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+Cardiovascular disease including heart disease, arrhythmias and hypertension, is the leading cause of morbidity and mortality in the Western world. There are numerous devastating conditions affecting the heart and/or the vasculature, leading to high demand for cardiovascular drugs. This chapter focuses on some key therapeutic targets within the cardiovascular system and the drugs used to combat cardiovascular disease.
+==Renin-Angiotensin-Aldosterone System==
+The renin-angiotensin-aldosterone system (RAAS) is an important hormone-based pathway within the body that regulates fluid balance and thus systemic blood pressure. The system is activated by decreases in blood volume or pressure detected in two ways: a drop in blood pressure detected by baroreceptors (pressure sensors) located in the carotid sinus or a drop in flow rate through the kidneys, detected by the juxtaglomerular apparatus. The body responds to these stimuli to effect a restoration in blood pressure via the actions of three hormones; renin, angiotensin and aldosterone. Following the detected drop in blood pressure, the enzyme renin is released from specialised cells within the kidney. The substrate of renin is the inactive precursor of angiotensin I, angiotensinogen. Angiotensin I is then enzymatically converted by angiotensin converting enzyme (ACE) into angiotensin II, a hormone with various actions throughout the body that ultimately increase blood pressure, restoring fluid balance within the body.
+'''Angiotensin II causes increases in blood pressure by actions at various sites:'''
+*'''Adrenal Glands:''' Angiotensin II augments release of the steroid hormone aldosterone, which acts locally to augment sodium retention and potassium secretion from the kidney. The net effect of this is water retention, thus restoring fluid balance.
+*'''Kidneys:''' Angiotensin II also increases sodium retention via direct actions on renal proximal tubules, as well as affecting glomerular filtration rate and renal blood flow.
+*'''Cardiovascular System:''' Angiotensin II is a potent endogenous vasoconstrictor, causing resistance arteries and veins to constrict, raising blood pressure. Furthermore in both the blood vessels and the heart, prolonged increases in Angiotensin II encourage cell growth and resultant hypertrophy.
+*'''Central Nervous System:''' In the brain, Angiotensin II acts on the posterior pituitary gland, stimulating release of antidiuretic hormone (ADH, also known as Arginine Vasopressin (AVP)). ADH increases water reabsorption in the renal collecting ducts. Angiotensin II also acts on the subfornical organ within the brain to cause increased ''thirst'', encouraging water intake.
+Chronic activation of the RAAS system can lead to deleterious remodelling and increased inflammation in the heart, vasculature and kidneys, as well as hypertension and chronic kidney disease.
+==Neural Control of the Cardiovascular System==
+===Sympathetic (Adrenergic) Nervous System===
+The adrenergic nervous system is a vital component of many processes throughout the body, including the cardiovascular system. Circulating catecholamines (e.g. adrenaline and noradrenaline) bind to and activate adrenergic receptors on cell membranes. Adrenergic receptors are a class of G-protein coupled receptors that elicit a variety of tissue-specific effects and exist in several subtypes.
+====Vasculature====
+The predominant receptor subtype present in blood vessels is the α1-adrenergic receptor, activation of which by catecholamine binding causes activation of the phospholipase-C (PLC), inositol triphosphate (IP3), diacylglycerol (DAG) intracellular signalling pathway. This ultimately results in myocyte contraction, vasoconstriction and consequent increases in systemic blood pressure.
+====Heart====
+Although the heart is myogenic, that is the impetus for contraction is self-initiated, the output of the heart is influenced by the central nervous system. The net effect of the sympathetic system on the heart is to increase cardiac output. The adrenergic receptors found in the heart belong to the β-receptor subfamily and include β1 and β3 receptors. Catecholamine binding to β1-receptors in the heart causes increases in cardiac output via a number of mechanisms: positive chronotropic effects, positive inotropic effects increased automaticity and conduction in both ventricular myocytes and the atrioventricular (AV) node. However β3-receptor activation antagonises these actions, producing a negative inotropic effect and providing an inbuilt control system within the heart.
+Prolonged increase catecholamine levels in the circulation (e.g. when secreted from adrenal tumours or times of stress) can lead to chronic cardiovascular problems such as hypertension and arrhythmias.
+===Parasympathetic Nervous System===
+The parasympathetic system relies on the binding of the neurotransmitter acetylcholine (Ach) to muscarinic receptors, and has various roles throughout the body.
+====Vasculature====
+Although blood vessels do express muscarinic receptors, they do not receive cholinergic innervation; however application of exogenous Ach results in a swift and profound vasodilation.
+====Heart====
+Activation of muscarinic receptors (M2-subtype) in the heart by Ach released from the vagus nerve causes a reduction in cardiac output via opposite effects to adrenergic stimulation: negative chronotropic effects and decreases in AV node conduction as well as decreasing the force of atrial contractions.
