ANTIARRYTHMICS AND ANTICOAGULANTS

ANTIARRYTHMICS AND ANTITHROMBOTICS

by Heather Weerdenburg

Class I Antiarrythmics

Mode of action

Block fast Na+ channels (affect phase 0 slope)

• Reduce the rate the cells depolarise and transmission through the conductive system
• Good for abnormal conduction arrythmias
• Note: only non-nodal cardiomyocytes (not SA or AV)

Some have effect on K+ channels

• affecting repolarisation and refractory period
• Alter length of AP

Can suppress abnormal automaticity in pacemaker cells

Electrical Activity

ECG

Sub Example Effect on Effect on Effect on Inhibitory

category phase 0 repolarisation AP duration length

Ia disopyramide Moderate Prolonged Increased Intermediate

procainamide

quinidine

Ib lidocaine Weak Shortened Decreased Fast

Ic flecainide Strong No effect No effect Slow

Class Ib: lidocaine and mexiletine

Class IC - Flecainide

Effect:

• Binds to open/inactive sodium channels (after AP)
• Weak effect phase 0
• Stays bound during inactive state extending refractory period decreasing AP frequency

Lidocaine

Use: ventricular arrythmias, pulseless ventricular tachycardia and ventricular fibrillation

• Has to be given IV ( approx 3% absorbed if given orally)
• May need to reduce dose in CHF or post surgery
• Side effects: parasthesia (anesthetic effect),drowsiness, hypotension and bradycardia

Mexiletine

Use: Management of serious ventricular arrhythmias; suppression of premature ventricular contractions

• Oral form, dose 1.4-5mg/kg TDS
• Monitoring required therapeutic range: 0.5-2 mcg/mL Potentially toxic: >2 mcg/mL
• Unlicensed
• Side effects: GI, liver abnormality, proarrythmic

• Strong phase 0 effect
• Slows action potential/excitability
• Will stay attached to channels for longer
• Increase in action by increase in heart rate
• Works on atria-His conduction
• Suppress premature ventricular contractions

Problems: Lengthens QT interval + toxicity risk

Use: re-entry supraventricular and ventricular tachycardias + arrythmias associated with accessory conduction pathways

• Side effects: proarrhythmic!, visual disturbances, liver problems, parasthesia, tinnitus, photosensitivity reactions
• Approx 2 days to reach steady state: Aim for level: 200-800micrograms/L
• Counseling: dairy interaction! liquids and anesthetic effect - 30 mins
• Getting liquid in community = challenge

OBJECTIVES

1. Impulse generated in SA node

2. Atria depolarises

3. Impulse delayed at AV node

4. Impulse travels down bundle

of His and Pukinji fibers

ventricular depolarisation

5. Ventricular repolarisation

Antiarrythmics

1. Review the electrical activity of the heart

2. Readdress cardiac myocyte action potentials and the role of electrolytes

3. Consider antiarrhythmic drugs

• mode of action
• side effects
• drug interactions

Antithrombotics

1. Briefly review normal haemostasis

2. Look at actions of antithrombotic agents

• anticoagulants (parenteral and oral)
• antiplatelets

Task 1: Action Potential of a cardiac myocyte

Match movement of electrolytes involved with each phase

Class II: Beta - blockers

Reduction in CO = decrease in pressure in heart = sympathetic NS activation

What happens when beta-1 receptors are stimulated:

• Calcium channels are open for longer (Phase 2)
• Shortens repolarisation (phase 4) and refractory period (Increase in the AP frequency)
• Lower K+ in cells affecting repolarisation
• Increase SA node automaticity, speed of conduction through AV node
• OVERALL: Increased opportunity for ectopic beats, tacchycardia

Use: supraventricular and ventricular arrythmias (note many other non-antiarrhythmic uses!), can block re-entry arrythmias,

Side effects: bronchospasm (care ASTHMATICS), fatigue, coldness of extremities, hypo/hyperglycaemia (diabetics)

Specifics

• Esmolol: cardioselective used short term e.g. peri-operative period
• Sotalol: non selective but has class III properties (can cause QT prolongation)
• Atenolol: cardioselective water soluble - less CNS effect

A: Ca 2+ voltage gated channels open and calcium moves into the cell

B: Na+ voltage gated channels open and sodium moves into the cell

C: Ca2+ voltage gated channels close and calcium is pumped out of the cell

D: K+ channels open and potassium moves pumps out of the cell

E: Na+ voltage gated channels close and become inactive and sodium is pumped out of the cell

F: K+ channels close

Class IV

Calcium channel Blockers

Blood cogagulation

Normal Haemostasis: Clotting cascade!

