- Email: [email protected]
Antihypertensive drugs
J.A. Steiner
21
Antihypertensive drugs
Since last year's chapter was written, some interesting developments have occurred. We are seeing much more of a move towards the treatment of hypertension with angiotensinconverting enzyme (ACE) inhibitors and calcium-channel antagonists (see Chapter 19) than previously. Despite initial difficulties with both captopril and enalapril, is seems clear that modern drugs, appropriately handled, provide treatment regimens which may be more acceptable to patients than older compounds which in one way or another interacted with the sympathetic nervous system. In addition, the concept of potassium-channel activators is being explored. At least one such compound is in Phase II evaluation and shows promise (P). During the year, a number of reviews have been published. In particular, further progress has been made by the Hypertension and Detection Follow-Up Program (2R). Unfortunately, as with many other large epidemiological reviews, the drugs included are rather oldfashioned. What this program does show, however (as mentioned in SEDA-11), is the high rate of patients' complaints prior to entry. This 'background noise' may be carried over into any study of side effects and the authors point out that the lack of a control group poses difficulties of interpretation. Two good reviews have appeared, one on the effects of antihypertensive drugs on lipids and looproteins (3 R) and the other on glucose tolerance (4R). In particular, it is becoming clear that many of the drugs associated with favorable lipid profiles, e.g. guanabenz, clonidine, labeta1ol, indapamide and guanfacine, may not be widely regarded as first-line therapy. It will be interesting to see the results of large-scale studies of the long-term effects of ACE inhibitors and calcium-channel antagonists on lipid and carbohydrate profiles. A review of the effects of centrally acting drugs administered neonataily to rodent pups has been published (5r). The authors claim that neonatally administered centrally acting drugs Side Effects of Drugs Annual 12 M.N.G. Dukes and L. Beeley, editors 9 Elsevier Science Publishers B.V., 1988
suppress REM sleep and cause hyperactivity, hyperanxiety, reduced sexual activity and decreased cerebral cortical size. Extrapolation to the human state seems to ignore several factors. The first is that the quantities of drugs given to these animals may be greater than would be expected either from transplacental transfer or exposure to breast milk. Secondly, the t/me of exposure in the process of development is significant. Thirdly, Redman et al have already published their findings on children exposed in utero to methyldopa and found no detectable effects (6c), although a study discussed later (60c) on clonidine does suggest some minor effects. Some more information about the association of stroke with sudden lowering of the blood pressure has been published (7~, 8"). Although, as might be expected, the elderly appear to be more vulnerable to cerebral infarction under these circumstances, it is clear that this can occur in young people as well. One novel development is the use of topical minoxidil to treat hair loss. Side effects associated with this approach will be dealt with later in this Chapter.
ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS (SED-IO, 356; SEDA-9,
193; SEDA-10, 174; SEDA-11,183) An overview of the effects of some currently available ACE inhibitors has recently been published (9R). In addition, a number of other reports have appeared. Captopril (SED-IO, 356; SEDA-9, 193;
SEDA-IO, 174; SEDA-11,183)
Cough Five further cases ofcaptopril-induced cough have been reported (10 ~, 1 lC). The mechanism for this is still unknown. One interesting feature is that the onset and offset of the symptom may be quite delayed (10c).