+==Platelet/Clotting System==
+Platelets (also known as thrombocytes) are small cells lacking nuclei that are responsible for haemostasis, or blood clotting. Damage or injury leading to blood loss and exposure of extracellular collagen fibres is detected, activating platelets. Once activated, platelets become adhesive, sticking to both the damaged vessel wall and each other, forming a clump of cells, or ‘clot’, helping to dam the vessel leak. They then begin to secrete cytokines that encourage invasion of fibroblasts present in the surrounding tissue which form a more permanent patch, either by creating healthy tissue, or depositing extracellular matrix to form a scar.
+There are several conditions in which abnormal clotting can be damaging to the body; excess clotting can lead to vascular blockage and ischaemia or stroke; less commonly, deficient clotting can lead to excess blood loss, for example in haemophilia. To combat these diseases, there are drugs that modulate the clotting process.
+===Anti-coagulants===
+Drugs that prevent clotting (anti-coagulants) are important in those with an increased risk of clotting-mediated damage such as a stroke or ischaemia.
+As well being an analgesic and anti-pyretic, Aspirin is an anti-thrombotic agent given in low doses to those at risk of damage from clotting (e.g. following a heart attack). Aspirin’s anti-coagulant actions come from its suppression of key pro-clotting factors such as prostaglanding and thromboxanes via irreversible inactivation of the PTGS cyclooxygenase enzyme. This suppression of factors such as thromboxane A<sub>2</sub> reduces platelet aggregation and thus prevents clot formation.
+P2Y<sub>12</sub> inhibitors such as clopidogrel exert their anti-coagulant effect via inhibition of the P2Y<sub>12</sub> subtype of the platelet ADP receptor. By blocking P2Y<sub>12</sub>, these drugs prevent activation of platelets and the formation of the fibrin network needed for clotting.
+Drugs such as abciximab and tirofiban prevent clotting via inhibition of the glycoprotein IIb/IIIa receptor preventing both platelet activation and aggregation.
+==Pharmacokinetics==
+When administering drugs to a patient, it is crucial to know several facts about the drug in order to maximise efficacy and minimise side-effects/toxicity. These include information about what dose is effective, how long the drug remains active in the body, how quickly it is broken down/removed from the body, and how easily the body can absorb/use that drug. The following table details these pharmacokinetic properties and how they are calculated:
+Property	Description	Standard units (Abbreviation)	Formula
+Dose	Amount of active drug given to patient	mg (D)	Drug Specific (From clinical studies)
+Concentration	Amount of drug in a given plasma volume	µg/ml (C)	= D / Vd
+EC50	The concentration of drug needed to elicit a response halfway between zero and maximal responses.	µg/ml (EC50)
+             y=bottom+  (Top-Bottom)/(1+ [x/EC50]  Hill Coefficient)
+Volume of Distribution	The theoretical volume the drug would occupy if distributed uniformly throughout the tissues to elicit the current plasma concentration. 	L (Vd)	D / C
+Elimination Constant (Rate)	The rate at which the drug is removed from the body.	h-1 (Ke)	ln(2) / t1/2   or  CL / Vd
+Bioavailability	How much of the administered dose is available for actual use by the body.	no units as expressing a fraction (f)
+×  (AUC (po)×D (iv))/(AUC (iv)×D (po))
+AUC = Area under curve  po = oral administration  iv = intravenous administration
+Cmax or Cmin	The maximum (Cmax) /  minimum (Cmin) plasma drug concentration reached following drug administration	µg/ml (Cmax or Cmin)	Identified via direct measurement of plasma C
+tmax	The time it takes for a drug to reach Cmax following administration	h (tmax)	Identified via direct measurement of plasma C over time
+Half-life	The time it takes for a drug to reach half its original concentration	h (t1/2)	ln(2) / Ke
+Drug Clearance	The volume of plasma cleared of the drug over a set time	l/h (CL)	Vd x Ke   or  D / Area under curve
+Common Drug-Drug Interactions
+It is important to be aware of the interactions that can occur between concomitantly administered drugs, as they may effect efficacy and/or toxicity, or produce adverse side effects. Such interactions could for example affect drug absorption, drug bioavailability or efficacy, or combine to produce unwanted metabolites, as well as possibly having effects on clinical analyses. If a combination of two drugs decreases the effect of one or both of them, the interaction is termed an antagonistic effect; however if, conversely, a combination of two drugs enhances the effect of one or both of them, the interaction is termed a synergistic effect. Drugs that act on the cardiovascular system are high in interactivity, which is an issue as cardiovascular patients normally receive more than one drug. Some common drug—drug interactions related to cardiovascular drugs are listed below:
+Drug	Drugs that ↑drug action	Drugs that ↓ drug action
