Hypertension ============ þ Treating HTN in the ED - Cherney et al: meta-analysis, studies not good; suggest using urapadil (only in EU) or nipride, ? avoid nifedipine - Fries et al 1987: RCT of 143 pts, DBP 115-120: need followup within 2 months - Preston, 1989: retrospective chart review: 89/91 treated in ED, but most noncompliant with F/U even if set up from the ED. Complications common, but related to noncompliance. Criticized clonidine and nifedipine as unreliable agents to start in ED. Conclusion: treat in ED but don't wait to check BP. Shane, AEM: "hypertensive urgency" doesn't really exist, but someone with previous CVA, AAA: with increased risk might need treatment. Suggest new term: "Uncontrolled severe HTN": 160/120, no end organ damage. þ "Regression to the Mean" - Pitts and Adams: if have high BP, rechecks seem to be lower, confirmed by retrospective study. - Lima et al: placebo vs. nifedipine had same drops in ED BP - Neilsen et al: 27% with ^ DPB, placed in dark room for 30-45 minutes, DPB much better. þ Are ^ BP in ED Reliable? - Becker et al: 12% of those with HTN in ED had JNC VI state 3 HTN; not related to pain. - Chernow et al, 1989: outpatient followup: 35% (about 1/3) of those with HTN in ED had HTN on followup. þ JNC VI Criteria - Stage I HTN: >= 140/90 - Stage II HTN: >= 160/100, treat with two drugs (i.e., in ED, contact PCP and arrange for followup and start PCP's choice of drugs) þ Definition: - Urgency: DBP > 120 no end organ damage; reduce in 24-48 hours - Emergency: HTN with end-organ damage, reduce in 1-2 hrs - Malignant/Accelerated: retinal hemorrhages, exudates, papilledema (as of 2003, lumped together) þ Common antihypertensives ACE antagonists and inhibitors (all known to cause angioedema): ANGIOTENSIN II RECEPTOR ANTAGONISTS (MedLtr updated 8/5/02) 30-day cost Candesartan cilexetil - Atacand 16-32 mg once $43.40 Eprosartan - Teveten 600-800 mg once or 80 mg divided 41.14 Irbesartan - Avapro (Bristol-Myers Squibb) 150-300 mg once 45.80 Losartan - Cozaar (Merck) 25-100 mg once or divided 45.44 Olmesartan medoxomil - Benicar 20-40 mg once 39.38 Telmisartan - Micardis 40-80 mg once 45.21 Valsartan - Diovan (Novartis) 80-320 mg once 43.98 ACE INHIBITORS Benazepril - Lotensin (Novartis) 20-40 mg once or divided 21.67 Captopril - generic price 25-150 mg bid or tid 4.00 Capoten - (Bristol-Myers Squibb) 48.95 Enalapril - Vasotec (Merck) 10-40 mg once or divided 32.09 Fosinopril - Monopril (Bristol-Myers Squibb)20-40 mg once or divided 24.87 Lisinopril - Prinivil (Merck); 20-40 mg once 27.11 Zestril (Stuart) 27.14 Moexipril - Univasc (Schwarz) 7.5-30 mg once or divided 15.80 Quinapril - Accupril (Parke-Davis) 20-80 mg once or divided 28.50 Rarnipril - Altace (Hoechst Marion Roussel) 2.5-20 mg once or divided 23.35 Trandolapril - Mavik (Knoll) 2-4 mg once or divided 18.76 Hypertensive Emergencies ------------------------ þ Clues to emergency: - Shea at all: no PCP, less so noncompliance, lack of insurance - Hymean et al: Age > 65, Black/Hispanic, poor awareness, noncompliant with PCP visits. þ Clues to a Hypertensive Emergency: - Diastolic over 130-140 - Headache - Weight loss (Na+ wasting) - Visual changes (blurry vision) - Altered mental status - CHF (pulmonary edema); may not be fluid overload - Hx of renal artery stenosis - Smoking - Oral Contraceptives þ Diagnosing a Hypertensive Emergency: - DBP over 130-140 - history, including headache, chest pain, neurological symptoms - physical exam, including funduscopic for hemorrhages or papilledema - dip urine for blood (per Dr. Richard O. Gray of Hennepin Co. Medical Center, MN, hypertensive renal disease will invariably show hematuria as well as increasing BUN/CR and a urine dip is a quick screen for this.) þ Acute HTN syndromes: - chronic HTN, off meds - young, acute onset (often women on BCPs) - encephalopathy -------------- + change in mental status + rarest; renal ischmia may be cause (Angiontensin II), no nipride or hydralazine may not be good + diastolics often 150-160 + goal is to decrease BP about 