• Verapamil and diltiazem (dihydropyridines)
• Indirect inhibition
• Act on SA node and AV node
• Prob affects overall body - global vasodilation

Others: Adenosine

• Occurs naturally in the body
• Reduces membrane potential making it harder to cause AP
• Prevents spontaneous firing
• Binds to calcium channels to inhibit calcium entry
• Effect on sinus and AV node conduction
• Inhibits NA release (sympathetic NS- b1 receptors)

Use: rapid treatment of supraventricular tachycardia's

• IV administration, very short half life (10-30 secs)

Side effects: bronchoconstriction (lasts longer), chest burning, vasodilation side effects (flushing)

Drug Therapies

Clotting Cascade - in a nut shell!

• More than a dozen circulating proteins involved
• Cascading series of proteolytic reactions to activate the next clotting factor to produce fibrin.
• One to remember: Thrombin - drug target!

Thrombin involved in:

• Converts fibrinogen to fibrin
• + other blood coagulation cascade reactions further up

Fibrin:

• Involved in clot formation
• acting as a meshwork
• Connects platelets together
• Natural control of this system - fibrin inhibition by enzymes such as antithrombin (protease inhibitor)

Aim: To restore sinus rhythm or to control heart rate (i.e does not to resolve problem)

The actions of antiarrythmics:

Alter the movements of electrolytes within the conduction pathways of the myocardium

Classification:

• Based on electro-activity (Vaughan Williams classificaton)
• Clinical use (see BNFC)

ARRYTHMIAS

VAUGHAN WILLIAMS CLASSIFICATION

Heart Conducting System

Any change in normal heart rhythm

1. Disorder of electrical impulse generation

2. Disorders of impulse conduction

Factors that can precipitate:

Ischemia, hypoxia, acidosis, alkalosis, electrolyte abnormalities (e.g. potassium), diseased/damaged tissue, drug therapy (digoxin, antiarrythmic drugs, caffeine, amitriptylline, catechloamines)

Need for treatment

• To relieve symptoms or prolong survival
• Urgency depends on the haemodynamic consequences e.g a decrease in cardiac output cant increase CHF (increase irritability, poor feeding, pallor etc ) and can enhance deterioration

SA node

• Contains pacemaker cells.
• Produces action potentials under normal conditions

AV node

• "Gate keeper" from atria to ventricles

Bundle of His

• L and R branches
• Carry electrical current from AV node down to apex

Purkinje Fibres

• Conduct action potentials through the ventricles

Class I: sodium channels blockers (Ia, Ib, Ic)

Class II: Beta blockers

Class III: Drugs that prolong the action potential

Class IV: Calcium channel blockers

Note: Not so clear cut segregation as actions can be ovelapping

Low Molecular Weight Heparin

Unfractionated Heparin

Action

• Potentiates the action of anti-thrombin III (normally slow to act)
• Result is inactivation of thrombin + other activation factors (IX,X,X1,X11 and plasmin)

Monitoring

Measurement: APTT (instrinsic) + UFH anti Xa (preferred at BCH)

Side effects

Bleeding, hyperkalaemia

Heparin induced thrombocytopenia (HIT)

• seen after 5-10 days of continuous treatment
• 30% reduction in platelets
• skin allergy
• thrombosis
• Alternative: danaparoid sodium

Additional points

• Made from animal origin - consider in certain religions/diet (?fondaparinux)
• Short acting - good for high risk patients at risk of bleeding
• Reversal by protamine sulphate

E.g. dalteparin (pregnancy), enoxaparin, tinzaparin,

Action:

• Indirectly inactivate thrombin - binds to antithrombin

Advantages:

• longer acting - OD/BD dosing

Disadvantages:

• Poor renal function: UFH preferred
• Partially reversed by protamine
• Small doses
• Multidose vials contain benzyl alcohol CI in neonates

Monitoring:

• LMWH Anti-Xa level

Side effects: As with UFH

• Still can cause HIT

Platelet aggregation inhibitors

Warfarin

Aspirin

Mode of action

• Certain clotting factors rely on vitamin k to work e.g. prothrombin
• Warfarin indirectly prevents these
• Indirectly inhibits vitamin K reductase in hepatocytes