+Digoxin	Diuretics
+Antiarrhythmics
+Macrolide antibiotics
+Cholestyramine, neomycin
+Keto- and intraconazole
+Calcium antagonists
+Cyclosporine, indomethacin
+HMG CoA reductase inhibitors
+Benzodiazepines
+Amiodarone
+Verapamil	Rifampicin
+Antacids (liquid)
+Warfarin	Furosemide
+Amiodarone
+Sulfa, macrolide and quinolone
+  antibiotics
+NSAIDs
+	Azathioprine
+Phenobarbitone
+Carbamazepine
+Dexamethasone
+Prednisolone
+Rifampicin
+Vitamin K
+Raloxifene
+Clopidogrel	Rifampicin
+Caffeine
+Methylxanthines
+Phosphodiesterase inhibitors	Statins
+Calcium channel blockers
+Warfarin
+Proton pump inhibitors
+Furosemide
+	NSAIDs
+Phenytoin
+Colesevelam
+ACE Inhibitors	NSAIDs
+Probenecid
+Calcium channel blockers		Indomethacin
+Antacids
+β-blockers	Amiodarone
+Calcium channel blockers
+Diltiazem
+Phenoxybenzamine	Phenobarbital
+Rifampicin
+Cimetidine
+Antacids (liquid)
+NSAIDs
+Statins	Amiodarone
+Verapamil
+Fibrates
+Amprenavir
+Diltiazem	Nevirapine
+Rifampicin
+There are several mechanisms by which drugs are broken down by the body, usually via degradation by enzymes. One common family of enzymes involved in drug metabolismis the cytochrome P450 (CYP) family; a large, diverse group of enzymes that encourage oxidation of a variety of substrates, both endogenous (e.g. steroid hormones) and exogenous (e.g.  toxins and drugs). CYP enzymes account for up to 75% of drug metabolism, aiding some drugs to form their active compounds but mostly deactivating drugs into inactive metabolites to be excreted. CYP enzymes can influence drug actions in several ways; they can increase drug metabolism (either increasing action via formation of the active by-product or decreasing action by metabolism of the active drug) or their action can be inhibited by drugs that compete for access to the CYP enzymes active site, preventing the normal interaction between drug and enzyme. Many drugs exert their interactions with other drugs viainterference with the CYP system. For example, if Drug A is metabolised by CYP and Drug B inhibits CYP activity, co-administration will result in a decreased bioavailability of Drug A. In humans there are 18 families and 43 subfamilies of the CYP group of enzymes, which target different substrates. Some CYP enzymes important in cardiovascular medicine, their cardiovascular-drug substrates and some of their interactions are shown in the table below:
+Enzyme	Substrates (e.g.)	Inhibitors (e.g.)	Inducers (e.g.)
+CYP2C19	Clopidogrel
+Propranolol
+Warfarin	Moclobemide
+Chloramphenicol
+Many anti-convulsants (Valproate)
+Proton pump inhibitors (Omeprazole)
+	Rifampicin
+Carbamazepine
+Prednisone
+CYP3A4	Donepezil
+Statins (Atorvastatin)
+Ca-channel blockers (Nifedipine)
+Amiodarone
+Dronedarone
+Quinidine
+PDE5 Inhibitors (Sildenafil)
+Kinins
+Caffeine
+Eplerenone
+Propranolol
+Salmeterol
+Warfarin
+Clopidogrel	Protease inhibitors (Ritonavir)
+Macrolides (Clarithromycin)
+Chloramphenicol
+Nefazodone
+Some Ca-channel blockers (Verapamil)
+Cimetidine
+Some azole anti-fungals (Ketaconazole)
+Grapefruit juice	Some anti-convulsants (Carbamazepine)
+Baribiturates (Phenobarbital)
+St. John’s Wort
+Some reverse transcriptase inhibitors (Efavirenz)
+Some Hypoglycaemics (Pioglitazone)
+Glucocorticoids
+Modafinil
+CYP2C9	Fluvastatin
+Angiotensin receptor II agonists (losartan)
+Warfarin
+Torasemide	Some azole anti-fungals (Fluconazole)
+Amiodarone
+Antihistamines (Cyclizine)
+Chloramphenicol
+Fluvastatin
+Fluvoxamine
+Probenecid
+Sertraline	Rifampicin
+Secobarbital
+CYP2D6	β-blockers (Propranolol)
+Class I anti-arrythmics (Flecainide)
+Donepezil
+	SSRIs (Fluoxetine)
+Quinidine
+Sertraline
+Terbinafine
+Amiodarone
+Cinacalcet
+Ritonavir
+Antipsychotics (Haloperidol)
+Antihistamines (Promethazine)
+Metoclopramide
+Ranitidine
+Mibefradil	Rifampicin
+Dexamethasone
+Glutethimide
+In addition to drug-drug interactions, the actions of many drugs are also affected by food or drink. For example, care should be taken with alcohol consumption with many kinds of drugs, as it can put stress on the liver which is already working hard to metabolise drugs in the body. Grapefruit juice too can cause issues, as it is known to inhibit CYP3a. For more information of interactions between drugs and food/drinks see this guide: http://www.fda.gov/downloads/Drugs/ResourcesForYou/Consumers/BuyingUsingMedicineSafely/EnsuringSafeUseofMedicine/GeneralUseofMedicine/UCM229033.pdf
+Cardiovascular Drugs
+Drug Category	Drug Type
+Examples (generic name)
+	Indications	Typical Dosage	Guidelines/Class of Indication	Side Effects (Prevalence %)
+Anti-hypertensives	Diuretics	Furosemide	Oedema	Furosemide: 20-40mg once daily		mild gastro-intestinal disturbances, pancreatitis, hepatic encephalopathy, postural hypotension, temporary increase in serum-cholesterol and triglyceride concentration, hyperglycaemia, acute urinary retention, electrolyte disturbances, metabolic alkalosis, blood disorders, hyperuricaemia, visual disturbances, tinnitus and deafness, and hypersensitivity reactions (including rash, photosensitivity, and pruritus).
