ACEM Primary
Cardiovascular Medication Pharmacology
Drugs used in cardiac arrest
| Adrenaline | Give immediately if asystole/PEA rhythm or after second shock if VF/pulseless VT MOA: Non selective adrenergic agonist-> alpha R = peripheral vasoconstriction, increases myocardial blood flow during CPR beta 1 R = positive inotrope/ chronotrope beta 2 R = bronchodilation + mast cell stabiliser AE: tachyarrhythmias, severe hypertension post resuscitation, tissue necrosis with extravasation Give IV/IO Dose: VT/VF/PEA: 1mg (1mL of 1:1000, 10mL of 1: 10,000) repeated every 3-5 minutes + 20mL saline flush After return of pulse, small aliquots/ infusion 0.01-0.5mcg/kg/min via CVL |
| Amiodarone | Give following 3rd shock in refractory VF/ pulseless VT MOA: membrane stabilising anti-arrhythmic (Na+/K+/Ca2+/alpha and beta adrenergic blocking properties) AE: Proarrhythmic, hypotension, bradycardia/ heart block Dose: initial bolus 300mg IV, repeat dose 150mg in 3-5 mins if VT/VF persists. If pulsatile VT/ recurrent VT, give loading dose over 20-60 mins as this prevents hypotension and heart block |
| Calcium | Essential for normal muscle and nerve activity Transiently increases myocardial excitability/ contractility Indicated for cardiac arrest associated with hyperkalaemia, hypocalcaemia, OD Ca2+ blocker MOA: Stabilises cardiac membrane Dose: 10mL of 10% calcium chloride or 30mL of 10% calcium gluconate IV |
| Lignocaine | MOA: Sodium channel blocker Can be used as alternative to amiodarone or prophylaxis in setting of recurrent VF/VT AE: Proarrhythmic, seizures, ALOC, hypotension, bradycardia Dose: 100mg IV bolus |
| Magnesium | Essential for membrane stability Hypomagnesaemia causes myocardial hyperexcitability Indicated for arrest associated with hypomagnesaemia, torsades or digoxin toxicity or refractory VF/pVT Dose: 10mmol IV |
| Potassium | Essential for membrane stability Consider for persistent VF due to suspected hypokalaemia Dose: 10 mmol IV |
| Sodium bicarbonate | Alkalinising solution, causes intracellular shift of K+ and buffers acidosis In most cardiac arrests, early CPR and adequate ventilation negate need for use Indicated for hyperkalaemia, metabolic acidosis, TCA overdose or protracted arrest >15 mins AE: Metabolic alkalosis, hypokalaemia/ natraemia, may worsen intracellular acidosis Dose: 1mmol/kg Regular VBG |
| Fluids | Insufficient evidence to recommend for/ against IVF in cardiac arrest Should be given if hypovolaemia is suspected ~20mL/kg |
Inotropes
| Adrenaline | MOA: b1 primarily – more chronotropic/ inotropic effects b2 – bronchodilator and mast cell stabiliser a1 – vasoconstrictor I: Cardiac arrest Vasopressor and inotrope for cardiogenic/ septic/ distributive shock Symptomatic bradycardia Severe bronchospasm Anaphylaxis Dose: Bolus 1mg (1mL of 1:1000 or 10mL of 1: 10,000) or aliquots of 0.25-0.5mcg Infusion 0.01-0.5mcg/kg/min Systemic effects – CVS dose dependent: Low dose b effects predominate-> increase CO, myocardial oxygen consumption, coronary artery dilation and reduced threshold for arrhythmias, reduced TPR. High dose-> a effects predominate causing rise in TPR. RESP: increase minute volume, increase pulmonary vascular resistance METABOLIC: increase BMR, stimulate glycogenolysis + gluconeogenesis, b initially increases insulin secretion however overridden by a. CNS: increase MAC and peripheral pain threshole RENAL: decrease blood flow and increase bladder sphincter tone Orally inactivated. SC slower than IV/ IM. |
| Noradrenaline | MOA: a1 primarily – vasoconstrictor b1 b2 I: Distributive shock With Dobutamine Dose: 0.5mcg/kg/min |
| Dopamine | MOA: b1 (dose 2mcg/kg/min) a (5mcg/kg/min) DA (D1/D2) 25% converted to noradrenalin at sympathetic nerve terminals. Systemic effects – CVS dose dependent: Lower dose b1 predominate-> increased contractility/ HR/ CO and coronary blood flow + stimulates release of endogenous noradrenaline. High dose a predominate-> increased SVR and VR RESP: increase pulmonary vascular resistance, attenuate response of carotid body to hypoxaemia SPLANCHNIC: vasodilate splanchnic vessels via D1 R CNS: modulates extrapyramidal movement and inhibits prolactin secretion, cannot cross BBB (precursor can) Caution in patients on MAO-I. |
| Dobutamine | MOA: b1 predominantly + vasodilator Give with vasoconstrictor (noradrenaline) I: Cardiogenic shock, acute HF, cardiac stress testing Dose: 3-5 mcg/kg/min |
