Pacemaker action potential

The pacemaker cells (e.g. in the sinoatrial node) do not maintain a stable resting membrane potential but instead depolarise spotaneously.

pacemakerpotential

Phase 4

Restoration of ionic gradients and resting state
Sodium slowly leaks into the cell, although potassium diffuses out of the cell simultaneously the net effect is a gradual increase in membrane potential. This continues until the threshold potential is reached at about -40mV.

Phase 0
Rapid depolarisation
Mainly due to T-type calcium channels
Slower than rapid sodium channels, therefore gradient less steep than myocyte action potential.

Phase 3
Repolarisation
Effectively phase 1 absent and phase 2 very brief, therefore repolarisation is a single phase.
Sodium and calcium pumped out and potassium is pumped in, this requires ATP.

How to alter pacemaker rate

Threshold potential
If the threshold potential becomes less negative, it takes longer to reach and therefore pacemaker rate decreased. E.g. quinidine, procainamide.

Hyperpolarisation
If membrane potential becomes more negative then it takes longer to reach the threshold potential during phase 4.
Increased acetylcholine levels increase potassium efflux by altering the permeability of the membrane – this explains how increased vagal tone causes bradycardia.

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Classification of antiarrhythmic drugs

Vaughan-Williams classification

Class Mechanism Drugs
Ia Sodium blockade – prolongs refractory period of cardiac muscle Quinidine, Procainamide
Ib Sodium blockade – shortens refractory period Lidocaine, Phenytoin
Ic Sodium blockade – no effect of refractory period Flecainide
II Beta blockade – prolongs phase 4 Propranolol, Atenolol
III Potassium channel blockade – slows rate of repolarisation and prolongs action potential Amiodarone, Sotalol
IV Calcium channel blockade (L-type) – prevents maintenance of action potential Verapamil, Dilatiazem

Class I
Sodium blockade, therefore membrane stabilisers.

Class II
Block the effect of catecholamines at the Beta-1 adrenergic receptor, decreasing sympathetic activity on the heart. Decrease conduction through the AV node.

Class III
Potassium channel blockers, therefore prolong repolarisation and action potential duration

Class IV
Decrease conduction through the AV node
Shorten phase II (plateau phase)
Reduce contractility
Adrenergic control of heart rate maintained

An alternative classification

Digoxin, adenosine and magnesium do not fit into the Vaughan-Williams classification.

Drugs that work on
Supraventricular tachycardias Class Ic – Flecainide
Class II – Beta blockers
Class IV – Ca channel blockers
Digoxin
Adenosine
Ventricular tachycardias Class Ia – Procainamide
Class Ib – Lidocaine and Phenytoin
Both Class III – Amiodarone

Review: Myocyte action potential, Pacemaker action potential.

Cardiac action potential

cardiacactionpotential

Phase 0
Initial rapid depolarisation/upstroke
Voltage gated sodium channels open and sodium rushes in down concentration gradient

Phase 1
Early rapid repolarisation
Closure of sodium channels
Continued diffusion of potassium out of the cell

Phase 2
Plateau phase
Voltage gated L-type calcium channels open
Influx of calcium balances efflux of potassium
Absolute refractory period around 150ms

Phase 3
Final rapid repolarisation
L-type calcium channels close
Potassium flows out restoring membrane to resting state
Relative refractory period – overshoots slightly so will require a greater than normal stimulus to depolarise again

Phase 4
Resting membrane potential
Na/K ATPase maintains ionic concentration gradients

Beta blockers

Relevant links

Lira A, Pinsky M. Should Beta blockers be used in patients with septic shock? Critical Care. 2014,18:304

Myburgh on beta blockers and sepsis from SMACC Gold

Beta blockers

Widely used in treatment of ischaemic heart disease and hypertension across the world. All have different affinities for beta-1 and beta-2.

Drug Beta-1 cardioselectivity Intrinsic sympathomimetic activity
Atenolol ++
Esmolol ++
Metoprolol ++
Propranolol
Timolol +
Labetalol +

All useful effects of beta blockers come from their beta-1 blockade, antagonism of beta-2 receptors gives unwanted side effects. (Review: Actions of adrenoceptors).

In theory beta blockers with intrinsic sympathomimetic activity (partial agonists) are less likely to cause severe bradycardia.

Effects

Cardiac
Negative inotropic and chronotropic
Sinoatrial node automacity decreased
Atrioventricular node conduction prolonged
Bradycardia increases coronary artery diastolic filling time
Class II antiarrhythmic agents

Circulatory
Inhibition of beta-1 receptors at juxtaglomerular apparatus reduces renin release and therefore reduces angiotensin II and aldosterone.
Inhibition of peripheral beta-2 receptors may cause an element of vasoconstriction: Responsible for side effects of cold hands and impotence.

Respiratory
All beta blockers given at a high enough dose will cause bronchospasm through beta-2 antagonism

Metabolic
Non-selective beta blockers can obtund normal blood glucose response to exercise
May mask symptoms of hypoglycaemia

CNS
Lipid soluble beta blockers (metoprolol and propranolol) more likely to cause side effects e.g. nightmares, fatigue.
Decreased production of aqueous humour, decreases intra-ocular pressure.