+			Resistant Hypertension	Furosemide: 40-80mg once daily	ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Hypertension in symptomatic (NYHA class II-IV) HF and LVD: Class IC
+	ACE Inhibitors	Captopril, Monopril	Hypertension	Captopril: 12.5mg twice daily	ESC and EASD Guidelines (European Heart Journal doi: 10.1093/eurheart/ehl261)
+Hypertension: Class IA
+ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Hypertension in symptomatic (NYHA class II-IV) HF and LVD: Class IA
+ESC Guidelines: (European Heart Journal
+doi:10.1093/eurheartj/ehs092):
+Hypertension in diabetics: Class IA	Hypotension (2.4%), renal impairment, persistent dry cough, angioedema, rash pancreatitis, upper respiratory-tract symptoms (2-10%), gastro-intestinal symptoms (1-2%), altered liver function tests, cholestatic jaundice, hepatitis, fulminant hepatic necrosis and failure, hyperkalaemia (2%), hypoglycaemia, blood disorders including thrombocytopenia, leucopenia, neutropenia, headache (3%), dizziness (2-12%), fatigue, malaise, taste disturbance, paraesthesia, bronchospasm, fever, serositis, vasculitis, myalgia (3%), arthralgia, positive antinuclear antibody, raised erythrocyte sedimentation rate, eosinophilia, leucocytosis, and photosensitivity.
+			Heart Failure	Captopril: 12.5mg 3 times daily	ESC Guidelines (European Heart Journal (2012) 33, 2569–2619
+doi:10.1093/eurheartj/ehs215):
+Post STEMI: Class IA
+ESC and EASD Guidelines (European Heart Journal doi: 10.1093/eurheart/ehl261)
+Diabetic patients: Class IC
+ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Symptomatic (NYHA class II-IV) HF: Class IA
+Acute heart failure with ACS: Class IA
+			Prophylaxis Following MI	Captopril: 6.25mg once daily
+			Diabetic nephropathy	Captopril: 75-100mg once daily
+	Angiotensin Receptor Blockers	Losartan. Candesartan	Hypertension	Losartan: 50mg once daily	ESC and EASD Guidelines (European Heart Journal doi: 10.1093/eurheart/ehl261)
+Hypertension: Class IA
+ESC Guidelines: (European Heart Journal
+doi:10.1093/eurheartj/ehs092):
+Hypertension in diabetics: Class IA	gastro-intestinal disturbances (<3%), dizziness (14%), angina, palpitation, oedema, dyspnoea, headache (14%), malaise, urticaria, pruritus, rash;
+			Left ventricular hypertrophy	Losartan: 12.5-150mg daily	ESC Guidelines (European Heart Journal (2012) 33, 2569–2619
+doi:10.1093/eurheartj/ehs215):
+LVH:  Class IB
+			Diabetic nephropathy	Losartan: 50mg daily
+	Alpha Blockers	Prazosin, Doxazosin	Hypertension	Prazosin: 1-10mg 2-3 times daily		Drowsiness, hypotension (notably postural hypotension) (10-70% initially), syncope (1%), asthenia, dizziness, depression, headache (8-18%), dry mouth, gastro-intestinal disturbances, oedema, blurred vision (<5%), intra-operative floppy iris syndrome, rhinitis (<4%), erectile disorders (including priapism), tachycardia and palpitations (7-14%), gastrointestinal side-symptoms (4-5%), hypersensitivity reactions including rash, pruritus and angioedema.