Cardiovascular There is a further report of a first-dose effect in a 61-year-old woman with con-
Antihypertensive drugs Chapter 21 gestive heart failure (12c). Hypotension occurred twice in response to oral doses of 12.5 mg. It is not clear whether this woman was taking diuretics at the time, but her serum electrolytes were said to be within the normal range. There is a report of 2 severely hypertensive patients who developed large falls in blood pressure in response to a single dose of captopril 6.5mg (13c). Both had extensive vascular disease complicated by renal and neck artery stenosis. Both became dizzy and one became aphasic at the same time. All symptoms and signs reversed as the blood pressure rose again. The authors conclude that stenosis of vessels supplying the brain may exacerbate the neurological response to hypotension and promote focal vascular lesions. There is an interesting account of a 34-yearold man with severe congestive cardiac failure who had been treated with captopril 150 mg/d for 4 months in addition to furosemide and digoxin (14c). The eaptopril was suddenly discontinued while the rest of the treatment regimen was continued. The patient developed ventricularfibrillation 1 week later and was found to have a serum potassium of 2.8 mmol/1. Previously he had been normokalemic. The authors conclude that the hypokalemia was due to a rebound after removal of captopril. However, since furosemide was continued without potassium supplementation, this argument may be little unconvincing. It should also be borne in mind that the dose of captopril used is vastly in excess of that recommended by the manufacturers today. If one assumes a rebound phenomenon, extrapolation to current dosage regimens is tenuous. The same authors describe a patient who became hyperkalemic and had a cardiac arrest while taking digoxin, captopril 150 mg/d and potassium salt substitute. Hematological A 68-year-old man was treated with captopril 37.5 mg t.d.s, for heart failure (15c). He was admitted to hospital septicemic and was treated with antibiotics in addition to his usual heart failure therapy. He became thrombocytopenic during this illness. The thrombocytopenia resolved when captopril was stopped. No other drugs were stopped at the same time. No other hematological abnormalities were observed. In particular, there was no evidence of disseminated intravascular coagulation or platelet antibodies. This complex history is difficult to interpret.
Urinary system Packer et al (16c) have also reviewed their experience of 86 patients with
173 heart failure taking captopril in doses of 75150mg/d. They conclude that where renal impairment occurs in this group of patients, it is always due to an excessive fall in left ventricular filling pressure or mean arterial pressure. It should again be borne in mind that the doses used are very high and that a different interpretation may be required for similar effects occurring with lower doses of captopril. Patients with pre-existing renal impairment can be treated with captopril, but some precautions will need to be observed. Hirakata et al (17 c) report their experience of 13 patients with chronic renal failure requiring hemodialysis. These patients became slightly more anemic when treated with captopril in a mean dose of 19.3 mg/d. Angiotensin II levels fell and correlated with the reticulocyte count both before and after exposure to captopril. Plasma erythropoietin concentrations remained unchanged, but it is not clear whether they were normal or not. The authors hypothesize that reduction of circulating angiotensin II levels may contribute to the anemia experienced by patients with severe chronic renal failure. There are several further reports of reversible renalfailure in patients with renal artery stenosis (18c-22~). At present, there is some discussion as to whether a 'captopril provocation test' is sufficiently predictable to be used to make the diagnosis of renovascular disease. A 40-year-old woman with severe hypertension developed signs of the nephrotic syndrome while taking captopril 450 mg/d (23c). She did not have renovascular disease. Renal biopsy revealed mesangial prominence with basement membrane thickening, crescents and focal glomerulosclerosis. The tubules demonstrated focal cellular loss with pronounced interstitial inflammatory infiltrates. Immunofluorescence showed granular deposits of C3 and IgG along the basement membrane. The signs resolved very slowly once eaptopril was stopped. They did not recur when the patient was treated with enalapril. Madeddu et al (24 c) report their experience with 10 psoriatic patients treated for hypertension with captopri125 mg t.d.s. Three developedproteinuria which resolved when captopril was stopped. Interestingly, 3 patients also experienced a marked and unexpected improvement in their skin disorder while taking captopill. Some other aspects of the renal effects of captopril are dealt with under 'Interactions' (below).
174
Chapter 21 J.A. Steiner
Skin and appendages A number of rashes have again been reported. There are 2 cases ofpemphigus (25 r 26c), a lichenoid eruption (27r a case of pityriasis rosea (28~) and an episode of psoriasis (29c). There was also an episode of buccal mucous membrane ulceration apparently not associated with dysgeusia (30~). There was 1 case ofonycholysis in a patient with renal artery stenosis treatment with captopri150 mg/d (31r Most of these lesions resolved when captopril was stopped.
zosin became hypotensive when given captopril 12.5 mg/d (37c). Captopril alone did not have this effect and the authors postulate an interaction between captopril and chlorpromazine. This seems credible, since hypotension is a wellknown complication of antipsychotic drugs which is readily potentiated by other agents (SED-10, 96, 104).
