S6: antiarrhythmics, antiplatelets & fibrinolytics

Question 1

What is an arrhythmia?

Answer 1

Heart condition where there are disturbances in:
1) Pacemaker impulse
2) Contraction impulse conduction
3) Combination of the two
Results in rate and/or timing of contraction of heart muscle that may be insufficient to maintain normal cardiac output

Question 2

Describe the mechanism of action of class 1 drugs

Answer 2

Block Na+ channels
Marked slowing conduction in tissue (phase 0)
Minor effects on action potential duration

Question 3

Describe the mechanism of action of class 2 drugs

Answer 3

Beta-blockers

Diminish phase 4 depolarisation and automaticity

Question 4

Describe the mechanism of action of class 3 drugs

Answer 4

Block K+ channels

Increase action potential duration

Question 5

Describe the mechanism of action of class 4 drugs

Answer 5

Calcium channel blockers decrease inward Ca+ currents resulting in decrease of phase 4 spontaneous depolarisation
Effect plateau phase of action potential

Question 6

Describe Wolf-Parkinson-White syndrome

Answer 6

Accessory pathway in the heart connecting atrium to ventricle
Present only in small populations – leads to pre-excitation

Question 7

Describe Vaughan-Williams classification

Answer 7

1B: no change in phase 0 (eg. lidocaine)
1C: marked phase 0 (eg. flecainide)
II: beta-adrenergic blockers (eg. bisoprolol, metoprolol)
III: prolong repolarisation (eg. amiodarone, sotalol)
IV: calcium channel blockers (eg. verapamil, diltiazem)
V: variable (eg. adenosine, digoxin, atropine, ivabradine)

Question 8

Describe class 1B agents

Answer 8

Decrease phase 0 conduction in fast beating or ischaemic tissue
Uses: acute ventricular tachycardia
Side effects: CNS effects (dizziness, drowsiness) & abdominal upset

Question 9

Describe class 1C agents

Answer 9

Substantially decreased phase 0 in normal, decreased automaticity, increased refractory period & APD
Uses: supraventricular arrhythmias, PVCs, Wolff-Parkinson-White syndrome
Side effects: pro-arrhythmia and sudden death in chronic use, CNS & gastrointestinal effects

Question 10

Describe class II agents

Answer 10

Increases APD & refractory period in AV node to slow AV conduction velocity, decreases phase 4 depolarisation
Uses: sinus and catecholamine dependent tachycardia, stable heart failure
Side effects: bronchospasm, hypotension

Question 11

Describe amiodarone (class III)

Answer 11

Increases refractory period & APD, decreases phase 0 conduction, increases threshold, decreases phase 4, decreases speed of AV conduction
Uses: very wide spectrum, effective for most arrhythmias
Side effects: pulmonary fibrosis, hepatic injury, photosensitivity

Question 12

Describe sotalol (class III)

Answer 12

Increases APD & refractory period, slow phase 4, slow AV conduction
Uses: wide spectrum, supraventricular and ventricular tachycardia
Side effects: proarrhythmic, fatigue, insomnia

Question 13

Describe class IV agents

Answer 13

Slow conduction through AV, increases refractory period in AV node, increases slope of phase 4 in SA to slow HR
Uses: control ventricles during supraventricular tachycardia, convert supraventricular tachycardias
Side effects: constipation, caution when partial AV block is present (can get asystole)

Question 14

Describe adenosine

Answer 14

Natural nucleoside that binds A1 receptors and blocks adenylyl cyclase thus reducing cAMP which is turn activates K+ currents in AV and SA node causing hyperpolarisation – reduces HR
Also reduces Ca2+ currents, increasing refractory period in AV node
Uses: convert re-entrant supraventricular arrhythmias

Question 15

Describe ivabradine

Answer 15

Slows the sinus node by blocking funny channels
Uses: reduce inappropriate sinus tachycardia, reduce HR in heart failure and angina
Side effects: flashing lights, teratogenicity not known

Question 16

Describe digoxin

Answer 16

Inhibition of Na+/K+ ATPase
Leads to rise in intracellular sodium, leads to decreased NCX, increased intracellular calcium, more stored in SR, increased force of contraction
Enhances vagal activity -> slows AV conduction and slows HR
Uses: treatment to reduce ventricular rates in atrial fibrillation and flutter

Question 17

Describe atropine

Answer 17

Selective muscarinic antagonist
Blocks vagal activity to speed AV conduction and increase HR
Uses: vagal bradycardia

Question 18

Define thrombus and embolus

Answer 18

Thrombus – clot adhered to vessel wall

Embolus – intravascular clot distal to site of origin

Question 19

Compare venous and arterial thrombosis

Answer 19

Venous thrombosis associated with stasis of blood and/or damage to the veins
-high red blood cell and fibrin content, low platelet content
Arterial thrombosis usually forms at site of atherosclerosis following plaque rupture
-lower fibrin content and much higher platelet content

