1330 Cardiovascular

2. Shawkett S, et a!. Prolonged effect of CGRP in Raynaud's patients: a I up to 6 years: initially 200 micrograms/kg daily, • double-blind randomised comparison with prostacyclin. Br J Clin adjusted according to response to 50 to 400 micro­ Pharmacol i99I; 32: 209-13. 3. Shekhar YC, et a!. Effects of prolonged infusion of human alpha grams/kg daily calcitonin gene-related peptide on haemodynamics, renal blood flow 6 up to 17 years and weighing less than 50 kg: initially 4 • Profile and hormone levels in congestive heart failure. Am J Cardiol i99I; 67: to 8 mg daily, adjusted according to response to 2 to 732-6. 16mg daily Butizide is a thiazide diuretic with properties similar to those 4. European CGRP in Subarachnoid Haemorrhage Study Group. Effect of 6 up to 17 years and weighing more than 50 kg: initially 8 of hydrochlorothiazide (p. 1403.2). It is used for oedema, calcitonin-gene-related peptide in patients with delayed postoperative • including that associated with heart failure (p. 1262.3), and cerebral ischaemia after aneurysmal subarachnoid haemorrhage. Lancet to 16 mg daily, adjusted according to response to 4 to 1992; 339: 831-4. lor hypertension (p. 1251.1). 32 mg daily 5. Bunker CB, et al. Calcitonin gene-related peptide in treatment of severe Butizide is given orally, usually with spironolactone; the peripheral vascular insufficiency in Raynaud's phenomenon. Lancet usual maintenance dose for oedema or hypertens:cn is 5 to 1993; 342: 80-2. Administration in hepatic impairment. The elimination of 10 mg daily. It has also been given with other aatihyper­ 6. Feuerstein G, et al. Clinical candesartan cilexetil is reduced in patients with hepatic peptide pharmacology. Can tensive drugs. impairment. For patients with hypertension, an initial oral 7. Gherardini G, et al. Venous ulcers: improved healing by iontophoretic dose of 4mg once daily is recommended in the UK in administration of calcitonin gene-related peptide and vasoactive those with mild or moderate impairment. In the USA, no Preparations intestinal peptide. Plast Reconstr Surg 1998; 101: 90-3...... M3rquez-Rodas I, Pathophysiology and therapeutic possibilities of adjustment is considered necessary for patients with mild . 8. et a/. Proprietary Preparations (details are given in Volume B) calcitonin gene-related peptide in hypertension. J Physiol Biochem 2006; impairment; an initial oral dose of 8 mg once daily is 62: 45-'56. recommended for those with moderate impairment. Multi-ingredient Preparations. Austria: Aldactone Saltudn; 9. Recober A, Russo AF. Calcitonin gene-related peptide: an update on the For patients with heart fa ilure, no dose adjustments are Indon.: Aldazide; Ita!. : Kadiur; Mex. : Aldazida; Philipp.: Alda­ biology. Curr Opin Neurol 2009; 22: 241-6. zide; S.Afr. : Aldazide; Switz.: Aldozonet. considered necessary in those with mild to moderate impairment as initial doses are lower for this condition (see Candesartan Cilexetil Uses and Administration, above). Cadralazine (BAN, r/NNJ There is no experience of use in patients with severe hepatic impairment.

Administration in renal impairment. The elimination of candesartan cilexetil is reduced in patients with renal impairment (including patients on haemodialysis1) and lower doses may therefore be required. For patients with hypertension, an initial oral dose of 4 mg once daily is recommended in the UK, including for patients on haemodialysis. In the USA, no initial dose adjustment is recommended for renal impairment, although dose reduction may be considered if patients are volume depleted. cadralazine. For patients with heart fa ilure, dose adjustments are not necessary as initial doses are lower for this condition (see Profile Uses and Administration, above). Candesartan may also have adverse effects on renal Cadralazine is a vasodilator with actions and uses similar to Ph. Eur.8: (Candesartan Cilexetil). A white or ahnost white function and regular monitoring is advised; treatment may those of hydralazine (p. 1401.2). It used has been in the powder. It exhibits polymorphism. Practically insoluble in need to be withheld or stopped if renal function management of hypertension. water; slightly soluble in dehydrated alcohol; freely soluble deteriorates. Reviews. in dichloromethane. 1. Ottosson P, et al. Candesartan cilexetil in haemodialysis patients. Clin l. McTavish D, et at. Cadralazinc: a review of its pharmacodynamic and Drug Invest 2003; 23: 545-50. pharmacokinetic properties, and therapeutic potential in the treatment USP 36: (Candesartan Cilexetil). A white to off-white of hypertension. Drugs 1990; 40: 543-60. powder. Practically insoluble in water; sparingly soluble in For mention of the potential use methyl alcohol. Store in airtight containers at a temperature Diabetic complications. of angiotensin II receptor antagonists, including candesar­ between 20 degrees and 25 degrees, excursions permitted tan, in the management oi diabetic complications such as between 15 degrees and 30 degrees. retinopathy see under Losartan, p. 1423.1.