+			Congestive Heart Failure	Prazosin: 4-20mg daily
+			Raynaud’s Syndrome	Prazosin: 1-2mg daily
+	Beta Blockers	Atenolol, Propranolol	Hypertension	Atenolol: 25-50mg daily		Gastro-intestinal disturbances (2-4%); bradycardia, heart failure, hypotension, conduction disorders, peripheral vasoconstriction, bronchospasm, dyspnoea; headache, fatigue, sleep disturbances (2-5%), paraesthesia, dizziness (2-5%), vertigo, psychoses; sexual dysfunction; purpura, thrombocytopenia; visual disturbances; exacerbation of psoriasis, alopecia; rarely rashes and dry eyes
+			Angina	Atenolol: 100mg once/twice daily	ESC and EASD Guidelines (European Heart Journal doi: 10.1093/eurheart/ehl261)
+ACS: Class IIaB
+ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Angina in symptomatic (NYHA class II-IV) HF and LVD: Class IA
+			Arrhythmias	Atenolol: 50-100mg daily	ESC Guidelines (European Heart Journal (2012) 33, 2569–2619
+doi:10.1093/eurheartj/ehs215):
+Atrial fibrillation: Class IA
+Polymorphic VT: Class IB
+ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Symptomatic (NYHA class II-IV) HF, LVD and AF: Class IA
+Management of VA in HF: Class IA
+ACC/AHA/ESC Guidelines (Blomström-Lundqvist and Scheinman et al. 2003):
+SVT: Class IIbC
+Wide QRS-complex tachycardia of unknown origin: Class IIIC
+Sinus tachycardia: Class IC
+Poorly tolerated AVNRT with haemodynamic intolerance: Class IIaC
+Recurrent symptomatic AVNRT: Class IC
+Documented PSVT with only dual AV-nodal pathways or single echo beats demonstrated during electrophysiological study and no other identified cause of arrhythmia: Class IC
+Infrequent, well tolerated AVNRT: Class IB
+Focal junction tachycardia: Class IIaC
+Nonparoxysmal junctional tachycardia: Class IIaC
+WPW Syndrome: Class IIaC
+AVRT, poorly tolerated: Class IIbC
+Since or infrequent AVRT episode(s): Class IIaB
+Acute treatment of Focal Atrial Tachycardia: Class IIaC
+Prophylactic therapy for AT: Class IC
+AF (Poorly tolerated): Class IIaC
+AF (Stable flutter): Class IC
+Prophylaxis of SVT during pregnancy: Class IIaB
+			Migraine	Atenolol: 50-200mg daily
+	Calcium Channel Blockers	Nifedipine, Verapamil, Diltiazem	Hypertension	Nifedipine: 20-30mg once daily	ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Hypertension in symptomatic (NYHA class II-IV) HF and LVD: Class IA	gastro-intestinal disturbance (2-11%); hypotension (1-5%), oedema (7-29%), vasodilatation, palpitation; headache (7-35%), dizziness (3-27%), lethargy (4-6%), asthenia (10-12%); less commonly tachycardia (<1-7%), syncope (<1%), chills, nasal congestion, dyspnoea (<3%), anxiety, sleep disturbance (<2%), vertigo (<3%), migraine, paraesthesia, tremor (1-8%), polyuria, dysuria, nocturia, erectile dysfunction (<2%), epistaxis, myalgia, joint swelling, visual disturbance (<2%), sweating (<2%), hypersensitivity reactions (<1%); rarely anorexia, gum hyperplasia, mood disturbances, hyperglycaemia, male infertility, purpura (<1%), and photosensitivity reactions (<1%); also reported dysphagia, intestinal obstruction, intestinal ulcer, bezoar formation, gynaecomastia, agranulocytosis, and anaphylaxis;
+			Raynaud’s Syndrome	Nifedipine: 5-20mg 3 times daily
+			Angina (prophylaxis)	Nifedipine: 5-20mg 3 times daily	ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Angina in symptomatic (NYHA class II-IV) HF and LVD: Class IIaA
+Anti-Arrhythmics	Class I (sodium channel blockers)	Flecainide, Lidocaine, Procainamide	Ventricular Arrhythmias	Flecainide: 50-100mg twice daily	ESC Guidelines(European Heart Journal (2012) 33, 2569–2619
+doi:10.1093/eurheartj/ehs215):
+Sustained VT and VF: Class IIbC
+ACC/AHA/ESC Guidelines (Blomström-Lundqvist and Scheinman et al. 2003):
+Pre-excited SVT/AF: Class IB
+Wide QRS-complex tachycardia of unknown origin: Lidocaine (Class IIbB) / Procainamide (Class IB)
+Wide QRS-complex tachycardia of unknown origin with LVD: Class IB
+Focal junction tachycardia: Class IIaC
+WPW Syndrome: IIaC
+AVRT, poorly tolerated: IIaC
+Single or infrequent AVRT episode(s): Class IIbC
+Acute treatment of Focal Atrial Tachycardia: Class IIaC
+Prophylactic therapy for AT: Class IIaC
+AF (Stable flutter): Class IIbA
