11: Drugs of the Heart Flashcards
Explain the channels involved in evoktion of an cardiac pacemaker cell potential
- If: Hyperpolarization-activated cyclic nucleotide–gated channels (HCN) (mediated via cAMP): If –> Funny- Chanels (spontaneous depolerisation via Kation influx)
- ICa(t): Transeient Ca2+ channels (open due to K+ influx)
- ICa(L): Long-Lasting Ca2+ channels
- IK: K+ Channels –> cause depolerisation
Which factors influence Heart contractility?
Mainly Calcium Levels, which are influenced by:
- Ca2+ influx via the L-type calcium channels due to depolerisation (25%)
- Ca2+ induced Ca2+ release from the SR vie the Ryanodine receptor (RyR) (75%)
- Calcium transport out of the cell
- Na+/Ca2+ exchanger
- –> Na+/K+ ATPase (influences Na+ levels, thereby influences Ca2+ levels)
What is the influence of the SNS on the Cardiac pacemaker potential?
- Increase cAMP--> triggering of Ifto occur which causes an
- increase in ICa
What is the impact of the PNS on the cardiac pacemeker current?
- decrease of cAMP –> decrease If
- IK (K+) increase –> higher polarization
Which facctors influence myocardial oxygen supply?
- Arterial O2 levels
- Coronary blood flow (mainly used as drug target)
Which factors influence myocardial oxygen demand?
- Preload
- Afterload
- Contractility
- Heart Rate
What are the effects of ß-blockers on the heart?
What is their MOA?
MOA:
- decrease cAMP which leads to a decrease in
- If–> less depolerisation, leading to
- decreased ICa
Causing
- Reduced HR (negative chronotropy)
- Reduced Contractility (negative inotropy)
What are the contraindications for administration of a ß-blocker?
Why?
- Heart failure
- might worsen HF
- even further decreased CO
- increased TPR (blocking of ß2 mediated vasodilation)
- might worsen HF
- Astmah
- Bronchospasm
- Heart block
- Might cause Bradycardia if there is decreased conduction at AV node
- Diabetis
- might mask symptoms of Hypoglycaemia
What are the common side effects of ß-blockers?
- Bradycardia
- Bronchospasm
- Cold extremities
- (Hypoglycaemia)
How could you overcome the negative effects of ß-blockers in Heart Failure and still use it as an effective treatment?
- Chose ß-blockers with ISA (e.g. Pindolol)
- Mixed alpha+ ß blockers –> a1 blocker gived additional vasodilation –> no problem with vasoconstriction (e..g Carvedilol)
What types of Calacium-Channel blockers are there?
Calcium anatgonists can be
-
Rate slowing (e.g. Phenylalkylamines (e.g. Verapamil), Benzothiazepines (e.g. Diltiazem)
- Caridiac and SM actions
-
Non-rate slowing (Dihydropyridines (e.g. amlodipine))
- only SM actions
What is the MOA of Calcium channel antagonists?
What is the effect?
- Decrease ICa
-
less intracellular Ca
- reduced contractility
- reduced HR (slower depolerisation hence activation of IK)
-
less intracellular Ca
Which Drugs are classified as Rate slowing Ca2+ channel antagonists?
- Phenylalkamines (e.g. Verapamil)
- Bezothiazepines (e.g. Diltiazem)
Which Drugs are classified as non-rate slowing Calcium channel blockers?
Dihydropyridines (e.g. amlodipine)
What are the side effects of the use of Verapamil?
Vermapril= Rate slowing CCB can lead to
- Bradicardia and AV block (due to Ca2+ block)
- Constipation (block of Ca2+ channles in gut)
What are the side effects of the use of Dihydropyridines?
Dihydropyridine= Non-rate slowing Calcium-Channel-Blocker (CCB)
- Strong Vasodilatory effects that might lead to
- ankle oedema (due to increased pressure in capillaries with increased blood)
- headaches, flushing (vasodilation in head)
- Palpitations (due to reflex tachicardia)
What is the MOA of the use of organic nitrates in the treatment of Angina?
What are the effects?
- NO increases the activity of Guanylyl cyclase
- Leads to an increase of cGMP
- Causes SM relaxation
- directly
- via K+ channel opeining causeingh hyperpolerisation
Leading to
- an increase in Coronary blood flow
- reduction in Pre+Afterload –> reduction in myocardial oxygen demand
What is the MOA of the use of K+channel openers in the treatment of Angina?