Uses and Administration Migraine. For reference to the use of angiotensin II recep­ Candesartan is an angiotensin II receptor antagonist with tor antagonists, including candesartan, in the prophylaxis actions similar to those of losartan (p. 1422.2). It is used in of migraine, see under Losartan, p. 1423.3. the management of hypertension (p. 1251.1) and may also be used in heart failure in patients with impaired left Adverse Effects and Precautions ventricular systolic function, either when ACE inhibitors As for Losartan Potassium, p. 1424.1. are not tolerated, or in addition to ACE inhibitors, (see under Losartan Potassium, p. 1423.2). Porphyria. The Drug Database for Acute Porphyria, com­ Candesartan is given orally as the ester prodrug piled by the Norwegian Porphyria Centre (NAPOS) and candesartan cilexetil. Onset of antihypertensive action the Porphyria Centre Sweden, classifies candesartan as not occurs about 2 hours after a dose and the maximum effect is porphyrinogenic; it may be used as a drug of first choice achieved within about 4 weeks of starting therapy. and no precautions are needed. 1 Profile In the management of hypertension the usual initial dose of candesartan cilexetil is 8 mg once daily in the UK, or 1. The Drug Database for Acute Porphyria. Available at: http://www. drugs-porphyria.org (accessed 13/10/ll) Cafedrine hydrochloride is a derivative of theophylline 16 mg once daily in the USA. The dose should be adjusted (p. 1229.3), used mainly in preparations with theodrenaline according to response; the usual maintenance dose is 8 mg Interactions hydrochloride in the treatment of hypotensive states. once daily, but doses up to 32 mg daily, as a single dose or in 2 divided doses, may be used. Lower initial doses should be As for Losartan Potassium, p. 1424.3. P.r.�P.?.r?li()_n.S.. considered in patients with intravascular volume depletion; Proprietary Preparations (details are given in Volume B) in the UK an initial dose of 4 mg once daily is suggested. Pharmacokinetics Patients with renal or hepatic impairment n1ay also require Multi-ingredient Prepara�ons. Austria: Akrinort: Fr.: low initial doses (see below). For doses in children, see Candesartan cilexetil is an ester prodrug that is hydrolysed Ger.: Akrinor; Indon.: Akrinor; S.Afr. : Akrlnor. Administration in Children, below. to the active form candesartan during absorption from the In heart failure, candesartan cilexetil is given in an gastrointestinal tract. The absolute bioavailability for initial dose of 4 mg once daily. The dose should be doubled candesartan is about 40% when candesartan cilexetil is Calcitonin Gene-related Peptide at intervals of not less than two weeks up to 32 mg once given as a solution and about 14% when given as tablets. daily if tolerated; blood pressure should be monitored Peak plasma concentrations of candesartan occur about 3 to during dose increases. 4 hours after oral doses as tablets. Candesartan is more than 99% bound to plasma proteins. It is excreted in urine and Reviews. bile mainly as unchanged drug with a small amount as blocker. inactive metabolites. The terminal elimination half-life is 2. Easthope SE, Jarvis Candesartan cilexetil: an update of its use in about 9 hours. Candesartan is not removed by haemodia­ Profile 62: essential hypertension. Drugs 2002; 1253-87. lysis. Calcitonin gene-related peptide is an endogenous peptide 3. Fenton C, Scott U. Candcsartan cilexetil: a review of its use in the management of chronic heart failure. Drugs 2005; 65: 537-58. Reviews. derived £rmn the calcitonin gene. It has vasodilating activity 4. McKelvie RS. Candesartan for the of heart failure: more I. Gleiter CH, Mi:irikeKE. Clinical pharmacokinetics of candesartan. Clin and has been investigated in the management of peripheral than an alternative. Expert 7: 194'5-56. Pharmacokinet 2002; 41: 7-17. vascular disease (Raynaud's syndrome), heart failure, and 5. Meredith PA. Candesanan review of elfects on cardiovas- for ischaemia following neurosurgery for subarachnoid <."ular complications in hypertension and chronic heart failure. Cun Med Res Opin 2007; 23: 1693-1705. haemorrhage. The endogenous substance