+Prophylaxis of SVT during pregnancy: Class IIbB	Oedema, pro-arrhythmic effects (1-13%); dyspnoea; nervous-system side-effects including dizziness, asthenia, fatigue, fever; visual disturbances (13-28%); rarely pneumonitis, hallucinations, depression, confusion, amnesia, dyskinesia, convulsions, peripheral neuropathy; also reported gastro-intestinal disturbances (1-4%), anorexia, hepatic dysfunction, flushing, syncope, drowsiness, tremor, vertigo, headache, anxiety, insomnia, ataxia, paraesthesia, anaemia, leucopenia, thrombocytopenia, corneal deposits, tinnitus, increased antinuclear antibodies, hypersensitivity reactions (including rash, urticaria, and photosensitivity), increased sweating
+	Class II (Beta blockers)	(See above)	(See above)	(See above)		(See above)
+	Class III (Potassium channel blockers)	Amiodarone,
+Sotalol	Ventricular Arrhythmias	Amiodarone: 200mg 2-3 times daily	ESC Guidelines(European Heart Journal (2012) 33, 2569–2619
+doi:10.1093/eurheartj/ehs215):
+Sustained VT and VF: Class IIaC
+Polymorphic VT: Class IC
+ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Management of VA in HF: Class IA
+Prevention of VA in HF: Class IIbB
+ACC/AHA/ESC Guidelines (Blomström-Lundqvist and Scheinman et al. 2003):
+SVT: Class IIBC
+Wide QRS-complex tachycardia of unknown origin: Class IB
+Wide QRS-complex tachycardia of unknown origin with LVD: Class IB
+Recurrent AVNRT unresponsive to beta blocker or calcium-channel blocker and patient not desiring RF ablation: Class IIbC
+Focal junction tachycardia: Class IIaC
+WPW Syndrome: IIaC
+AVRT, poorly tolerated: Class IIaC
+Since or infrequent AVRT episode(s): Class IIbB
+Acute treatment of Focal Atrial Tachycardia: Class IIaC
+Prophylactic therapy for AT: Class IIaC
+AF (Poorly tolerated): Class IIbC
+AF (Stable flutter): Class IIbC
+Prophylaxis of SVT during pregnancy: Class IIIC	Gastro-intestinal disturbances (2-20%)), taste disturbances, hepatic disturbances (up to 50%); bradycardia; pulmonary toxicity (1-17%); tremor (9-59%), sleep disorders; hypothyroidism (5-10%), hyperthyroidism (5-10%); reversible corneal microdeposits (up to 98%); phototoxicity, persistent slate-grey skin discoloration (1-7%), injection-site reactions; less commonly onset or worsening of arrhythmia, conduction disturbances, peripheral neuropathy (1-105) and myopathy; very rarely sinus arrest, bronchospasm, ataxia (2-37%), benign intracranial hypertension, headache, vertigo, epididymo-orchitis, impotence, haemolytic or aplastic anaemia, thrombocytopenia, rash, hypersensitivity including photosensitivity (2-20%), anaphylaxis on rapid injection, hypotension (10-30%), respiratory distress syndrome, sweating, and hot flushes
+	Class IV (Calcium channel blockers)	(See above)	(See above)	(See above)		(See above)
+	-	Digoxin	Supra-ventricular Arrhythmias	Acute: 0.75-1.5mg over 24 hours
+Maintenance: 125-150µg daily	ACC/AHA/ESC Guidelines (Blomström-Lundqvist and Scheinman et al. 2003):
+SVT: Class IIbC
+WPW Syndrome: Class IIIC
+AVRT, poorly tolerated: Class IIIC
+Since or infrequent AVRT episode(s): Class IIIC
+Prophylaxis of SVT during pregnancy: Class IC	Gastro-intestinal disturbances (vomiting, diarrhoea, anorexia, abdominal pain) (25%); arrhythmias (up to 50%), AV conduction disturbances (50%); nervous system disturbances (dizziness, apathy, confusion, headache, fatigue, weakness) (25%); blurred or yellow vision; rash, eosinophilia, depression, anorexia, intestinal ischaemia and necrosis, psychosis, gynaecomastia on long-term use, and thrombocytopenia
+			Heart Failure	62.5-125 µg daily	ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Symptomatic (NYHA class II-IV) HF: Class IIbB
+ESC Guidelines Symptomatic (NYHA class II-IV) HF, LVD and AF: Class IB
+Acute HF with AF and VT: Class IC
+Anti-platelet Drugs	-	Aspirin	Prevention of thrombotic cerebro- or cardio-vascular disease	75mg once/day	ESC and EASD Guidelines (European Heart Journal doi: 10.1093/eurheart/ehl261)
+Prevention in AF: Class IC
+Prevention in diabetic patients: IIaB
+ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Prevention in Symptomatic (NYHA class II-IV) HF and AF: Class IIA
+ESC Guidelines: (European Heart Journal
+doi:10.1093/eurheartj/ehs092):
+Prevention in hypertensive patients with CV events: Class IA
+Prevention in hypertensive patients without CV history but with reduced renal function/high risk: Class IIbA
+ESC Guidelines: (European Heart Journal
+doi:10.1093/eurheartj/ehs092):
+Post-MI: Class Ia
+	Bronchospasm (10-30% in asthmatics); gastro-intestinal irritation (up to 83%), gastro-intestinal haemorrhage (occasionally major), also other haemorrhage (e.g. intracranial (0.5%), subconjunctival), chest pain (8.3%), oedema (4.5%), hypertension (4.3%).