Alpha blockers

Related links

Emcrit on peripheral vasopressors and extravasation management (use phentolamine)

Darr et al. Pheochromocytoma – an update in disease management. Ther Adv Endocrinol Metab. Feb 2012; 3(1): 11–26

Alpha receptors

Receptor type Action
Post-synapatic
Alpha-1 Vasoconstriction
Mydriasis
Contraction of the bladder sphincter
Alpha-2 Platelet aggregation
Hyperpolarisation of some CNS neurones
Pre-synaptic
Alpha-2 Inhibits noradrenaline release

Phentolamine

Non-selective alpha blocker, though affinity for alpha-1 three times that for alpha-2.

Uses

Treatment of hypertensive crises due to excessive sympathomimetics or during phaochromocytoma
Intracavernosal injection treats erectile dysfunction
Subcutaneous injection may limit damage caused by extravasation of vasopressors

Effects

Cardiovascular
Hypotension and peripheral vasodilatation.
Alpha-2 blockade can facilitate noradrenaline release when given intravenously.

Metabolic
May can hypoglycaemia due to increased insulin secretion

Misc
Nasal congestion

Phenoxybenzamine

Long acting non-selective alpha blocker with a high affinity for alpha-1 receptors.
Reactive intermediate forms irreversible covalent bond to alpha adrenoceptor.

Used for pre-operative management of phaochromocytoma to allow expansion of intravascular compartment. Also can be used in hypertensive crisis.
Often require co-administration of a beta blocker to limit reflex tachycardia.

Effects

Cardiovascular
Hypotension (particularly on standing)
Note: Treat overdose with noradrenaline, to avoid unopposed beta action of adrenaline (severe tachycardia +/- hypotension)

Other effects common to phentolamine.

Effects may last up to three days whilst new receptors are made.

Prazosin

Selective alpha-1 blocker
Used to treat hypertension, congestive cardiac failure, Raynaud’s and urinary symptoms associated with prostate hypertrophy/hyperplasia.

Effects

Cardiovascular
Decreased SVR due to peripheral vasodilatation.
Reflex tachycardia less common.
May help increase cardiac output in heart failure.

Urinary
Reduces bladder sphincter tone.
May cause priapism.

Misc
May create a false positive when screening for urinary metabolites of noradrenaline (VMA and MHPG) e.g. when testing for phaeochromocytoma.

Synthetic agents

Only isoprenaline, dobutamine and dopexamine are classified as catecholamines as only they contain the 3,4-dihydroxybenzene group.

Phenylephrine

Direct acting sympathomimetic amine with potent alpha-1 actions. No beta effects.

Dilute to 100mcg/ml (10mg vial in 100ml normal saline)

Effects

Cardiovascular

Raised SVR and BP, often causes reflex bradycardia and so may decrease cardiac output.
Not arrhythmogenic.

Renal

Blood flow falls in a dose dependant manner similar to noradrenaline.

Metabolised by monoamine oxidase.

Isoprenaline

Highly potent synthetic catecholamine with predominantly beta-1 effects. It is no longer available in the UK.

Dobutamine

Direct acting synthetic catecholamine with predominantly beta-1 effects.

Effects

Cardiovascular

Increased heart rate and contractility, increased cardiac output and myocardial oxygen consumption. Increased AV node conduction therefore can precipitate arrhythmias.

Metabolised by COMT in the liver, inactive metabolites excreted in the urine.

Dopexamine

Synthetic analogue of dopamine. Has beta-2 and dopamine-1 receptor activity and may inhibit reuptake of noradrenaline and presynaptic nerve terminals.

Effects

Cardiovascular

Positive inotropic effects and increased cardiac output due to reduced afterload.

Splanchnic

increased blood flow to kidneys and gut caused by vasodilation and increased cardiac output.

Respiratory

Bronchodilation.

Salbutamol

Synthetic sympathomimetic amine with selective Beta-2 action.

Effects

Respiratory

Relaxes bronchial smooth muscle. Can reverse hypoxic pulmonary vasoconstriction causing increased shunt, which can cause hypoxaemia.

Cardiovascular

Effects more profound when given IV.

Tachycardia, beta-2 mediated vasodilation with decreased blood pressure.

Misc

Stimulates Na/K ATPase, increased intracellular potassium movement.

Relaxes gravid uterus.

Ephedrine

Both direct and indirect sympathomimetic actions.

Direct alpha and beta action, also inhibits action of MAO on noradrenaline, increasing the amount of noradrenaline in the synapse. Prone to tachyphylaxis due to depletion of noradrenaline stores in sympathetic nerve terminals.

Patients taking monoamine oxidase inhibitors will have exaggerated effect and duration of action.

Effects common to other synthetic sympathomimetics.

65% excreted unchanged in the urine, the rest is metabolised in the liver. Half-life of four hours.