25% + headache, nausea, vomiting + minority may not have papilledema + TIA-like pattern, may resolve as BP lowers + admit to ICU + current drug of choice: Nipride (only use drug that can easily be reversed, to avoid steal syndromes or CVA); use only IV continous infusion. + Rx: Nipride (good), trimethaphan (may get overshoot; very potent); nicardipene (Cardene; protective for heart and watershed areas of brain) avoid clonidine and methyldopa (Aldomet) as may cloud CNS exam. - HTN and CVA ----------- + if know that HTN preceded CVA, treat HTN (HTN causative) + if know that HTN after CVA, don't treat HTN (HTN protective) + if don't know, but has bleed on CT and either comatose or evidence of compression on CT, treat HTN + traditional: reduce BP 25% or to DBP of 100 _now disproven_ instead: reduce systolic by 30-40, diastolic by 10-20 - HTN and MI and pulmonary edema ------------------------------ + ACE inhibitors helpful, maybe also beta blockers + give NTG IV (may be enough; if so, likely need to treat fluid overload); + if need to treat more, start nitroprusside (Nipride), but may want to avoid as primary treatment as may cause coronary steal and worsen ischemia + 10-15% reduction often adequate - HTN and pregnancy ----------------- + incidence 7% in US (low in Japan, high in Africa, high with low socioeconomic status in U.S.) + not highly associated with chronic hypertension + proteinuria, rise of 20 systolic, 10 diastolic + mild: no symptoms, can treat as outpatient + severe: neuro symptoms, decrease DPB to about 100 + Mg++: treats seizures, only slightly lowers BP (use large amounts; 6g over 15 minutes to start; monitor by checking reflexes) + hydralazine: drug of choice, but now discontinued; have enough through 1995; nicardipine being studied. + Nipride: avoid, as steals blood from placenta - Workup: CXR, CBC, EKG, lytes/BUN/Creatinine þ Pathophysiological theory: - BP finally overcomes autoregulatory ability of organ system þ Coronary Steal: Peripheral vasodilitation decreasing coronary perfusion pressure; 1-2 case reports of CP with nifedipine. þ HTN and chest pain - NTG, Nipride - avoid labetalol if CHF þ Aortic dissection: see also - treat quickly: want to decrease aortic pulse wave; just vasodilating not adequate - beta blocker (or calcium blocker) to pulse of 60-70: + propanolol, but IV propanolol has large variability in patient response; may need 15-20 mg (_large_ dose) + metoprolol + esmolol: selective beta-1, may need nipride as well + Labetalol (but not as good as Esmolol, because has some alpha effects but not enough to be single agent), "I like labetalol for aortic dissections for a few reasons: 1) At 1% death per hour risk, I don't even want to wait 15 minutes to order, set up, and get in an esmolol drip, which must be given BEFORE the nipride in order to ensure shear forces do not increase with therapy, worsening the situation. Labetalol is titrateable, quick, easy, and effective. Further, I have not _yet_ seen it cause anyone's BP to plummet when given for this purpose. 2) I believe it is cheaper than esmolol (not really a consideration for me in cases of aortic dissection, but others may appreciate this). 3) Effective as single drug therapy - you do not have to titrate up the esmolol until the patient is effectively beta-blocked, then add the nipride and titrate it as well. This double titration can lead to prolonged time before effective BP control is acheived. 4) Esmolol still has a half-life of 9 minutes or so, not just seconds like nipride. If you overly drop someone's pressure, that would be a long time to wait, though granted not as long as waiting for labetalol to wear off." --Jon Handler, M.D. + (verapamil OK if bad COPD or asthma) - additional antihyertensive if needed to get diastolic down to 110-120 + nipride + trimethaphan (Arfonad) 1-2 mg/min + labetalol 10-20 mg bolus then 1-2 mg/min + nicardipine IV infusion? - surgeons want DBP 90, internists DBP 120 - avoid diazoxide, hydralazine: increase strength of contractions þ Catecholamine-induced HTN - clonidine - pheo - cocaine (start with benzodiazepine) - EtOH withdrawal (start with benzodiazepine) Rx: Labetolol (? if paradoxical effect at low doses with pheos) OR Phentolamine and Inderal OR Nipride þ Eclampsia: - Mg Sulfate as preventive for seizures has some anti-HTN effect - Rx with hydralazine - diazoxide gives variable effects, hyperglycemia, so avoid - labetolol- may be toxic to uterus but may use for short periods - Nipride: avoid. Antihypertensive drugs ---------------------- þ diazoxide (Hyperstat): - Arterial vasodilator - Unpredictable response. - second line in HTN encephalopathy. - old dose of 300 mg push, but used to cause cardiac arrest regularly 50 mg Q 5 minutes - very popular in community - hyperglycemia in diabetics þ diuretics - may potentiate other drugs, especially Lasix (furosemide) - the combination of ACE inhibitors and potassium-sparing diuretics can cause hyperkalmia. Reference: Tintinalli 3rd ed. p 244. þ esmolol (Breviblock) - ultra-short acting beta blocker, no alpha blocker activity. þ hydralazine: - IM absorbtion erratic - drug of choice for pregnancy - avoid with cardiovascular HTN problems. - may cause severe headache þ labetalol: - slight alpha-1 and non-selective beta blocker - good for cocaine intoxication - drug of choice for high catecholamine states - 20-40 mg IVP, double q10-20' up to max 300 mg total OR, 2mg/min constant infusion. Intermittent boluses very cumbersome. - Beta blockade may worsen CHF or asthma. þ nicardipine (Cardene) - start 5-15 mg/hour drip (_not_ 20 mg/hour), no bolus needed - not much effect on conduction, decreases contractility slightly but by unstretching myocardial fibers usually increases cardiac output - not clear about affect on fetus - after turning off, BP increases, but not to pretreatment levels þ nifedipine (Procardia, Adalat) - don't use: causes problems if used for HTN without sx, and - can't be turned off like a NTG or nipride if patient does have symptoms and needs treatment [Rehman F, et al. "Inappropriate" physician habits in prescribing oral nifedipine capsules in hospitalized patients. Am J Hyperten 1996;9:1035.] [Grossman E, et al. Should a moratorium be placed on sublingual capsules given for hypertensive emergencies and pseudoemergencies? JAMA 1996;276(16):1328-1331.] - not absorbed sublingually [Van Harten J, et al. Negligible sublingual absorption of nifedipine. Lancet 1987;2(8572):1363.] þ nitroglycerine/NTG (Tridil) - vein and coronary dilatation; afterload effect at high doses - start at 10 mcg/min, ramp up 10 mcg Q3-5'. May want to bolus with SL NTG to start. þ nitroprusside (Nipride): + add Inderal to avoid secondary tachycardia + good for everything except pregnancy + start 10-30 mcg/min, ramp up as needed. + in renal or hepatic failure, watch for CN toxicity + major complications: CVA, steal syndrome, thiocyanate poisoning = fatigue, nausea, vomiting, rash (give B-12) þ phentolamine (Regitine) þ propanolol (Inderal) - nonselective beta blocker - 0.1 mg/kg on up - very wide dose sensitivity þ trimethaphan (Arfonad) - Ganglia blocker; so reverse Trendelenburg very effective - tachycardia, ileus, urinary retention. - sometimes recommended for dissection, but Inderal and phentolamine may be better - easy to overshoot - contraindicated in pregnancy - histamine release Hypertensive Urgencies ---------------------- þ nifedipine: may help CHF, but rarely may precipitate CHF, e.g., in aortic stenosis; increases cerebral blood flow, so good in encephalopathy; sublingual faster than oral (but see above), but bite and swallow faster than both. þ clonidine: 0.2 mg PO then 0.1 PO Q1H up to 0.7mg. avoid in those with second degree heart block or sick sinus; may decrease AV node conduction. References: Calhoun DA, Oparil S. Treatment of hypertensive crisis. N Engl J Med 1990;323:1177-1183. Houston MC. The comparative effects of clonidine hydrochloride and nifedipine in the treatment of hypertensive crises. Am Heart J 1988;115:152-159. O'Mailia JJ, et al. Nifedipine-associated myocardial ischemia or infarction in