood flow!
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
Classically what is angina defined as?
Classic mismatch between myocardial O2 supply & demand!
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?
- 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