may be involved 6. Mendis B, Page SR. Candcsartan: Proprietary Preparations (details are given in Volume B) in the pathophysiology of headache and migraine, and angiotensin II receptor blocker? Expert Opin antagonists are under investigation in the 1nanagement of 1995-2007. Single-ingredient Preparations. Arg.: Atacand; Dacten; Tiadyl; these conditions. Austral.: Atacand; Austria: Atacand; Blopress; Belg.: Atacand; Administration in children. Candesartan cilexetil is used Braz.: Atacand; Blopress; Canad.: Atacand; Chile: Atacand; References. for the treatment of hypertension in children from 1 year (�1Z, JfX); Johnston FG, et a!. Effect of calcitonin-gene-related peptide on Bilaten; Blopress; Blox; Candex; China: Ao Bi Xin L (&,ii'>Wi); om"ooem,tivc neurological deficits aher subarachnoid haemorrhage. of age. It is given in the following oral doses, either as a Blopress Eo Li Gao (j;!l;/Jill'J); Da Mai (it:ia); Di Zhi 335: 869-72. single daily dose or in 2 divided doses: Ya Ni Li An (f!C.fU'ti'); Su Na Wei Er Ya (ilt!J; 1 (ii1!Z1'it); (JHJ!J);

All cross-references refer to entries in Volu1ne A Cadralazine/Captopril 1331

!111); Xi Jun Ning (�i!'t'i'); Cz.: Atacandt; Texacand; Xaleec; given in usual doses of 50 to 200 mg daily. Doses of up to twice daily is recommended if captopril is given in addition Denm.: Amias; Atacand; Candemox; Candexetilt; Fin.: Ata­ 300 mg daily may be required in some patients. to a diuretic or to elderly patients; if possible the diuretic cand; Candemox; Candestad; Candexetil; Kandrozid; Fr. : Ata­ should be stopped 2 or 3 days before introducing captopril. cand; Kenzen; Ger.: Atacand; Blopress; Gr.: Atacand; Hong The usual maintenance dose is 25 to 50mg twice daily and Kong: Blopress; Hung.: Atacand; India: Candelong; Candesar; � . . �� F.��.!��.�� ...... should not normally exceed 50mg three times daily. If Candestan; Cantar; Ipsita; Indnn.: Blopress; Irl. : Atacand; Blo· Proprietary Preparations (details are given in Volume B) hypertension is not satisfactorily controlled at this dosage, press; Candist; Catasart; Israel: Atacand; Ital. : Blopress; Rata­ addition of a second drug or substitution of an alternative cand; Jpn: Blopress; Malaysia: Atacand; Blopress; Mex. : Ata­ Single-ingredient Preparations.Ita/. : Luvion. cand; Blopress; Neth.: Aldireca; Amiast; Atacand; Blopress; drug should be considered. In the USA higher doses of up to Casarlic; Kairasec; Karbis; Omegacand; Ratacandt; Silardaf; !50 mg three times daily have been suggested for patients Texacand; Norw.: Amias; Atacand; NZ: Atacand; Cardosart; with hypertension uncontrolled by lower doses of captopril Philipp.: Blopress; Candelong; Candez; Pol. : Atacand; Karbis; used with diuretic therapy. Port.: Atacand; Blopress; Rus.: Atacand (ATarhypotension on introduction of an ACE inhibitor is Parapres; Swed.: Atacand; Candesarstad; Candexetil; Switz. : ·common in patients on loop diuretics, but their temporary Atacand; Blopress; Cansartan; Pemzek; Thai.: Blopress; Turk.: withdrawal may cause rebound pulmonary oedema. Thus Atacalid; Ayra; Candexil; Cantab; Tensart; UK: Amias; Ukr.: an initial oral dose of 6.25 to 12.5 mg of captopril is given Atacand (ATaKaH,ll); Candesar (Krumecap); Kasark (KacapK); under close medical supervision; the usual maintenance USA: Atacand; Candepressin; Venez. : Atacand; Blopress. dose is 25 mg two or three times daily, and doses should not Multi-ingredient Preparations. Arg.: Atacand D; Atacand Duo; normally exceed 50 mg three times daily. Again, in the USA Dacten D; Tiadyl Plus: Austral. : Atacand Plus; Austria: Atacand higher doses of up to !50 mg three times daily have been Plus; Blopress Plus; Be/g.: Atacand Plus; Braz.: Atacand Comb; NOTE. Compounded preparations of captopril may be suggested. Atacand HCT; Canad.: Atacand Plus; Chile: Atacand Plus; Bila· represented by the following names: After myocardial infarction, captopril is used Co-zidocapt (BAN)-captopril 2 parts and hydrochloro- ten-D; Blopress D; Blox-D; Candex-D; China: Bokaiqing (�7f • prophylactically in clinically stable patients with sympto­ i!!l); Cz. : Atacand Plust; Texacandozid; Xaleec Combi; Denm.: thiazide 1 pan (w/w). matic