+			Pain / pyrexia	300-600mg every 4-6 hours as necessary
+	-	Clopidogrel	Prevention of thrombotic events (esp. when warfarin not tolerated)	75mg once/day	ESC and EASD Guidelines (European Heart Journal doi: 10.1093/eurheart/ehl261)
+Prevention in diabetic patients: IIaB
+Primary and secondary prevention of stroke: Class IB
+ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Prevention in Symptomatic (NYHA class II-IV) HF and AF: Class IIA
+Prevention in Symptomatic (NYHA class II-IV) HF and AF: Class IIA
+ESC Guidelines: (European Heart Journal
+doi:10.1093/eurheartj/ehs092):
+Acute phase of coronary artery syndrome: Class IB
+Non-cardioembolic cerebral ischaemic events: Class IA	Dyspepsia (5.2%), abdominal pain (5.6%), diarrhoea (4.5%); bleeding disorders including gastro-intestinal (2.0%) and intracranial (0.4%), nausea (3.4%), vomiting, gastritis, flatulence, constipation, gastric and duodenal ulcers, headache (7.6%), epistaxis (2.9%), dizziness (6.2%), paraesthesia, leucopenia, decreased platelets (very rarely severe thrombocytopenia), eosinophilia, rash (4.2%), pruritus (3.3%), vertigo, colitis, pancreatitis, hepatitis (<1%), acute liver failure, hypertension (4.3%), chest pain (8.3%), oedema (4.1%), vasculitis, confusion, hallucinations, taste disturbance, cough (3.9%), fatigue (4.8%) stomatitis, bronchospasm, interstitial pneumonitis, pyrexia (2.2%), blood disorders including thrombocytopenic purpura (5.3%), agranulocytosis, neutropenia (0.04%) and pancytopenia and hypersensitivity-like reactions (<0.1%)including fever, glomerulonephritis, arthralgia, Stevens-Johnson syndrome, toxic epidermal necrolysis, lichen planus
+			Acute myocardial infarction	300mg daily initially then 75mg once/day	ESC Guidelines(European Heart Journal (2012) 33, 2569–2619
+doi:10.1093/eurheartj/ehs215):
+Post STEMI: Class IA
+			Acute coronary syndrome	300mg daily initially then 75mg once/day	ESC and EASD Guidelines (European Heart Journal doi: 10.1093/eurheart/ehl261)
+ACS: Class IIaC
+	-	Prasugrel	Prevention of thrombotic events.	60mg bolus then 5-10mg once daily	ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Prevention in Symptomatic (NYHA class II-IV) HF and AF: Class IIA
+ESC Guidelines: (European Heart Journal
+doi:10.1093/eurheartj/ehs092):
+Acute phase of coronary artery syndrome: Class IB
+	Haemorrhage (11.3%) (including gastro-intestinal (1.5%) and intracranial), haematoma, haematuria, hypertension (7.5%), hypotension (3.9%), headache (5.5%), back pain (5.0%), dyspnoea (4.9%), nausea (4.6%), dizziness (4.1%), cough (3.9%), fatigue (3.7%), chest pain (3.1%), arrhythmias including atrial fibrillation (2.9%) and bradycardia (2.9%), rash (2.8%), pyrexia (2.7%), oedema (2.7%), diarrhoea (2.3%), hypercholesterolaemia/hyperlipidaemia (7.5%), anaemia, rash,hypersensitivity reactions including angioedema (0.06%), thrombocytopenia (0.06%), thrombotic thrombocytopenic purpura
+	-	Ticragelor	Prevention of thrombotic events.	180mg bolus then 90mg twice daily	ESC Guidelines (European Heart Journal
+doi:10.1093/eurheartj/ehs104):
+Prevention in Symptomatic (NYHA class II-IV) HF and AF: Class IIA
+ESC Guidelines: (European Heart Journal
+doi:10.1093/eurheartj/ehs092):
+Acute phase of coronary artery syndrome: Class IB
+	dyspnoea (13.8%), haemorrhage, bruising; nausea (4.3%), vomiting, diarrhoea (3.7%), hypertension (3.8%), hypotension (3.2%), back pain (3.6%), abdominal pain, dyspepsia, gastritis, dizziness (4.5%), chest pain (3.7%), headache (6.5%), cough (4.9%), rash, pruritus, fatigue (3.2%),  constipation, arrhythmias including atrial fibrillation (4.2%), paraesthesia, confusion, hyperuricaemia, raised serum creatinine (7.4%), vertigo