Special senses Sekimoto and Tomita (32r suggest that zinc deficiency due to chelation of zinc by captopril or other antihypertensive agents may cause the taste disturbances which are sometimes experienced. This is based on a study of 193 patients with taste disorders while taking a variety of drugs. Fifty-six percent were zinc-deficient. Unfortunately, there is no control group for comparison.
An open study of 42 patients with heart failure taking either captopril 150mg/d or enalapri140 mg/d as a single daily dose has been presented (38c). Enalapril is said to have been associated with a more prolonged hypotensive effect than captopril, although the actual trough blood pressure values are not given. A greater fall in creatinine clearance and rise in serum potassium concentrations was observed in the enalapdl group. This has been interpreted as a response to prolonged hypotension and possibly ACE inhibition. These data are difficult to relate to normal therapeutic practice given that the dose used is so much higher than the 2.5 mg recommended by the manufacturers.
Hypersensitivity New cases of angioedema have been reported to the U.K. Committee on Safety of Medicines. Of 6 patients, 3 also developed urticaria (33r All resolved when treatment was suspended. A 49-year-old woman taking captopril 150 mg/d developed facial edema and a rash. Captopril was discontinued, but she developed agranulocytosis and septicemia of which she died (34~). In the same paper there is a description of a 55-year-old man given captopril 12.5 mg. He also developed facial edema which resolved when captopril was stopped. It is clear that drug-related angioedema may occur with relatively small doses of captopril. Interactions Administration of captopril and metolazone together has been claimed to cause a sufficient degree of renal impairment to cause problems, although the evidence comes from a ease with multiple medication and is therefore not easy to interpret. A 65-year-old woman with congestive cardiac failure was treated with captopril 25mg b.d., furosemide, digoxin, mianserin, warfarin and spironolaetone (35~). Addition ofmetolazone 5 mg produced nausea, anorexia and malaise. This was attributed to renal failure with associated digoxin toxicity. Discontinuation of captopril and metolazone led to a return to normal renal function with resolution of symptoms. Another report of 32 patients, however, demonstrates that captopril inhibits renal clearance of digoxin (36c). A 49-year-old schizophrenic taking chlorpromazine, hydrochlorothiazide, nadolol and pra-
Enalapril (SED-IO, 358; SEDA-9, 195; SEDA-IO, 176; SEDA-11,185)
Cough As with captopril, there are a number of reports of dry cough (11 c, 33~ 39c, 40c). Gavras in an open study of 276 patients, estimates the incidence to be 0.7% (39c). There was also a 45-year-old woman taking enalapril 10mg/d who presented with severe nasal obstruction (41c). The symptom reversed when enalapril was stopped and recurred on rechallenge. Nervous system A 66-year-old man developed a transient fight hemiparesis 2 hours after a single dose ofenalapril (39r His blood pressure at the time is not given. However, he was found to have bilateral carotid artery stenosis. A 41-year-old patient given enalapril 2.5 mg and atenolol 100 mg decreased his blood pressure from 200/140 to 100/60mmHg. Several hours later he became paraplegic. The authors postulate an infarction of the thoracic spinal cord secondary to hypotension (42c). Mineral and fluid balance A 75-year-old man with a creatinine clearance of 30 ml/min became hyperkalemic after being given enalapril 5 mg/d and furosemide 20 mg/d (43c). Urinary system Evidence is presented that enalapril in doses of 20-40 m u d in patients with