the treatment of hypertensive urgencies. Ann Intern Med 1987;107:185-186. Houston MC. Treatment of hypertensive emergencies and urgencies with oral clonidine loading and titration. A review. Arch Intern Med 1986;146:586-589. --------------------------------------------------------------------------- The study implicating nifedipine in excess mortality was a long term one that looked at short acting Ca blockers used over a period of time and does not apply to a single acute administration (1). There is little to choose among the available agents for p.o. use namely, nifedipine (10 or 20 mg), clonidine (0.2 mg), labetalol (up to 200 mg) and captopril (6.25 to 25 mg) . No significant differences have been seen between labetalol and clonidine (2) or between clonidine and nifedipine (3) in the treatment of urgent hypertension. Certain specific situations may suggest one therapy over another e.g., captopril for CHF or labetalol for CVA (although I would would proceed very cautiously with the latter and probably not administer anything in the field and possibly not in the ED either). Of course NTG would not be a bad choice for HTN complicating ischemia. By the way, there is no need to administer nifedipine SL as p.o. administration is at least as fast and more convienent (4). More important than the actual drug used is making sure one has a good indication for treating HTN in the field. There are relatively few indications for this. Even in the ED, HTN is overtreated, particularly in the asymptomatic population to no obvious benefit and with the assumption of some risk (5). H. Louzon MD (1) Furberg CD, Psaty BM, Meyer JV Nifedipine. Dose-related increase in mortality in patients with coronary heart disease [see comments] Circulation 1995 Sep 1;92(5):1326-31 BACKGROUND: The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur. METHODS AND RESULTS: We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality (P = .01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects. CONCLUSIONS: In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists. (2) Atkin SH, Jaker MA, Beaty P, Quadrel MA, Cuffie C, Soto-Greene ML Oral labetalol versus oral clonidine in the emergency treatment of severe hypertension. Am J Med Sci 1992 Jan;303(1):9-15 This study was designed to compare the clinical efficacy and safety of oral clonidine and oral labetalol in the treatment of severe hypertension in an emergency department setting. Thirty-six patients with severely elevated blood pressure (mean baseline blood pressure 199/132 mm Hg) without acute end-organ dysfunction were treated with either oral labetalol or oral clonidine in a randomized double-blind prospective study. Labetalol was administered as an initial dose of 200 mg, followed by hourly 200 mg doses up to 1,200 mg. Clonidine was administered as an initial dose of 0.2 mg, followed by hourly 0.1 mg doses up to 0.7 mg. Labetalol reduced diastolic blood pressure in 94% of the patients within 6 hours, with a mean reduction in blood pressure of 54/37 mm Hg. Clonidine reduced diastolic blood pressure in 83% of the patients within 6 hours, with a mean reduction in blood pressure of 57/32 mm Hg. The authors conclude that oral labetalol was comparable to clonidine in efficacy, had a similar incidence of side effects, and offered the clinician a useful alternative for the treatment of severe hypertension in an emergency department setting. Further studies are indicated to determine appropriate dosing regimens for oral labetalol in the acute treatment of severe hypertension. (3) Just VL, Schrader BJ, Paloucek FP, Hoon TJ, Leikin JB, Bauman JL Evaluation of drug therapy for treatment of hypertensive urgencies in the emergency department. Department of Pharmacy Practice, University of Illinois, Chicago 60612. Am J Emerg Med 1991 Mar;9(2):107-11 Oral nifedipine (N) and clonidine (C) are often used in the treatment of hypertensive urgencies; however, until recently, there were no comparative studies using the same patient population. The authors reviewed the records of