What are the effects?
Hyperpolerisation of the cell –> decreased Ca2+ influx
–> relaxation
How would you treat Angina?
- Either ß-blocker or CCB
- Switch if drug of 1 is not well tolerated
- Combine ß-blocker + CCB
- If both are not tolerated consider
- nitrates
- Ivabriandin (If inihibitor)
What are the aims of treatement of Arrythmias?
- To reduce sudden death
- To decrease the risk of stroke
- To alleviate symptoms
What is the Vaughan-Williams Classification?
It is a way of classifiing Anti-arrythmic drugs
Recall the Vaughan-Williams-Classification of anti-arrythmic drugs
There are 4 types of drugs:
- Sodium Channel blocker
- ß-blocker
- Prolongation of repolerisation (membrane stabelising drugs), mainly due to K+ blocker
- CCB
What are the limitations of the Vaughan-Williams Classification of anti-arrythmic drugs
It was developed when
- little number of drugs were known
- Mechanisms were not known too well
–> Now:
- Mechanisms of drugs are better understood–> many drugs have several effects and can fit into more than 1 class –> no clear classification possible
What is the ending most ACE inhibitors end on?
-pril
Which drugs whould you use for treatment of Supraventricular Arrythmias?
- Adenosine
- Verapamil
Explain the MOA, effect and use of Adenosine
It is used in the Treatment of Supraventricular tachy-arrythmias
- Binds to Adenosine Receptors on
- SA node–> reduced cAMP –> reduction in If and therefore rate-slowing
- Smooth muscle –> SM relaxation –> decrease in TPR
Due to its short t1/2 (30s) –> mainly used in IV hospital settings (safe due to short t1/2)
Explain the connection between HR controll and controll of arrythmias
In many arrythmias (expecially supraventricular) there is an irregular contraction of muscle
When HR is slowed–> there is the hope for more regular/ more controlled contraction of muscle leading (hopefully) to a longer filling phase and better ejection
What is the MOA and effect of Verapamil?
Verapamil= Supraventricular anti-arrythmic
CCB
MOA:
- Depresses SA automaticity and subsequent AV node conduction
Effect:
- Reduction of ventricular responsiveness to atrial arrythmias
What is the MOA of Digoxin
VIa 2 Mechanisms:
- Binds to Na+/K+ pumps (inhibitory)
- Higher intracellular Na+
- Slows down Na+/Ca2+ exchanger –> less Ca2+ transport out of the cell
- Increase in Intracellular Ca2+
- Increase in contractility
- Vagal activation–> causes increased refractory period and reduced rate of conduction through the AV node
Why is hypokalaemia a contraindication of digoxin?
Digoxin compedes with K+ on the K+/Na+ATPase –> in hypokalaemia –> risk of toxic dose becasue it is more effective
Risk of Heart Block
Name a cardiac glycoside
e.g. Digoxin
What are the indication for use of Digoxin?
Why?
Normally used in AF/arteriral Flutter with begining signs of Heart Failure because of
- positive inotropic effect
- with rate slowing effect (AV-conductance reduced) –> less beats are conducted onto the atria
What are the side-effects of Digoxine?
•dysrhythmias (e.g. AV conduction block, ectopic pacemaker activity)
–> Beware Hypercalcaemia (risk of digitalis toxicity); hypokalaemia (risk of digitalis toxicity)! (drug is more effective)
What is Reentry arrythmia?
A form of arrythmia that is caused by occurance of an additional way of conductance (e.g. due to damage to fibres that block out the option for neutralising a potential) (Reentry shown in blue) that triggers a second contraction/potential of a single pacemaker potential
What are the indication for use of Amiodarone?
•superventricular and ventricular tachyarrhythmias – often due to reentry
What is Amiodarone?
A drug used in the treatment of arrythmias (• Complex action probably involving multiple ion channel block)
What is the effect and MOA of Amiodarone?
• Complex action probably involving multiple ion channel block
leading to a prolonged repolerisation–> new potential is generated later
What are the side-effects of Amiodarone?
- Long t1/2–> accumulation in the body (t½ 10 - 100days) whith chronic intake (not really safe to take)
- photosensitive skin rashes
- hypo- or hyper-thyroidism
- pulmonary fibrosis