Antihypertensive drugs Chapter21 heart failure decreases renal function through a sustained fall in mean arterial of let~ ventricular filling pressure just as does captopril (16 c ). This sort of problem has prompted the manufacturers to limit the starting dose in this group of patients to 2.5 mg and in hypertensives to 5 mg (44r). However, enalapril also decreases renal function in post-renal-transplant patients. Six of 18 patients experienced a reversible decrease in renal function while the rest had no renal effect as estimated by creatinine clearance (45r The dose used is not mentioned. There were no obvious differences between those whose creatinine clearances deteriorated and the others. In particular, differences in blood pressure do not appear to have been important. In an intriguing study, enalapril 10-40 mg/d and hydrochlorothiazide were compared with triple therapy (hydrochlorothiazide, timolol and hydralazine) for efficacy and safety in 75 patients with documented unilateral or bilateral renal artery stenosis (46c). Ten of 49 patients taking enalapril developed a rise in serum creatinine of 0.3 mg/100 ml or greater and a fall in inulin clearance. Enalapril was associated with an increase in effective renal plasma flow as measured by PAH clearance in all patients, even those whose serum creatinine concentrations rose significantly. No patient developed clinical renal failure. This is of some interest since it suggests that enalapril may be used cautiously, if needed, in patients with renal artery
stenosis.
Hypersensitivity
New cases of angioedema have been reported to the U.K. Committee on Safety of Medicines (33c). All resolved when treatment was suspended. A case of reversible angioedema is reported in a 59-year-old man who took a single dose of 10 mg of enalapril (47c). Apparently, he had never been exposed to ACE inhibitors in the past.
Overdosage A 56-year-old woman with heart failure took enalapril 440 mg in a suicidal attempt (48c). She became severely hypotensive, uremic, acidotic, hyperkalemic and hyponatremic. ACE inhibition was virtually complete for a week and angiotensin II and aldosterone were suppressed for the same time. The patient recovered with supportive therapy.
175 compound-related and which are likely to be common to the entire group.
CUazapril In a study of 27 patients, cilazapril caused dizziness in one patient (49c). Another patient developed a r/se in serum creatinine concentration. This was reversible and did not reappear on rechallenge.
Lisinopril Four cases of dry cough have been reported with lisinopril (50c). Two resolved when therapy was stopped and one resolved despite continuing therapy. One patient had a cough prior to therapy which persisted thereafter and may not have been drug-related. D R U G S A C T I N G ON THE SYMPATHETIC NERVOUS SYSTEM: PRESYNAPTIC ~ - A D R E N O C E P T O R AGONISTS (SED-IO, 361; SEDA-9, 197;
SEDA-IO, 179; SEDA-11, 186)
Clonidine (SED- I O, 361; SEDA-9, 197; SEDA-IO, 179; SEDA-I 1,186) Cardiovascular A patient suffering from a myocardial infarct was given clonidine 0.5 mg to control sudden severe hypertension (51~). He developed prolonged hypotension and was treated with naloxone with a prompt rise in blood pressure. Nervous system
Clonidine has been evaluated in the treatment of spinal spasticity in 12 patients (52c). A number of these experienced dizziness and lethargy or drowsiness, as would be expected. Three patients had episodes of autonomic hyperreflexia. In 2 of these, the spells were associated with involuntary neck and face movements which had not occurred previously. The situation is difficult to evaluate since the subjects had also taken antihistamines at the time, but the drug has long been known to have effects on the nervous system (SED-10, 362). An infant aged 9 months accidentally received clonidine from a transdermal patch (53 ~ He became irritable, drowsy, anorexic and polydipsic. The symptoms resolved promptly when the patch was removed.
Endocrine, metabolic
Other ACE inhibitors
In the past, clonidine has variously exhibited hyperglycemic or hypoglycemic effects, depending on the situation in which it was used (SED-10, 363).