| Isoprenaline | MOA: b1 and b2 Nil alpha effects – risk of vasodilation and hypotension I: Symptomatic bradycardias and heart block |
| Ephedrine | Non selective catecholamine Similar to adrenalin but less potent and more long lasting Used for transient drug induced hypotension (anaesthesia) |
| Metaraminol | Catecholamine selective for a R Similar to noradrenaline 0.5-1mg IV doses Used for transient drug induced hypotension (anaesthesia) |
| Phenylephrine | Catecholamine selective for a R Nil effect on b R |
| Vasopressin | Potent peripheral and splanchnic vasoconstrictor used for refractive vasodilatory shock. Dose 0.1 – 0.4U/min |
Overview of R + actions:
| R | S | Location | Action | Mechanism |
| a | 1 | Vascular smooth muscle | Vasoconstriction | Gq activated-> increased IP3-> increase Ca2+ |
| 2 | Nervous system | Sedation, analgesia, attenuation of sympathetically mediated responses | Gi inhibited-> increase cAMP | |
| b | 1 | Heart PLT | Positive inotrope/ chronotrope Platelet aggregation | Gs activated-> increase cAMP |
| 2 | Bronchi Vascular smooth muscle Uterus (and heart) | Relaxation of smooth muscle | Gs activated-> increase cAMP-> Na/K ATPase activity and hyperpolarisation | |
| 3 | Adipose tissue | Lipolysis | Gs activated-> increase cAMP | |
| D | 1 | CNS peripheral | Modulates extrapyramidal activity Vasodilation of renal and mesenteric vasculature | Gs activated-> increase cAMP |
| 2 | CNS peripheral | Reduced pituitary hormone output Inhibit further noradrenaline release | Gi inhibited-> increase cAMP |
Anti-anginals
- Angina = chest pain caused by accumulation of metabolites in setting of myocardial ischaemia
- Due to imbalance of oxygen delivery and myocardial demand
- Drugs work to:
- Increase oxygen delivery via coronary blood flow (duration of diastole/ aortic diastolic pressure)
- Reduce demand via ventricular wall stress (preload = diastolic wall stress and afterload = systolic wall stress + HR and contractility) ~ reduce heart size, HR and force
- Mechanisms:
- Myocytes = NO activates guanylyl cyclase-> increase cAMP-> dephosphorylation myosin-> reduced interaction between actin/ myosin-> reduced contractility
- Reduce intracellular calcium
- Smooth muscle = vasodilation
- Myocytes = reduce heart rate and contractility
Nitrates
- Nitroglycerin
- Metabolised in liver via nitrate reductase (oral bioavailability ~10-20%)
- Sublingual route preferred, takes effect in few minutes
- Oral sustained release available (ISMN bioavailability 100%)
- Cause NO release and vascular smooth muscle relaxation
- Increased coronary blood flow, however concentric atheroma prevents significant dilation
- Systemic vasodilation-> reduced preload and CO
- AE = orthostatic hypotension, headache, reflex tachycardia, tolerance
- I = heart failure (preload abnormally high)
- Contraindicated in raised ICP
- Workers exposed to organic nitrates get headache/ dizziness on return to work (Monday) which improves during the week as tolerance develops-> disappears over weekend when exposure ceased-> symptoms return Monday (Monday disease)
- Nitrate free period of 8 hours required to prevent tolerance
Calcium Channel Blockers
- L- type channels in cardiac, skeletal, smooth muscle, neuron, endocrine and bone cells
- Orally active, high first pass effect and extensive metabolism
- Two classes as bind different region of a1 subunit:
| Dihydropyridine (Block of vascular L-type channels in vessels > heart) | PO | Nifedipine – can be used in AV conduction abnormalities, shortest onset of action 5-20min Amlodipine – Safe in CCF Felodipine Nimodipine – evidence to treat cerebral vasospasm following SAH Associated with hypotension |
| Non- dihydropyridine (Non-selective block of calcium channels) | PO/IV | Verapamil Diltiazem Can worsen CCF in conjunction with beta blockers Any-arrhythmic properties |
- Reduce intracellular Ca2+
- Vasodilation
- Reduced contractility
- Reduced HR due to slowed velocity impulses through SA/AV nodes (non-dihydropyridine effective for SVT/ AF)
- Relieve and prevent focal coronary artery vasospasm
- AE:
- Minor = flushing, dizziness, nausea, constipation (verapamil especially) and peripheral oedema
- Serious = bradycardia, heart block, heart failure, cardiac arrest
Beta Blockers
- Two types:
- Selective (b1) = metoprolol, atenolol (less risk of bronchospasm)