hypertensive patients treated in the emergency department between October 1, 1987 and September 30, 1988. Selected patients had a diastolic blood pressure (DBP) of greater than 115 mm Hg without evidence of acute end organ damage. Patients were stratified into three treatment groups: N, C, and group 3 (G3). G3 received a variety of drug therapies but not exclusively N or C. Systolic blood pressure (SBP), DBP, mean arterial pressure (MAP), percent decrease in MAP (%MAP), time to lower blood pressure, admissions, and discharges were evaluated. Efficacy and safety were defined as reaching a DBP less than 110 mm Hg but %MAP of no greater than either 25% or 40%, respectively. Thirty-five N, 32 C, and 27 G3 patients were identified with no statistical difference between groups in race, gender, pretreatment SBP, DBP, or MAP. N, C, and G3 significantly reduced SBP, DBP, and MAP (P less than .01). Comparing N, C, and G3, no differences were observed in %MAP, admissions, discharges, efficacy, or safety. Time required to decrease blood pressure differed between all three groups (44 +/- 32 N v 77 +/- 57 C v 152 +/- 94 min G3) (p less than .05). These results indicate that N, C, and a variety of drug therapies are equally effective and safe in the treatment of hypertensive urgencies. (4) McAllister RG Jr Kinetics and dynamics of nifedipine after oral and sublingual doses. Am J Med 1986 Dec 15;81(6A):2-5 Nifedipine is frequently administered by the sublingual route to provide rapid onset of intense effect, especially in patients in whom urgent reduction of elevated blood pressure is indicated. Previously available data, however, suggest that peak levels of nifedipine are higher and occur earlier when the drug is administered orally. Results of pharmacodynamic studies show that maximal hypotensive effects occur between 30 and 60 minutes after administration by either route, but that such effects are often achieved earlier when the drug is given orally. Recent work implies that the absorption of nifedipine through the buccal mucosa is poor, if it occurs at all, and that the appearance of nifedipine in plasma requires delivery of the drug to the stomach for active absorption. The small time lag in absorption that may be attributed to the dissolution of the nifedipine capsule may be obviated by biting through the capsule and swallowing the contents; this bite-and-swallow approach to dosing provides the most rapid rise in plasma nifedipine concentrations, and produces peak levels well above those achieved with sublingual administration. (5) Schwartz et. al. Oral nifedipine in the treatment of hypertensive urgency. Cerebral-vascular Accident Following a Single Dose. Arch Int Med 150;686:1990 Sublingual Drugs for HTN ------------------------ The earliest reference I have been able to find via Medline is this 1972 article (1). Early studies comparing p.o. to SL administration of nifedipine did find an advantage (in onset time) to the SL route (2,3). These findings have been contradicted, however, by more recent observations (4,5). I think that it is important when giving it p.o. to have the patient bite and chew the capsule before swallowing so as to avoid the delay in capsule dissolution (if this is felt to be important). By contrast everything that I have read indicates that SL administration of captopril is somewhat faster in onset than p.o. (6,7,8). Although the differences to onset (10 vs 30 minutes) and peak effect (30 min vs 1 - 2 hours) are not clinically significant in most cases. H. Louzon MD (1) Raff WK, Kosche F, Lochner W [Studies on nifedipine, a coronary vasodilator agent with rapid sublingual effects] Arzneimittelforschung 1972 Jan;22(1):33-9 (2) Bartorelli C, Magrini F, Moruzzi P, Olivari MT, Polese A, Fiorentini C, Guazzi M Haemodynamic effects of a calcium antagonistic agent (nifedipine) in hypertension: therapeutic implications. Clin Sci Mol Med Suppl 1978 Dec;4():291s-292s 1. In 27 severe primary hypertensive patients nifedipine (10 mg), administered orally, induced prompt (-21% of control at 30 min) and persistent (-17% at 120 min) fall of mean arterial pressure mediated through reduction of peripheral vascular resistance with rise of cardiac output. 