As the number of ACE inhibitors increases, so it becomes clearer which adverse effects are
A 52-year-old woman suffering from non-insulindependent diabetes mellitus was given clonidine
176 0.225 mg/d in addition to methyldopa and metoprolol. Her blood glucose and hemoglobin AI levels had previously been controlled with diet and an oral hypoglycemic agent but became abnormal once clonidine was started (54c). The authors demonstrated that when she was taking clonidine, her insulin responseto a glucose load diminished compared with her response a~er clonidine was stopped. Skin and appendages A number of trials of transdermal clonidine have been published. In all, the main adverse event was contact derraalitis (55c-57r This seems mainly due to the adhesive in the patch (58 c) and on occasion has been severe enough to warrant stopping of therapy. Even systemic clonidine is however known to produce rash (SED-10, 362). Withdrawal effects The cardiovascular response to clonidine withdrawal is well documented (SED-10, 362). Labetalol continues to be a useful treatment for this condition (59"). However, a study of the effects of abrupt withdrawal of clonidine in Giles de la Tourette syndrome has now been published (60c). Five of 7 young patients showed marked worsening of their tics. Increases in motor restlessness, blood pressure and pulse rate were also observed. When clonidine was reinstituted, it took 2 weeks to 4 moaths to control the tic symptoms again. The authors postulate that the neurological expressions of withdrawal may be due to increased CNS catecholamine turnover.
Second-generationeffects Twenty-two children have been studied whose mothers were treated with clonidine in pregnancy (6P). Eighteen were full-term deliveries. They were compared with 22 matched controls 3-91/2 years after birth. The children treated with clonidine showed an excess of disturbed sleep patterns as assessed by a comprehensive questionnaire. No other neurological or developmental differences were found between the two groups. It is not clear whether the sleep disturbances resolved as the children grew older. This type of'behavioral' effect in the second generation can be difficult to study, but approaches to it are now being better defined than in the past (62R). DRUGS I N T E R F E R I N G WITH NEUROTRANSMITTERS
Methyldopa (SED-IO, 358; SEDA-9, 198; SEDA-IO, 180; SEDA-11,187) Hematological Hemolytic anemia is a wellknown complication of methyldopa therapy.
Chapter 21 J.A. Steiner Seven patients with a positive direct antiglobulin test were examined (63c). Two of these had signs of hemolysis. In these 2 patients, ehiates from red cells contained antibodies of the IgG subclass and supported antibodydependent mononuclear-cell-mediated phagocytosis and cytotoxicity of the patients' red cells even after remission. This was not found in the 5 patients without hemolysis. Another patient with hemolytic anemia was studied by a Japanese group (64c). In this case, an IgG kappa antibody was eluted which agglutinated 44 different groups of red cell specimens but did not agglutinate Rh null red cells. Liver A 40-year-old male patient taking methyldopa and hydrochlorothiazide developed signs and laboratory signs of mild cholestasis (65c). A liver biopsy was not performed. Both drugs were suspended and the jaundice resolved promptly. Clearly it is difficult to assess which of the two drugs may have been responsible, but methyldopa has been associated with a range of hepatic complications in the past (SED-10, 359) while thiazides very rarely cause such problems, if at all (SED-10, 377).
Autoimmune effects A 78-year-old woman treated with methyldopa 500 mg t.d.s., cyclopenthiazide and naftidrofuryl oxalate developed a lupus-like syndrome (66c). Antinuclear antibodies were present in a titre of 1:320. Methyldopa was stopped and some of her signs resolved. However, on the next visit she had developed some of the features of scleroderma. It is difficult to assess whether this illness is drug-related or not. Miscellaneous A 48-year-old man treated with methyldopa 250 mg b.d. developed hyperpigmentation of the tongue. Biopsy was refused. The signs resolved slowly once methyldopa was suspended (67c).
