Textbook of Cardiology

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====Vasculature====
====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.
The predominant receptor subtype present in blood vessels is the a1-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====
====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.
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 ß-receptor subfamily and include ß1 and ß3 receptors. Catecholamine binding to ß1-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 ß3-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.
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.
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|-
!Drug
!Drug
!Drugs that ↑drug action
!Drugs that ?drug action
!Drugs that ↓ drug action
!Drugs that ? drug action
|-
|-
|Digoxin
!Digoxin
|Diuretics
|valign="top"|
Antiarrhythmics
*Diuretics
Macrolide antibiotics
*Antiarrhythmics
Cholestyramine, neomycin
*Macrolide antibiotics
Keto- and intraconazole
*Cholestyramine
Calcium antagonists
*Neomycin
Cyclosporine, indomethacin
*Keto- and intraconazole
HMG CoA reductase inhibitors
*Calcium antagonists
Benzodiazepines
*Cyclosporine, indomethacin
Amiodarone
*HMG CoA reductase inhibitors
Verapamil
*Benzodiazepines
|Rifampicin
*Amiodarone
Antacids (liquid)
*Verapamil
|valign="top"|
*Rifampicin
*Antacids (liquid)
|-
|-
|Warfarin
!Warfarin
|Furosemide
|valign="top"|
Amiodarone
*Furosemide
Sulfa, macrolide and quinolone  
*Amiodarone
antibiotics
*Sulfa
NSAIDs
*Macrolide and quinolone antibiotics
|Azathioprine
*NSAIDs
Phenobarbitone
|valign="top"|
Carbamazepine
*Azathioprine
Dexamethasone
*Phenobarbitone
Prednisolone
*Carbamazepine
Rifampicin
*Dexamethasone
Vitamin K
*Prednisolone
Raloxifene
*Rifampicin
*Vitamin K
*Raloxifene
|-
|-
|Clopidogrel
!Clopidogrel
|Rifampicin
|valign="top"|
Caffeine
*Rifampicin
Methylxanthines
*Caffeine
Phosphodiesterase inhibitors
*Methylxanthines
|Statins
*Phosphodiesterase inhibitors
Calcium channel blockers
|valign="top"|
Warfarin
*Statins
Proton pump inhibitors
*Calcium channel blockers
*Warfarin
*Proton pump inhibitors
|-
|-
|Furosemide
!Furosemide
|
|
|NSAIDs
|valign="top"|
Phenytoin
*NSAIDs
Colesevelam
*Phenytoin
*Colesevelam
|-
|-
|ACE Inhibitors
!ACE Inhibitors
|NSAIDs
|valign="top"|
Probenecid
*NSAIDs
Calcium channel blockers
*Probenecid
|Indomethacin
*Calcium channel blockers
Antacids
|valign="top"|
*Indomethacin
*Antacids
|-
|-
|β-blockers
!ß-blockers
|Amiodarone
|valign="top"|
Calcium channel blockers
*Amiodarone
Diltiazem
*Calcium channel blockers
Phenoxybenzamine
*Diltiazem
|Phenobarbital
*Phenoxybenzamine
Rifampicin
|valign="top"|
Cimetidine
*Phenobarbital
Antacids (liquid)
*Rifampicin
NSAIDs
*Cimetidine
*Antacids (liquid)
*NSAIDs
|-
|-
|Statins
!Statins
|Amiodarone
|valign="top"|
Verapamil
*Amiodarone
Fibrates
*Verapamil
Amprenavir
*Fibrates
Diltiazem
*Amprenavir
|Nevirapine
*Diltiazem
Rifampicin
|valign="top"|
*Nevirapine
*Rifampicin
|}
|}