or asymptomatic left ventricular dysfunction to Atacand Zid; Atazidt; Candemox Comp; Candexetil comp; Pharmacopoeias. In Chin., Bur. (see p. vii), Int., Jpn, and US. improve survival, delay the onset of symptomatic heart Hytacand; Ratacand Plus; Ratacand Zidt; Fin.: Atacand Plus; Ph. Eur.8: (Captopril). A white or almost white crystalline failure, and reduce recurrent infarction. Captopril is Candemox Comp; Candestad Comp; Candexetil Comp; Fr. : licensed for acute treatment starting within 24 hours of the Cokenzen; Hytacand; Ger.: Atacand Plus; Blopress Plus; Gr.: powder. Soluble in water; freely soluble in dichloromethane onset of symptoms in patients with stable haemodynamics. Atacand Plus; Hong Kong: Blopress Plus; Hung. : Atacand Plus; and in methyl alcohol. lt dissolves in dilute solutions of A 6.25-mg test dose is given, followed by 12.5 mg after 2 India: Candelong-H; Candesar-H; Indon.: Blopress Plus; Irl. : alkali hydroxides. A 2% solution in water has a pH of 2.0 to hours, and 25 mg after another 12 hours. If tolerated, a dose Atacand Plus; Blopress Plus; Candist Plus; Catasart Plus; Israel: 2.6. of 50 mg twice daily may be started the following day and Atacand Plus: Candesartan Plus; Ita/.: Blopresid; Ratacand Plus; USP 36: (Captopril). A white or off-white crystalline powder Jpn: Malaysia: continued for 4 weeks, before considering adjustment to the Unisia; Atacand Plus; Mex. : Atacand Plus; Blo­ which may have a characteristic sulfide-like odour. Freely Neth.: maintenance dose for chronic treatment described below. press Plus; Atacand Plus; Blopresid; Cocardax; Omega­ soluble in water, in alcohol, in chloroform, and in methyl cand HCT; Texacand HCT; Norw. : Atacand Plus; Philipp.: Blo­ If not given within 24 hours of the onset of symptoms, alcohol. Store in airtight containers. press Plus; Pol.: Candepres HCT; Port.: Blopress Comp; chronic treatment with captopril may be started within 3 to Hytacand; Rus.: Atacand Plus (ATarCangrelor Tetrasodium (BANM, USAN, r/NNM) they advise that since it contains no preservative it should be used within 2 days of preparation.• Others have Administration. Captopril is generally given orally. Sublin­ reponed wide variations in stability depending upon the guaP and intravenous2'' dosage has also been tried, but formulation. In one study' the shelf-life of a solution of these routes are not established. captopril 1 mg/mL prepared from crushed tablets and tap 1. Angeli P, et al. Comparison of sublingual captopril and nifedipine in water was estimated to be 27 days when stored at 5 immediate treatment of hypertensive emergencies: a randomized, degrees. However, in another study' captopril was much single-blind clinical trial. Arch InternMed 1991; 151: 678--82. less stable; in sterile water for itrigation captopril was 2. Savi L, et a[. A new therapy for hypertensive emergencies: intravenous stable for at least 3 days when stored at 5 degrees, but in captopril. Curr Ther Res 1990; 47: 1073-8 1. 3. Langes K, et al. Efficacy and safety of intravenous captopril in congestive tap water it disappeared at a much faster rate. Increased heart failure. Curr Ther Res 1993; 53: 167-76. stability has been reponed after the addition of sodium ascorbate to the solution, 7 and with captopril powder Administration in children. Experience with captopril in rather than crushed tablets.• A 1 mg/mL preparation made children is limited, but it may be given orally for indica­ with crushed tablets and undiluted syrup has also been Profile tions similar to those in adults (see Uses and Administra­ reponed to be stable for 30 days at 5 degrees and may be tion, above). UK licensed product information suggests an Cangrelor is an adenosine triphosphate analogue, similar to more palatable than aqueous formulations.• initial dose of 300 micrograms/kg in children and adoles­ ticagrelor (p. 1511.3). It has a short half-life and is given 1. Lund W, Cowe HJ. Stability of dry powder formulations. 