Rauwolfia alkaloids (SED- I O, 364; SEDA-9, 199; SEDA-IO, 181) A case-control study of 1362 rauwolfia users and 1250 controls was conducted in a multicenter breast cancer screening program (67r Allowing for other variables such as age, menopausal status and family history, prolonged rauwolfia use was associated with about a 4-fold increase in relative risk of developing breast cancer. This conflicts with the results of some previous studies (SEDA-6, 205) but not others (SED-10, 364).
Antihypertensive drugs Chapter 21 ~q-ADRENOCEPTOR A N T A G O N I S T S
(SED-IO,361; SEDA-9, 197; SEDA-IO, 179) Doxazosin Doxazosin, a member of the quinazoline family to which prazosin belongs, has been compared double-blind to atenolol and placebo in a small study (69c). Symptoms which were attributed to it were postural dizziness, headache,
abdominal discomfort, blurred vision, edema, lack of energy, chest discomfort, sedation, constipation and dry mouth. It should be said that all of these also occurred with atenolol at about- the same frequency and, to a lesser extent, with placebo. In another study (70r total serum cholesterol was lowered in comparison to atenolol by about 10% of baseline values and LDL cholesterol by about 20%. HDL cholesterol rose marginally. The lipid effects are thus comparable in type to those seen with prazosin. lndoramin (SED- I O, 361) Newer work on indoramin largely confirms the preliminary impressions recorded in these volumes as early as 1984. Two large open studies of the use of indoramin in Step II antihypertensive therapy have been published. The first (70 ~) included hypertensive patients taking indoramin 50-200 mg/d and diuretic. By far the most common side effect was drowsiness ( 1 9 ~ ) which also caused the largest number of withdrawals. Other common side effects were dizziness ( 8.3 ~o), headache ( 5.2 % ), lack of energy (4.3 %), dry mouth (2.8 %), depression (2.7 %), nausea (1.9%), weight gain (1.7%), ejaculator), failure (2.5 %) and impotence (1.9 %). Another study (72c) included 3708 patients taking fl-adrenoceptor antagonists and diuretics in addition to indoramin 50-125 mg/d. The most common side effects were tiredness (8.3 %), dizziness (5.6%), dry mouth (4.0%), nausea (3.4%) and headache (2.8%). A similar profde has been obtained in the elderly (73c). Like other drugs of this class, indoramin appears to lower total serum cholesterol concentrations (74c). Prazosin (SED- I O, 360; SEDA-9, 197;
SEDA-IO, 179; SEDA-II, 187) Nervous system Mental changes with prazosin have been reported sporadically in the past, but sufficiently convincingly to show that a minority of patients will experience them.
177 Three patients are described all with chronic renal impairment who developed mental abnormalities while taking prazosin (75c). In 2 eases, these consisted of psychotic symptoms and in the 3rd drowsiness, confusion and disinhibited behavior. In 2 of these patients, abnormal EEGs with diffuse slow-wave activity were obtained. One of these returned to normal when prazosin was stopped. The mental abnormalities resolved in all 3 cases alter stopping prazosin. The authors attributed the side effect to reduced prazosin clearance or decreased protein binding of prazosin in patients with chronic renal failure. Terazosin (SEDA-I 1,187) Approximately 1000 patients who have been enrolled in terazosin studies have been reported upon (76c). Of these, 567 received terazosin in placebo-controlled studies and the rest in open studies. Side effects in these 567 patients were dizziness (29.1 ~ ), asthenia (13.6 % ), somnolence (6.2 ~o),peripheral edema (6.0 ~ ) , nausea (5.1 ~o), palpitations (4.6%) and blurred vision (1.6%). These incidences all exceeded those in the placebo group considerably. In the entire group, the main side effects were dizziness (29.0%), headache (28.8%), asthenia (21.3~), nasal congestion (12.0 ~o) and cold symptoms (11.5 ~ ) . The dose ofterazosin was up to 40 mg/d. It may be that the increased frequency of side effects in the group as a whole is due to a greater average dose ofterazosin than in controlled trials alone, but it is difficult to define this from the publication. None of the symptoms, however, seem at all unexpected in view of experience with prazosin.