- Non selective (b1/2) = propranolol
- MOA = decrease HR, BP and contractility = decrease myocardial oxygen demand
- Lower HR allows more diastolic perfusion time
- Nil vasodilation (except carvedilol and nebivolol)
- Decrease mortality of patients post MI, improve survival in stroke and HTN
- Undesirable effects in angina = increase EDV and ejection time (can increase oxygen requirement)-> can be balanced by concomitant nitrate use
- Contraindications = asthma, severe bradycardia, AV block, severe unstable LV failure
- Complications = fatigue, impaired ET, insomnia, erectile dysfunction
Antiarrhythmics
| I Na+ channel blockade | IA Procainamide MOA: Na and rapid K blockade-> slow conduction velocity, prolong APD and depress pacemakers. Dissociates from Na channel with intermediate kinetics I: Atrial and ventricular arrhythmias, 3rd line for ventricular arrhythmias post MI Route: Oral, IV or IM Hepatic metabolism and renal elimination AE: hypotension, QT prolongation and torsades Lupus like symptoms with long term use Quinidine = more toxic (tinnitus, torsades), rarely used in arrhythmias Disopyramide = anti-muscarinic effects, may cause HF |
| IB Lidocaine MOA: Na blockade-> blocks activated and inactivated channels with fast kinetics. Does not prolong APD, may shorten. I: Ventricular tachycardias, prevents VF post cardioversion Route: IV loading 150-200mg + 2-4mg/min infusion First pass hepatic metabolism. Dose reduction in patients with heart failure or liver disease. AE: hypotension, neurologic sx Mexiletine = used in ventricular arrhythmias and chronic pain syndrome | IB Lidocaine MOA: Na blockade-> blocks activated and inactivated channels with fast kinetics. Does not prolong APD, may shorten. I: Ventricular tachycardias, prevents VF post cardioversion Route: IV loading 150-200mg + 2-4mg/min infusion First pass hepatic metabolism. Dose reduction in patients with heart failure or liver disease. AE: hypotension, neurologic sx Mexiletine = used in ventricular arrhythmias and chronic pain syndrome |
| IC Flecainide MOA: Na blockade-> dissociates with slow kinetics, nil change in APD I: SVT in structurally normal heart, do not use in ischaemic conditions Route: PO Hepatic and renal metabolism, half life ~ 20 hours AE: Proarrhythmic | |
| II Beta blockers | Propranolol MOA: b R blockade-> direct membrane effects, prolongs APD, slows SA node automaticity and AV conduction velocity I: Atrial arrhythmias and prevent of recurrent infarction/ sudden death Route: PO or IV Esmolol = short acting, IV only for intraoperative or acute arrhythmias Sotalol = non selective b + K (rapid) channel blocker |
| III Amiodarone | MOA: Blocks sodium, L-type calcium (slow) and K (rapid) channels and b adrenoceptors-> prolong APD and QT interval-> slows HR and AV conduction I: Ventricular arrhythmias and SVT Route: Oral or IV Variable absorption and tissue accumulation Hepatic metabolism, elimination is slow and complex AE: bradycardia, heart block in diseased heart Hypotension Pulmonary and hepatic toxicity (pulmonary fibrosis) Hyper or hypothyroidism (inhibits T4 conversion to T3 and acts as inorganic iodine) Many interactions based on CYP metabolism |
| IV Calcium L-type channel blockade | Non -dihydropyridines: Verapamil/ Diltiazem MOA: Slows SA automaticity and AV node conduction velocity-> decreases contractility and reduces BP I: SVT, hypertension, angina Route: Oral, IV Hepatic metabolism AE: hypotension |
| Miscellaneous | Adenosine MOA: Binds to adenosine R -> increases K+ efflux via inactivation of inward rectifier K+ channel and blocks Ca current-> very brief, complete AV blockade I: Paroxysmal SVT Route: IV only 6-12mg, duration 10-15 seconds AE: flushing, chest tightness and feeling of doom Magnesium MOA: Poorly understood, ?interacts with Na/K ATPase and Ca2+ channels-> normalise or increase plasma Mg2+ I: Torsades, digitalis induced arrhythmias Route: IV 1g over 20 min Potassium MOA: Increases K+ permeability and current-> slow ectopic pacemakers and heart conduction velocity I: Hypokalaemia, digitalis induced arrhythmias Route: PO, IV AE: Re-entrant arrhythmias, fibrillation or arrest in overdose |