Question 20

Describe prevention of platelet aggregation in healthy endothelium

Answer 20

Prostacyclin (PGI2) produced and released by endothelial cells – inhibits platelet aggregation
PGI2 binds to platelet receptors -> increased [cAMP] in platelets
Increased [CAMP] - > decreased calcium – prevents platelet aggregation
Decrease in platelet aggregatory agents, stabilises inactive GPIIb/IIIa receptors

Question 21

Describe aspirin (cyclo-oxygenase inhibitor)

Answer 21

Potent platelet aggregating agent thromboxane A2 formed from arachidonic acid by COX-1
Aspirin – inhibits COX1 and reduces platelet aggregation (irreversible)
Low non-analgesic doses (75mg), loading doses of 300mg used in ACS
Higher doses inhibit endothelial prostacyclin (PGI2)

Question 22

What are the adverse effects, warnings, contraindications & important drug interactions of aspirin?

Answer 22

Adverse effects: GI irritation, GI bleeding, haemorrhage, hypersensitivity
Warnings, contraindications: Reye’s syndrome (avoid under 16s), hypersensitivity, 3rd trimester (premature closure of ductus arteriosus)
Important drug interactions: caution other antiplatelets and anticoagulants

Question 23

List aspirin indications

Answer 23

Some AF patients post stroke
Secondary prevention of stroke and TIA
Secondary prevention of ACS
Post PCI and stent to reduce ischaemic complications
NSTEMI/STEMI
Gastric protection required for long term use in at risk patients

Question 24

Describe the mechanism of action of ADP receptor antagonists

Answer 24

Inhibit binding of ADP to P2Y12 receptor -> inhibit activation of GPIIb/IIIa receptors
Clopidogrel and prasugrel are irreversible inhibitors of P2Y12 (prodrugs)
Clopidogrel – slow onset of action without a loading dose, others have more rapid onset of action
Ticagrelor acts reversibly at different site to clopidogrel and has active metabolites

Question 25

What are the adverse effects, warnings, contraindications & important drug interactions of ADP receptor antagonists?

Answer 25

Adverse effects: bleeding, GI upset, thrombocytopenia rarely
Warnings, contraindications: caution in high bleed risk patients with renal and hepatic impairment
Important drug interactions: clopidogrel requires CYPs for activations (CYP inhibitors – omeprazole, ciprofloxacin, erythromycin, some SSRIs); ticagrelor can interact with CYP inhibitors and inducers

Question 26

List ADP receptor antagonist indications

Answer 26

Second agent in ‘dual antiplatelet therapy’
Ischaemic stroke
Where aspirin is contraindicated
Age, coronary anatomy and bleed risk dictate which agent added to aspirin

Question 27

Describe phosphodiesterase inhibitors

Answer 27

Dipyridamole inhibits cellular reuptake of adenosine -> increased [adenosine] -> inhibits platelet aggregation via adenosine A2 receptors
Also acts an phosphodiesterase inhibitor -> prevents cAMP degradation -> inhibit expression of GPIIb/IIIa
Uses: secondary prevention of ischaemic stroke and TIAs, adjunct for prophylaxis of thromboembolism following valve replacement, stroke

Question 28

What are the adverse effects and important drug interactions of phosphodiesterase inhibitors?

Answer 28

Adverse effects: vomiting, diarrhoea, dizziness

Important drug interactions: antiplatelets, anticoagulants, adenosine

Question 29

Describe glycoprotein IIb/IIIa inhibitors

Answer 29

Blocks binding of fibrinogen and vWF, target is final common pathway
Abciximab – blocks GPIIb/IIIa receptors
Administered IV
Specialist use in high risk percutaneous transluminal coronary angioplasty patients with other drugs

Question 30

What are the adverse effects and important drug interactions of glycoprotein IIb/IIIa inhibitors?

Answer 30

Adverse effects: bleeding

Important drug interactions: caution with other antiplatelet and anticoagulant agents

Question 31

Describe fibrinolytic agents

Answer 31

Fibrinolytics dissolve the fibrin meshwork of thrombus
Alteplase in acute ischaemic stroke <4.5 hours from symptoms, following STEMI diagnosis acutely vs primary PCI
Streptokinase can only be used once as antibodies develop
Tranexamic acid – stops bleeding (opposite effect)

Question 32

What are the adverse effects and important drug interactions of fibrinolytic agents?

Answer 32

Adverse effects: bleeding

Important drug interactions: antiplatelets and anticoagulants

Question 33

Compare thrombolysis and primary PCI following MI

Answer 33

Offer primary PCI if indicated, as the preferred coronary reperfusion strategy for people with acute STEMI if:
-presentation is within 12 hours of onset of symptoms
-AND primary PCI can be delivered within 120 minutes of the time when fibrinolysis could have been given
Reperfusion injury is a negative consequence of PCI
NSTEMI patients may also be candidates for PCI

Question 34

Describe secondary prevention of ACS

Answer 34

Once haemodynamically stable:
-ACEi
-B-blocker
-dual antiplatelet therapy (75mg + ADP receptor antagonist)
-statin 
PLUS cardiac rehabilitation