Discovered in a bark of willow tree

Anti-platelet action:

• inhibits COX enzymes = reduction in thromboxane A2 production
• Thromboxane causes platelet aggregation

Use:

Shunt placement, Fontan, Kawasaki syndrome or patients unable to tolerate warfarin

Side effects: Increased gastric bleeding due to direct action on mucosa and aslo reduction in prostaglandins (mucosal protection effect)

Clopidogrel

Thienophyridine

Action: Inhibits platelet aggregation - (not via protein clotting factors in the blood)

• Binds to P2Y12 receptor on platelets surface which prevents them ultimately binding to fibrin.

Side effects: GI upset, haemorrhage (increased in combination with aspirin)

Use: stents??

• Oral anticoagulant (coumarin)

Discovered after a herd of cows dies of major haemorrhage due to eating hay that contained mouldy sweet clover.

Use:

• Treatment of a clot or prophylaxis
• Can be monitored/reversed so preferred!

Measurement: INR (clotting tendency of blood - extrinsic pathway)

• Reversal: phytomenadione (Vit K)
• Care: Infant formula, drug interactions

Warfarin Drug Interactions

Using the BNFC record the effect of each drug on warfarin

• Paracetamol liquid (regular)
• Miconazole oral gel
• Tramadol tablets
• Co-amoxiclav liquid
• Cranberry juice
• Lactulose
• Omeprazole (MUPS)
• Diet change - more greens/leafy veg!

Action potentials in cardiac myocytes

Class III

amiodarone & sotalol

Action potential

• Affect conductance of K+ increasing duration of AP and time it takes to repolarise (refractory period)
• Note no drug is solely K+ channel blocker
• Problem: pro-arrythmic properties, can lengthen QT interval

Amiodarone - complex!

• Also has other 3 class properties!!!

Use: supraventricular & ventricular tachycardias

• IV: rapid onset Oral: slow needs higher dosing
• Half life: Very long (several weeks!)
• Side effects: (many) photosensitive reactions, microcorneial deposits, thyroid dysfunction, pulmonary fibrosis, liver dysfunction, proarrythmic

Problems:

• liquid in community very difficult to obtain!
• Drug interactions - including for months after stopping!

Phase 4: "Resting potential"

• Cell is more negative inside
• Ca2+ and Na+ voltage gated channels are closed
• K+ channels are closed but 'leaky' so K+ can still move move out

Phase 0: 'Rapid depolarisation'

• AP generated from SA node causes excitation
• Cell becomes more positive
• Na+ channels open quickly and sodium moves into cell

Phase 1

• Ca2+ channels open and external influx of calcium into cell
• Na+ channels close and become inactive as too positive
• Some K+ channels open (fast), K+ moves out

Phase 2

• More Ca2+ channels and K+ channels open (slow) = plateau

Phase 3

• More K+ channels open (slow)
• K+ efflux > Ca2+ influx
• Ca2+ channels close and cell becomes more negative

Pacemaker Cells in SA node

• Any cardiac myocyte have a potential to create an AP!
• PM have fewer sodium channels just Ca2+ and K+ input
• Able to depolarise much faster because more positive in cell (-65mV)

Different for Pacemaker cells!

References

Opie L et al. 1995. Drugs for the Heart 4th edition. Saunders. London pp207

National Heart Lung and Blood Institute:

http://www.nhlbi.nih.gov/health/health-topics/topics/hhw/electrical

Benitz W, Tatro D. 1995. The paediatric drug handbook 3rd edition. Mosby. Missouri

Park M. 1997. The Paediatric Cardiology Handbook 2nd edition. Mosby

Katzung B. 1992. Basic & Clinical Pharmacology 2nd edition. Appleton & Lange

Paediatric Formulary Committee. BNF for Children 2014/15. London: BMJ Group, Pharmaceutical Press, and RCPCH Publications; 2014

Klabunde R. 2007. Cardiovascular Pharmacology Concepts. http://www.cvpharmacology.com/antiarrhy/antiarrhythmic

UpToDate. Mexiletine: Pediatric drug information. http://www.uptodate.com/contents/search?search=mexilitine&sp=0&searchType=PLAIN_TEXT&source=USER_INPUT&searchControl=TOP_PULLDOWN&searchOffset= UpToDate (Access it via Athens account)