Coumarin derivative used widely for prophylaxis of systemic thromboembolism in patients with AF, prosthetic heart valves and in the treatment of DVT/PE.


Warfarin inhibits the synthesis of vitamin K dependant clotting factors (II, VII, IX and X).



Clotting factor precursors are produced in the liver and are activated by the gamma carboxylation of their glutamic acid residues. This process is linked to the oxidation of reduced vitamin K. Warfarin inhibits to action of vitamin K epoxide reductase, preventing the return of vitamin K to it’s reduced active state.

Warfarin doesn’t effect circulating factors that are already active so onset can take 72 hours. It can also inhibit the effect of protein C and protein S first, creating a prothrombotic state initially. In some patients this period of time will need to be covered with LMWH or unfractionated heparin.

Side effects

Teratogenicity – in particular during organogenesis in the first trimester, however in the third trimester warfarin can cross the placenta and cause foetal haemorrhage in particular intraventricular haemorrhage.
Drug interactions – metabolised by hepatic cytochrome P450 system, therefore any enzyme inhibitors or inducers will effect circulating levels of warfarin.


Vitamin K can take time to work as it will not be effective until new clotting factors are activated. Also in high doses (e.g. 10mg) it can prevent anticoagulation for a number of days.

More rapid reversal can be achieved with FFP or clotting factor concentrates e.g. Octaplex.


Completed absorbed from the gut and 95% protein bound. Hepatic metabolism and renal excretion.


Prothrombin time (PT) is a measure of extrinsic system (factor VII) activity, as well as common factors like factor X. This is converted into the INR which standardises the result for laboratory variations in PT measurement across the world.



Unfractionated heparin

3-30 kilodaltons

An anionic mucopolysaccharide organic acid containing many sulphate residues.

Used as a continuous intravenous infusion to treat DVT, PE and in critical arterial occlusion. May have a role in DIC.


Heparin potentiates antithrombin III, increasing the rate of formation of the the antithrombin-thrombin complex by 1000 fold. Factors XIIa, XIa and IXa also inhibited as dose increases.

Side effects

Haemorrhage is the most common due to a relative overdose.

Heparin Induced Thrombocytopaenia (HIT)

Non-immune mediated (type 1): Onset around four days post heparin, mild and self-limiting – recovers when heparin stopped. Unusual to have severe complications from this.

Immune mediated (type 2): Onset around four to fourteen days after administration. Much more severe than type 1, incidence around 1-5% with unfractionated heparin but less than 1% with low molecular weight heparins. Heparin and platelet complexes bound by IgG causing aggregation and occlusive symptoms. 50% of patients will get serious thrombotic events e.g. pulmonary embolus.

A good review of heparin induced thrombocytopaenia is available on Life in the Fast Lane.


Ineffective orally therefore given SC or IV.
Low lipid solubility – doesn’t cross placenta or blood brain barrier.
Negatively charged and highly protein bound.

Hepatic metabolism by heparinases – desulphated and excreted in the urine.


A basic protein originally isolated from salmon sperm, though now synthesised through recombinant biotechnology.

Given intravenously to reverse effects of unfractionated heparin.

It is a positively charged molecule that forms an inactive complex with heparin that is cleared by the reticuloendothelial system.

1mg of protamine will reverse 100  units of heparin.

Side effects

Hypotension, dyspnoea and flushing (mediated by histamine release)
Anaphylaxis in particular in individuals with fish allergy

Low molecular weight heparin (LMWH)

e.g. Dalteparin, enoxaparin

6-8kDa, formed from depolymerisation of heparin. More effective at inhibiting factor Xa and less effective at potentiating antithrombin-thrombin complex formation.

Can be given as a single daily dose with less need for monitoring. Less risk of HIT (<1%).


APTT (activated partial thromboplastin time) measures activity of intrinsic pathway factors (XII, XI, IX, VIII).

LMWH inhibit Xa and therefore will not effect APTT, need to measure activated factor X levels.

Anti-platelet drugs


Cyclo-oxygenase 1 inhibitor

Used to reduce the risk of unstable angina progressing to MI and reduces mortality following acute MI. Reduces risk of stroke for patients suffering from TIAs. May potentially reduce cardiovascular risk when taking daily in a low dose, though the benefits vs risks of this remain controversial.

Mechanism: Irreversibly inibits cyclo-oxygenase isoenzyme 1 within the platelet, reduced the production of thromboxane A2. This reduces platelet activation and aggregation.


Platelet phosphodiesterase inhibitor

May reduce stroke risk when combined with aspirin.

Mechanism: Inhibits phosphodiesterase in the platelet which normally breaks down cyclic AMP. This counteracts the effects of calcium on the glycoprotein IIb/IIIa receptor by limiting vesicular release of thromboxane A2 and other activating substances. This potentiates the effects of prostacyclin which works in a similar way by increasing the concentration of cyclic AMP.


Inhibition of ADP binding

Used to reduce risk of stent thrombosis following coronary artery intervention. It also reduces stroke risk in peripheral vascular disease.

Mechanism: Irreversibly prevents ADP from binding to it’s platelet receptor, therefore preventing glycoprotein IIb/IIIa receptor from transforming into it’s active form.

Tirofiban and Abciximab

Glycoprotein IIb/IIIa antagonists

Used concurrently with heparin around the time of acute coronary events.

Mechanism: Antagonises the glycoprotein IIb/IIIa receptor, limiting platelet activation and aggregation. It doesn’t effect the final common pathway or coagulation cascade.

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
Ventricular tachycardias Class Ia – Procainamide
Class Ib – Lidocaine and Phenytoin
Both Class III – Amiodarone

Review: Myocyte action potential, Pacemaker action potential.

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 ++
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.


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

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.

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

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

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
Alpha-1 Vasoconstriction
Contraction of the bladder sphincter
Alpha-2 Platelet aggregation
Hyperpolarisation of some CNS neurones
Alpha-2 Inhibits noradrenaline release


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


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


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

May can hypoglycaemia due to increased insulin secretion

Nasal congestion


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.


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.


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


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

Reduces bladder sphincter tone.
May cause priapism.

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.


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

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



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


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

Metabolised by monoamine oxidase.


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


Direct acting synthetic catecholamine with predominantly beta-1 effects.



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.


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



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


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




Synthetic sympathomimetic amine with selective Beta-2 action.



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


Effects more profound when given IV.

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


Stimulates Na/K ATPase, increased intracellular potassium movement.

Relaxes gravid uterus.


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.


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.



Clear solution



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


Attenuate the response of the carotid body to hypoxaemia


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


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


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


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.



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



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


Renal and hepatic blood flow fall due to vasoconstriction


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.


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


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.



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



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


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


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 blood flow moderately decreases


Increases MAC
Increases peripheral pain threshold


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


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