S6: antiarrhythmics, antiplatelets & fibrinolytics Flashcards
What is an arrhythmia?
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
Describe the mechanism of action of class 1 drugs
Block Na+ channels
Marked slowing conduction in tissue (phase 0)
Minor effects on action potential duration
Describe the mechanism of action of class 2 drugs
Beta-blockers
Diminish phase 4 depolarisation and automaticity
Describe the mechanism of action of class 3 drugs
Block K+ channels
Increase action potential duration
Describe the mechanism of action of class 4 drugs
Calcium channel blockers decrease inward Ca+ currents resulting in decrease of phase 4 spontaneous depolarisation
Effect plateau phase of action potential
Describe Wolf-Parkinson-White syndrome
Accessory pathway in the heart connecting atrium to ventricle
Present only in small populations – leads to pre-excitation
Describe Vaughan-Williams classification
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)
Describe class 1B agents
Decrease phase 0 conduction in fast beating or ischaemic tissue
Uses: acute ventricular tachycardia
Side effects: CNS effects (dizziness, drowsiness) & abdominal upset
Describe class 1C agents
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
Describe class II agents
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
Describe amiodarone (class III)
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
Describe sotalol (class III)
Increases APD & refractory period, slow phase 4, slow AV conduction
Uses: wide spectrum, supraventricular and ventricular tachycardia
Side effects: proarrhythmic, fatigue, insomnia
Describe class IV agents
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)
Describe adenosine
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
Describe ivabradine
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
Describe digoxin
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
Describe atropine
Selective muscarinic antagonist
Blocks vagal activity to speed AV conduction and increase HR
Uses: vagal bradycardia
Define thrombus and embolus
Thrombus – clot adhered to vessel wall
Embolus – intravascular clot distal to site of origin
Compare venous and arterial thrombosis
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
Describe prevention of platelet aggregation in healthy endothelium
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
Describe aspirin (cyclo-oxygenase inhibitor)
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)
What are the adverse effects, warnings, contraindications & important drug interactions of aspirin?
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
List aspirin indications
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
Describe the mechanism of action of ADP receptor antagonists
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
What are the adverse effects, warnings, contraindications & important drug interactions of ADP receptor antagonists?
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
List ADP receptor antagonist indications
Second agent in ‘dual antiplatelet therapy’
Ischaemic stroke
Where aspirin is contraindicated
Age, coronary anatomy and bleed risk dictate which agent added to aspirin
Describe phosphodiesterase inhibitors
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
What are the adverse effects and important drug interactions of phosphodiesterase inhibitors?
Adverse effects: vomiting, diarrhoea, dizziness
Important drug interactions: antiplatelets, anticoagulants, adenosine
Describe glycoprotein IIb/IIIa inhibitors
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
What are the adverse effects and important drug interactions of glycoprotein IIb/IIIa inhibitors?
Adverse effects: bleeding
Important drug interactions: caution with other antiplatelet and anticoagulant agents
Describe fibrinolytic agents
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)
What are the adverse effects and important drug interactions of fibrinolytic agents?
Adverse effects: bleeding
Important drug interactions: antiplatelets and anticoagulants
Compare thrombolysis and primary PCI following MI
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
Describe secondary prevention of ACS
Once haemodynamically stable: -ACEi -B-blocker -dual antiplatelet therapy (75mg + ADP receptor antagonist) -statin PLUS cardiac rehabilitation