2. The sublingual route (nine cases) showed more rapid onset of action and equal antihypertensive effectiveness. 3. In five patients with hypertensive crisis and acute left ventricular failure, the drug strikingly reduced systemic and pulmonary arterial pressures and relieved pulmonary oedema. 4. Prompt efficacy, ease of administration, absence of important side effects indicate that nifedipine may be a useful therapeutic agent in severe hypertension and in critical conditions that require rapid lowering of blood pressure. (3) Guazzi M, Olivari MT, Polese A, Fiorentini C, Magrini F, Moruzzi P Nifedipine, a new antihypertensive with rapid action. Clin Pharmacol Ther 1977 Nov;22(5 Pt 1):528-32 Oral (17 cases) or sublingual (9 cases) administration of nifedipine (10 mg), a new coronary dilator, induced a prompt and large pressure reduction in patients with severe primary hypertension. Pressure started to fall within 20 and 5 min after oral and sublingual administration, respectively, and reached the lowest levels in the next 10 min. Maximal mean arterial pressure reduction averaged 36 mm Hg; 120 min after the drug, mean arterial pressure was diminished by 19.5% of control. The hypotension was mediated through diminished peripheral resistance associated with rise of cardiac output and pulse rate. Nifedipine was also administered siblingually in 3 cases with hypertensive encephalopathy and acute left ventricular failure with average systemic and pulmonary arterial pressures from 307/164 and 91/55 mm Hg, respectively, which fell to 237/115 and 68/35 mm Hg 15 min after 10 mg of the drug, and were further reduced to 176/89 and to 47/19 mm Hg by an additional 10 mg. (4) Oliver S Sublingual nifedipine: the continuing controversy. Aust Crit Care 1994 Jun;7(2):12-4 Sublingual, as opposed to oral, administration of Nifedipine (Adalat) has gained wide popularity as the method of choice when the most rapid onset of anti-hypertensive action is required. However recent research indicates that this delivery method may be without scientific validation, and may in fact delay the attainment of peak plasma concentrations of the drug. Peak Nifedipine serum concentrations have been shown to be less following sublingual administration than following oral administration, and the time to peak concentration has been shown to be longer following sublingual administration than with the oral dose. The lack of a standardised technique for the administration of sublingual Nifedipine means that in many cases the patient may be receiving sub-therapeutic doses of the drug. (5) Diker E, Erturk S, Akgun G Is sublingual nifedipine administration superior to oral administration in the active treatment of hypertension? Angiology 1992 Jun;43(6):477-81 Nifedipine, a calcium-channel-blocking agent, was administered orally to 44 untreated patients (Group A) and sublingually to 51 untreated patients (Group B) who had a diastolic blood pressure more than 90 mm Hg and systolic blood pressure more than 140 mm Hg. The mean pretreatment systolic and diastolic blood pressure values were 185.3 +/- 26.0 and 115.1 +/- 13.4 mm Hg in Group A patients and 193.6 +/- 23.1 and 118.1 +/- 14.1 mm Hg in Group B patients respectively (p greater than 0.05). The hypotensive activity of nifedipine was observed at the tenth minute in both groups. Mean systolic and diastolic pressures were 168.9 +/- 23.7 and 101.9 +/- 14.2 mm Hg in Group A and 170.6 +/- 26.2 and 103.0 +/- 15.8 mm Hg in Group B, (p less than 0.001) Diastolic blood pressures dropped under 100 mm Hg at the twentieth minute in both groups. Maximal reduction of blood pressure was observed at the fortieth minute in both groups and the degree of reduction in blood pressure was also the same (mean systolic and diastolic blood pressures: 143.7 +/- 22.1 and 86.9 +/- 11.7 in Group A and 148.7 +/- 21.4 and 91.7 +/- 17.0 in Group B (p