+Vitamin K Antagonists	-	Warfarin	Prevention of thrombotic/ embolic events (esp. after prosthetic valve insertion)	5-10mg initially then tailored to individual (usually 3-9mg once daily at the same time)		haemorrhage, nausea, vomiting, diarrhoea, jaundice, hepatic dysfunction, pancreatitis, pyrexia, alopecia, purpura, rash, ‘purple toes’, skin necrosis (increased risk in patients with protein C or protein S deficiency)
+	-	Acenocoumarol	Prevention of thrombotic/ embolic events (esp. after prosthetic valve insertion)	4mg initially, followed by 1-8mg daily		haemorrhage, nausea, vomiting, diarrhoea, jaundice, hepatic dysfunction, pancreatitis, pyrexia, alopecia, purpura, rash, ‘purple toes’, skin necrosis (increased risk in patients with protein C or protein S deficiency)
+Lipid-Lowering Drugs	Statins	Simvastatin, Atorvastatin	Primary hyper-cholesterolaemia, combined hyperlipidaemia	Simvastatin: 10-20mg once daily	ESC and EASD Guidelines (European Heart Journal doi: 10.1093/eurheart/ehl261)
+Dyslipidaemia: Class IA
+Low HDL-C: Class IIbB
+Elderly patients with CVD: IB
+Elderly patients with no CVD but CV risk factors: IIbB
+Type I diabetes: IC
+Patients with CKD: IIaC
+Transplant patients: Class IIaB
+PAD: Class IA
+HIV patients: IIaC
+ESC Guidelines: (European Heart Journal
+doi:10.1093/eurheartj/ehs092):
+Hypertension in diabetics: Class IA
+ACS: Class IA	Oedema (2.7%), abdominal pain (5.9%), nausea (5.4%), atrial fibrillation (5.7%), constipation (2.2%), gastritis (4.9%), diabetes mellitus (4.2%), myalgia (3.7%), headache (2.5%), insomnia (4.0%), vertigo (4.5%), bronchitis (6.6%), sinusitis (2.3%), eczema (4.5%), urinary tract infection (3.2%)
+			Familial hyper-cholesterolaemia	Simvastatin: 40mg once daily	ESC and EASD Guidelines (European Heart Journal doi: 10.1093/eurheart/ehl261)
+HeFH: Class IC
+			Prevention of cardiovascular events	20-40mg once daily	ESC and EASD Guidelines (European Heart Journal doi: 10.1093/eurheart/ehl261):
+Class IA
+	Fibrates	Gemfibrozil	Hyperlipidaemias of types IIa, IIb, III, IV and V 	Gemfibrozil: 0.9-1.2mg daily	ESC and EAS Guidelines (European Heart Journal (2011) 32, 1769–1818
+doi:10.1093/eurheartj/ehr158)
+Low HDL-C: Class IIbB
+Transplant patients (with HTG, low HDL-C): Class IIbC	gastro-intestinal disturbances including dyspepsia (19.6%), nausea (4%), abdominal pain (9.8%), diarrhoea (7.2%), vomiting (1.2%); headache (1.2%), fatigue (3.8%), vertigo (1.5%), eczema, rash (1.7%), atrial fibrillation (0.7%), pancreatitis, appendicitis, disturbances in liver function including hepatitis and cholestatic jaundice, dizziness, paraesthesia, sexual dysfunction, thrombocytopenia, anaemia, leucopenia, eosinophilia, bone-marrow suppression, myalgia, myopathy, myasthenia, myositis accompanied by increase in creatine kinase, blurred vision, exfoliative dermatitis, alopecia, and photosensitivity
+	-	Ezetimibe	Primary and familial hyper-cholesterolaemia	10mg once daily	ESC and EAS Guidelines (European Heart Journal (2011) 32, 1769–1818
+doi:10.1093/eurheartj/ehr158)
+Transplant patients (with high LDL-C): Class IIbC	gastro-intestinal disturbance including diarrhoea (4.1%) and abdominal pain (3.0%); headache, fatigue (2.4%); myalgia, arthralgia (3.0%), sinusitis (3.6%), pharyngitis (2.3%), viral infection (2.2%), coughing (2.3%), hypersensitivity reactions including rash, angioedema, and anaphylaxis, hepatitis,pancreatitis, cholelithiasis, cholecystitis, thrombocytopenia, raised creatine kinase, myopathy, and rhabdomyolysis

Cardiac Pharmacology: Difference between revisions

Cardiac Pharmacology (view source)

Revision as of 17:14, 23 May 2013