Dopamine

In the literature

Bellomo R, Chapman M, Finfer S, Hickling K, Myburgh J. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000 Dec 23-30;356(9248):2139-43.

Plus read the great appraisal by The Bottom Line.


 

Presentation

Clear solution

Effects

Cardiovascular

Arrhythmogenic
Similar to adrenaline at lower doses the dopamine and beta effects predimominate, whereas at higher doses the alpha effects predominate.

Review: Actions of different adrenoceptors

Respiratory

Attenuate the response of the carotid body to hypoxaemia

Splanchnic

Vasodilate mesenteric vessels via D1 receptors
Improved urine output may be due to inhibition of sodium resorption in proximal tubule of nephron as well as increased cardiac output

CNS

Modulates extrapyramidal effects and inhibits prolactin release
Dopamine can’t cross the blood brain barrier, though it’s precursor L-dopa can
Stimulates chemoreceptor trigger zone causing nausea and vomiting

Pharmacokinetics

25% is converted to noradrenaline in sympathetic nerve terminals

Uptake 1: Taken actively back into nerve terminal and metabolised by monoamine oxidase or recycled.
Uptake 2: Diffuses away from nerve and metabolised by catechol-O-methyl transferase

Noradrenaline

In the literature

Noradrenaline should be the first line vasopressor in septic shock (Surviving Sepsis guidelines).
For a good review of the surviving sepsis guidelines visit the PulmCCM.org site.

De Backer D, Aldecoa C, Njimi H, Vincent JL. Dopamine versus norepinephrine in the treatment of septic shock: a meta-analysis. Crit Care Med. 2012 Mar;40(3):725-30. doi: 10.1097/CCM.0b013e31823778ee.


 

Presentation

Clear solution, diluted to use as an infusion. Commonly 4mg or 8mg made up to 50ml in normal saline.

Effects

Cardiovascular

Causes peripheral vasoconstriction, increasing systolic and diastolic blood pressure.
May cause reflex bradycardia.
Cardiac output may fall due to increased systemic vascular resistance
Increased myocardial oxygen demand

Splanchnic

Renal and hepatic blood flow fall due to vasoconstriction

Uterus

Blood flow to pregnant uterus decreased which can cause foetal distriss
May cause uterine contraction due to alpha-1 effects

Effects may be exaggerated/prolonged in patients taking monoamine oxidase inhibitors.

Pharmacokinetics

Uptake 1: Taken actively back into nerve terminal and metabolised by monoamine oxidase or recycled.
Uptake 2: Diffuses away from nerve and metabolised by catechol-O-methyl transferase

Inactive metabolites excreted in the urine

Half-life two minutes

Adrenaline

In the literature

Marik PE, Bellomo R. Lactate clearance as a target of therapy in sepsis: A flawed paradigm. OA Critical Care 2013 Mar 01;1(1):3.
Great article, useful section on catecholamine driven lactate production.

Hagihara A, et al. Prehospital Epinephrine Use and Survival Among Patients With Out-of-Hospital Cardiac Arrest. JAMA. 2012;307(11):1161-1168

Choice of vasopressor in septic shock: does it matter?

Some emcrit thoughts: Abandon epinephrine? & Haemodynamic-directed dosing of epinephrine.


 

Presentation

Clear solution. 0.1mg/ml (1:10,000) and 1mg/ml (1:1000) available.

Effects

Cardiovascular

Effects vary according to dose.

Low dose: Beta effects predominate.
Increased cardiac output and myocardial oxygen consumption
Decreased SVR due to peripheral B2 effects

High dose: Alpha effects predominate
Increased SVR

Respiratory

Produces small rise in minute volume.
Potent bronchodilator effects, though secretions can thicken.

Metabolic

Increases basal metabolic rate
Stimulates gluconeogenesis and glycogenolysis in liver and muscle, increasing plasma glucose concentration
Stimulates renin-angiotensin-aldosterone system
Increased serum lactate due to increased glycolysis and conversion of pyruvate to lactate

Renal

Renal blood flow moderately decreases

CNS

Increases MAC
Increases peripheral pain threshold

Pharmacokinetics

Inactivated orally
SC absorption slower than IM
Tracheal absorption erratic and not reliable

Metabolism

Mitochondrial monoamine oxidase and catechol-O-methyl transferase in liver, kidneys and blood.
Inactive metabolites excreted in urine
Half life two minutes

Actions of adrenoceptors

Receptor Subtype Location Action when stimulated
Alpha 1 Vascular smooth muscle Vasconstriction
2 Throughout CNS Sedation, analgesia, decreased sympathetic outflow
Beta 1 Heart Positive inotropy and chronotropy
Platelets Platelet aggregation
2 Bronchi Bronchodilation
Uterus Uterine relaxation, tocolysis
Vascular smooth muscle Vasodilatation
Dopamine 1 Within CNS Modulates extrapyramidal activity
Peripherally Vasodilation of renal and mesenteric vasculature
2 Within CNS Decreased pituitary gland secretion, in particular prolactin
Peripherally Inhibits further noradrenaline release