less than 0.05). The authors conclude that sublingual nifedipine administration is not superior to oral nifedipine administration (in capsular form) in the acute treatment of hypertension. (6) al-Furaih TA, McElnay JC, Elborn JS, Rusk R, Scott MG, McMahon J, Nicholls DP Sublingual captopril--a pharmacokinetic and pharmacodynamic evaluation. Eur J Clin Pharmacol 1991;40(4):393-8 In this study we compared the pharmacokinetics and pharmacodynamics of captopril after sublingual and peroral administration. Single 25 mg doses of captopril were administered sublingually and perorally on two different occasions in a randomised cross-over fashion to eight healthy volunteers aged 22-35 years. The kinetics of unchanged captopril, plasma renin activity (PRA). BP and heart rate were studied over three hours after both peroral and sublingual administration of captopril. Mean pharmacokinetic parameters for unchanged captopril after sublingual administration were: Cmax, 234 ng.ml-1; tmax, 45 min; AUC (0-3 h), 15.1 micrograms.ml-1.min. Mean pharmacokinetic parameters for unchanged captopril after peroral administration were; Cmax, 228 ng.ml-1; tmax, 75 min; AUC (0-3 h), 17.0 micrograms.ml-1.min.tmax was significantly shorter when captopril was administered sublingually; all other pharmacokinetic parameters were equivalent. The plasma captopril concentrations achieved post drug administration led to increases in PRA and reductions in BP.tmax for PRA was 86 min for sublingual captopril and 113 min for perorally administered drug. Peak PRA values were, however, not significantly different. BP, as expected, was not reduced dramatically in these healthy volunteer subjects, however, in systolic BP vs time profiles, BP was significantly lower after volunteers received sublingual captopril. Heart rate increased slightly after captopril administration; there were no differences between the two routes of administration. Administration of captopril sublingually, therefore led to a more rapid attainment of plasma captopril concentrations and had a more rapid onset of pharmacological effect when compared with peroral administration. (7) Longhini C, Ansani L, Musacci G, Mele D, Vaccari M, Baracca E, Sgobino P The effect of captopril on peripheral hemodynamics in patients with essential hypertension: comparison between oral and sublingual administration. Cardiovasc Drugs Ther 1990 Jun;4(3):751-4 A comparative study of the effects of oral and sublingual captopril on the hemodynamics of the peripheral musculocutaneous vasculature was carried out on ten patients with essential hypertension. Both routes of administration of captopril lead to lower blood pressure and decreased regional resistance, and to an increased arterial blood flow at rest. The first measurable effect and the peak effect on blood pressure and peripheral hemodynamics appear slightly earlier with sublingual administration. The data provided in this study support the usefulness of the sublingual route in clinical situations in which oral administration of captopril is not feasible. (8) [Sublingual captopril in hypertensive crises] Recenti Prog Med 1992 Sep;83(9):503-5 Captopril is widely used in severe hypertension. Oral administration takes one-two hours to achieve a maximum effect and is not useful in hypertensive crisis. Few reports describe a more rapid effect on blood pressure following sublingual administration. We evaluated the effect of sublingual captopril 50 mg, in 26 patients with hypertensive crisis. Blood pressure levels started to decrease within 10 minutes and the maximum effect was observed 30 minutes after administration of the tablet. In all patients mean (CI 95%) systolic blood pressure dropped from 202.5 (199-206) mmHg to 160.6 (156-165) mmHg and diastolic blood pressure from 105.6 (102-109) mmHg to 86.9 (83-7-90.1) mmHg. This effect was maintained over two hours. There were no side effects. Sublingual captopril is highly effective in hypertensive crisis and its gradual hypotensive action avoid dangerous abrupt fall in blood pressure.