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!Inducers (e.g.)
!Inducers (e.g.)
|-
|-
|CYP2C19
!CYP2C19
|Clopidogrel
|valign="top"|
Propranolol
*Clopidogrel
Warfarin
*Propranolol
|Moclobemide
*Warfarin
Chloramphenicol
|valign="top"|
Many anti-convulsants (Valproate)
*Moclobemide
Proton pump inhibitors (Omeprazole)
*Chloramphenicol
|Rifampicin
*Many anti-convulsants (Valproate)
Carbamazepine
*Proton pump inhibitors (Omeprazole)
Prednisone
|valign="top"|
*Rifampicin
*Carbamazepine
*Prednisone
|-
|-
|CYP3A4
!CYP3A4
|Donepezil
|valign="top"|
Statins (Atorvastatin)
*Donepezil
Ca-channel blockers (Nifedipine)
*Statins (Atorvastatin)
Amiodarone
*Ca-channel blockers (Nifedipine)
Dronedarone
*Amiodarone
Quinidine
*Dronedarone
PDE5 Inhibitors (Sildenafil)
*Quinidine
Kinins
*PDE5 Inhibitors (Sildenafil)
Caffeine
*Kinins
Eplerenone
*Caffeine
Propranolol
*Eplerenone
Salmeterol
*Propranolol
Warfarin
*Salmeterol
Clopidogrel
*Warfarin
|Protease inhibitors (Ritonavir)
*Clopidogrel
Macrolides (Clarithromycin)
|valign="top"|
Chloramphenicol
*Protease inhibitors (Ritonavir)
Nefazodone
*Macrolides (Clarithromycin)
Some Ca-channel blockers (Verapamil)
*Chloramphenicol
Cimetidine
*Nefazodone
Some azole anti-fungals (Ketaconazole)
*Some Ca-channel blockers (Verapamil)
Grapefruit juice
*Cimetidine
|Some anti-convulsants (Carbamazepine)
*Some azole anti-fungals (Ketaconazole)
Baribiturates (Phenobarbital)
*Grapefruit juice
St. John’s Wort
|valign="top"|
Some reverse transcriptase inhibitors (Efavirenz)
*Some anti-convulsants (Carbamazepine)
Some Hypoglycaemics (Pioglitazone)
*Baribiturates (Phenobarbital)
Glucocorticoids
*St. John’s Wort
Modafinil
*Some reverse transcriptase inhibitors (Efavirenz)
*Some Hypoglycaemics (Pioglitazone)
*Glucocorticoids
*Modafinil
|-
|-
|CYP2C9
!CYP2C9
|Fluvastatin
|valign="top"|
Angiotensin receptor II agonists (losartan)
*Fluvastatin
Warfarin
*Angiotensin receptor II agonists (losartan)
Torasemide
*Warfarin
|Some azole anti-fungals (Fluconazole)
*Torasemide
Amiodarone
|valign="top"|
Antihistamines (Cyclizine)
*Some azole anti-fungals (Fluconazole)
Chloramphenicol
*Amiodarone
Fluvastatin
*Antihistamines (Cyclizine)
Fluvoxamine
*Chloramphenicol
Probenecid
*Fluvastatin
Sertraline
*Fluvoxamine
|Rifampicin
*Probenecid
Secobarbital
*Sertraline
|valign="top"|
*Rifampicin
*Secobarbital
|-
|-
|CYP2D6
!CYP2D6
|β-blockers (Propranolol)
|valign="top"|
Class I anti-arrythmics (Flecainide)
*ß-blockers (Propranolol)
Donepezil
*Class I anti-arrythmics (Flecainide)
|SSRIs (Fluoxetine)
*Donepezil
Quinidine
|valign="top"|
Sertraline
*SSRIs (Fluoxetine)
Terbinafine
*Quinidine
Amiodarone
*Sertraline
Cinacalcet
*Terbinafine
Ritonavir
*Amiodarone
Antipsychotics (Haloperidol)
*Cinacalcet
Antihistamines (Promethazine)
*Ritonavir
Metoclopramide
*Antipsychotics (Haloperidol)
Ranitidine
*Antihistamines (Promethazine)
Mibefradil
*Metoclopramide
|Rifampicin
*Ranitidine
Dexamethasone
*Mibefradil
Glutethimide
|valign="top"|
*Rifampicin
*Dexamethasone
*Glutethimide
|}
|}


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!Indications
!Indications
!Typical Dosage
!Typical Dosage
!Guidelines/Class of Indication !Side Effects (Prevalence %)
!Guidelines/Class of Indication
!Side Effects (Prevalence %)
|-
|-
|Anti-hypertensives
|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
|
|Oedema
|Furosemide: 20-40mg once daily
|
|
|-
|
|Diuretics
|Furosemide
|Resistant Hypertension
|Furosemide: 40-80mg once daily
|ESC Guidelines (European Heart Journal
doi:10.1093/eurheartj/ehs104):
doi:10.1093/eurheartj/ehs104):
Hypertension in symptomatic (NYHA class II-IV) HF and LVD: Class IC
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)
|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).
Hypertension: Class IA
|-
|
|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
ESC Guidelines (European Heart Journal
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ESC Guidelines: (European Heart Journal
ESC Guidelines: (European Heart Journal
doi:10.1093/eurheartj/ehs092):
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.
Hypertension in diabetics: Class IA
Heart Failure Captopril: 12.5mg 3 times daily ESC Guidelines (European Heart Journal (2012) 33, 2569–2619
|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):  
doi:10.1093/eurheartj/ehs215):  
Post STEMI: Class IA
Post STEMI: Class IA
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Symptomatic (NYHA class II-IV) HF: Class IA
Symptomatic (NYHA class II-IV) HF: Class IA


Acute heart failure with ACS: 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)
|
|
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|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
Hypertension: Class IA


ESC Guidelines: (European Heart Journal
ESC Guidelines: (European Heart Journal
doi:10.1093/eurheartj/ehs092):
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;
Hypertension in diabetics: Class IA
Left ventricular hypertrophy Losartan: 12.5-150mg daily ESC Guidelines (European Heart Journal (2012) 33, 2569–2619
|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):  
doi:10.1093/eurheartj/ehs215):  
LVH:  Class IB
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
|
|
|
|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
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  
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  
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