1986; Pharm J cents; half this dose should be given initially to neonates intravenously. It is under investigation as an antiplatelet 237: 179-80. and infants (including premature infants), and children drug in the management of acute coronary syndromes but 2. Taketomo CK. et al. Stability of captopril in powder papers under three storage conditions. Am J Hosp Pharm 1990; 47: 1799-1801. with renal impairment. The dose is adjusted according to large studies have not shown any benefit over currently 3. TimminsP, et al. Factors affecting captopril stability in aqueous solution. response to a maximum of 6 mg/kg daily in 2 or 3 divided available drugs. Int J Pharmaceutics 1982; 11: 329-36. doses. 4. Andrews CD, Essex A. Captopri.l suspension. Pharm J 1986; 137: 734-5. References. 5. Pereira CM, Tam YK. Stability of captopril in tap water. Am J Hosp Pharm Captopril, given in an initial dose of 250 micrograms/kg 1. Harrington RA, et al. Platelet inhibition with cangrelor in patients 1992; 49: 612-15. daily, increased to up to 2.5 or 3.5 mg/kg daily in 3 divided undergoing PCI. N Engl J Med 2009; 361: 2318--29. 6. Anaizi NH, Swenson C. Instability of aqueous captopril solutions. Am J 2. Bhatt DL, et al. CHAMPION PLATFORM Investigators. Intravenous doses, has also been reponed to produce benefit in infants Hosp Pharm 1993; 50: 486-8. platelet blockade with cangrelor during PCI. N Eng! J Med 2009; 361: with severe heart failure secondary to congenital defects 7. Nahata MC, et al. Stability of captopril in three liquid dosage forms. Am J 2330-41. Hosp Pharm 1994; 51: 95-6. (mainly manifesting as left-to-right shunt).1•2 8. Chan DS, et al. Degradation of captopril in solutions compounded from The following doses of captopril are suggested by the tablets and standard powder. Am J Hosp Pharm 1994; 51: 1205-7. BNFC for hypertension, heart failure, or proteinuria in Canrenone (USAN, pJNN! 9. Lye MYF, et al. Effects of ingredients on stability of captopril in nephritis: ® extemporaneously prepared oral liquids. Am J Health-SystPharm 1997; neonate: test dose, 10 to 50 micrograms/kg (if the 54: 2483-7. • neonate is less than 3 7 weeks postmenstrual age give I 0 Uses and Administration micrograms/kg) with careful monitoring of blood pressure for I to 2 hours; if tolerated, give I 0 to Captopril is a sulfhydryl-containing ACE inhibitor 50 micrograms/kg 2 or 3 times daily, increased as (p. 1282.2). It is used in the management of hypertension necessary to a maximum of 2 mg/kg daily in divided (p. 1251.1), in heart failure (p. 1262.3), after myocardial doses (maximum of 300 micrograms/kg daily in divided infarction (p. 1257.1), and in diabetic nephropathy (see doses if the neonate is less than 37 weeks postmenstrual Kidney Disorders, p. 1284.1). age) After oral doses captopril produces a maximum effect child I month to 12 years: test dose, 100 micrograms/kg • within 1 to 2 hours, although the full effect may not develop (maximum 6.25 mg) with careful monitoring of blood Profile for several weeks during chronic dosing. The duration of pressure for I to 2 hours; if tolerated, give 100 to action is dose-dependent and may persist for 6 to 12 hours. 300 micrograms/kg 2 or 3 times daily, increased as Canrenone is a potassium-sparing diuretic with properties In the treatment of hypertension the initial oral dose is necessary to a maximum of 6 mg/kg daily in divided similar to those of spironolactone (p. 1501.2) and is given 12.5 mg twice daily, increased gradually at intervals of 2 to 4 doses (maximum of 4 mg/kg daily in divided doses in orally in the treatment of refractory oedema assodated with weeks according to the response. Since there may be a child I month to 1 year) heart failure (p. 1262.3), renal, or hepatic disease, and in precipitous fail in blood pressure in some patients when child 12 years to 18 years: test dose, 100 micrograms/kg • hypertension (p. 1251.1). It is a metabolite of both starting therapy with an ACE inhibitor, the first dose should or 6.25 mg with careful monitoring of blood pressure for spironolactone and potassium canrenoate (p. 1472.2). It is preferably be given at bedtime. An initial dose of 6.25 mg 1 to 2 hours; if tolerated, give 12.5 to 25 mg 2 or 3 times

The symbol t denotes a preparation no longer actively marketed The symbol ® denotes a substance whose use may be restricted in certain sports (see p. viii)