| Digoxin | Derived from digitalis plant P’kinetics: Oral bioavailability 65-80% Not extensively metabolised 2/3 excreted unchanged by kidneys Half life 36-40 hours, requires dose adjustment in renal impairment P’dynamics: Inhibit Na/K ATPase-> Mechanical effects = increase intracellular sodium-> relative reduction in calcium expulsion by sodium- calcium exchanger-> increase Ca2+ concentration = increase contraction of sarcomere Electrical effects = Early brief prolongation of AP followed by shortening = decrease APD secondary to increased potassium conductance Higher conc: RMP reduced (made less negative, as reduced intracellular K+) causing oscillatory depolarizing after potentials-> reach thresholds to elicit ectopic beats-> tachycardia and arrhythmia. Sympathetic outflow increased which can lead to supraventricular tachyarrhythmias. High dose toxicity can lead to heart block and slow ventricular rates. Low therapeutic dose: parasympathomimetic effects (aka direct vagal effect) AE: Cardiac = AV junctional rhythm, premature ventricular depolarisations, bigeminy, VT and AV blockade Acute toxicity 2-4 hours: nausea, vomiting, diarrhoea, abdominal painHyperkalaemia Enhanced automaticity (tachyarrhythmias) then AV block/ VF/ VTHypotension, shockLethargy, confusion Chronic toxicity – typically occurs in context of intercurrent illness/ acute renal failure Insidious onset over days to weeks Symptoms are those of acute as well as visual disturbances (reduced acuity, yellow halos and altered colour perception) Interactions: With K = inhibit binding to Na/K ATPase, thus hyperkalaemia reduces enzyme inhibiting actions of digoxin and hypokalaemia increases themWith Ca = accelerates overloading of intracellular calcium stores-> abnormal automaticity and arrhythmia |
Antihypertensives
Beta Blockers
- Non-selective
- b1/b2 = timolol, propranolol, sotalol
- b1/b2/a1 = labetalol (hypertensive emergencies), carvedilol (reduce atherosclerosis/ROS)
- Selective b2 = metoprolol, atenolol, esmolol, bisoprolol
- MOA:
- b1 effect = reduce HR/ contractility-> reduce myocardial oxygen demand and BP + reduce renin release from JGA in kidney-> reduce ATII, sodium water retention
- b2 effect = bronchodilation, reduce aqueous humour production and IOP, reduce glucagon from pancreatic alpha cells/ reduce gluconeogenesis in liver-> hypoglycaemia, mild vasoconstriction in vessels to brain and skeletal muscle, decreased generation of FFA from TG thus increased TG levels, increased gut motility
- Used for treatment:
- CAD, SVT, HTN, compensated CCF
- Glaucoma, anxiety, essential tremors, thyrotoxicosis, migraine prophylaxis
- Contraindicated in phaeochromocytoma and cocaine due to unopposed alpha agonism
- Antidote in overdose = IVF, glucagon and atropine
- AE: bradycardia, heart block, hypotension, diarrhoea, hypoglycaemia unawareness, insomnia, fatigue, hypertriglyceridaemia, postural hypotension
- Propranolol = highly lipid soluble thus crosses BBB (can cause seizures) and Na+ blocking activity (widening QRS, VF arrest in overdose-> treat with bicarbonate)
- Half-lives = propranolol 3.5-6 hr, metoprolol 3-4 hr, atenolol 6-9 hr, labetalol 5 hr
Alpha blockers
- Prazosin
- MOA: selectively block a1 R
- Prevent sympathetic vasoconstriction
- Reduce prostatic smooth muscle tone
- Indications = HTN, BPH
- AE: postural hypotension
ACE inhibitors: PRILS
- Inhibit ACE-> reduce angiotensin II levels
- Reduce vasoconstriction
- Reduce aldosterone secretion
- Increase bradykinin
- I = HTN, CCF, diabetes
- AE = cough, angioedema, hyperkalaemia, renal impairment, teratogenic
Angiotensin R blockers: SARTANS
- Block AT1 angiotensin R
- Same as ACE I
- Nil increase in bradykinin
- I = HTN, CCF
- AE = same as ACE-I but less cough
Renin inhibitor: Aliskiren
- Inhibits enzyme activity of renin
- Reduces angiotensin I/II/ aldosterone
Vasodilators:
- Verapamil, diltiazem = block L type calcium channels
- Nifedipine, amlodipine = block vascular calcium channels > cardiac
- Hydralazine, nitroprusside = causes NO release, dilates arterioles not veins
- Minoxidil = metabolite opens K channels in vascular smooth muscle
Centrally acting sympathoplegics:
- Methyldopa, clonidine
- MOA = activate a2 adrenoceptors
- Reduce sympathetic outflow
- Reduce NE release from nerve endings
Sympathetic nerve terminal blockers: Rarely used
- Reserpine = blocks vesicular amine transporter in noradrenergic nerves and depletes transmitter stores
- Guanethidine = interferes with amine release and replaces NR in vesicles
Last Updated on September 24, 2021 by Andrew Crofton
Andrew Crofton
0
Tags :