Ct- AND fl-ADRENOCEPTOR ANTAGONISTS Labetaloi (SED- I O, 328; SEDA-9 , 178;
SEDA-11,166) Pyrexia as a reaction to beta-blockers must be very rare; 1 case with oxprenolol was reported in 1980 (77 c) and there are now 2 exceptionally well-documented case-reports with labetalol
(78cr).
The Netherlands Centre for Monitoring of Adverse Reactions to Drugs has published details of 2 cases in which labetalol caused fever. One was a woman of 61 with hypertension and a history of myocardial infarct who had earlier developed cold feet when treated with metoprolol and an itching rash with urticaria when treated with pindolol; the rash disappeared when she was transferred to labetalol (300 mg/d) and other concurrent medication was continued, but 3 weeks later
Chapter 21 J.A. Steiner
178 she developed pronounced pyrexia (39.80 ~C) without shivering or pain. The fever disappeared when labetalol was withdrawn but reappeared on 2 different attempts at rechallenge, the latter with a dose of only 100 mud. The second patient, a woman of 67, showed a very similar reaction to 300 mud oflabetaloi and to rechailenge with 100 mud.
D I R E C T V A S O D I L A T O R S (SED-IO, 352;
SEDA-8,206; SEDA-9, 195; SEDA-IO, 177; SEDA-11, 187) Cadralazine (SEDA-I O, 178; SEDA- I1,187) In two small studies of the use ofcadralazine, typical vasodilator side effects were found (79 r 80r These included headache, edema, weight
gain, flushing and palpitations. Hydralazine (SED-IO, 353; SEDA-9, 195;
SEDA-IO, 177; SEDA-11,188) Nearly a decade after a full review of lupuslike-complications to hydralazine in these volumes (SED-9, 318, 319) new features continue to be observed. A 52-year-old woman developed a lupus-like syndrome with some interesting features after having taken hydralazine 150 mud for 18 months (81c). The rare manifestations were pulmonary hypertension, lesions on the lung scan presumed to be pulmonary vasculitis and, in addition to slow acetylator status and HLADR4 antigen, a null allele for CA. In addition, she had antibodies to double-stranded DNA, lupus erythematosus (LE) cells and antinuclear antibodies (ANA). The syndrome resolved completely when hydralazine was stopped and prednisolone given. Another patient also presented with unusual cardiovascular features (82c). This was a 53-year-old woman taking hydralazine 200 mg/d as well as a number of other antihypertensive medications. She presented with a chronicpericardial effusion. She was negative for LE cells and ANA and was a fast acetylator. Antibody titers to doublestranded DNA were elevated. She was HLA-DR4 negative. A number of coagulation function tests were abnormal. Interestingly, she had elevated antibody titers for respiratory syncytial (RS) virus. The effusion was drained and did not recur once hydralazine was stopped. The authors argue that the effusion was unlikely to be due to the RS virus since so many features of the case are unusual for such an infection. Urinary system Two cases of rapidly progressive nephritis are reported (83c). These occurred without the usual signs of the lupus-like syn-
drome although A N A was present and both patients were slow acetylators. Both cases had rapidly progressive renal failure, proteinuria, hematuria and granular casts. In one renal biopsy there was a focal segmental proliferative pattern, positive for IgM and C3 on immunofluorescence. In the other, there was a crescentic nephritis with focal mesangial deposits of IgG and IgM. Both patients were taking hydralazine 150 mg/d which was stopped. Both responded well to cyelophosphamide and prednisolone. Risk situations A 14-year-old boy known to have apheochromocytoma was given hydralazine 6.25 mg i.m. to control a hypertensive crisis (84c). He became very hypotensive and developed angina pectoris and signs of isehemia in the anteroseptal E C G leads. These fortunately resolved without sequelae with the passage of time. Skin and appendages There are 2 reports of cutaneous manifestations, possibly linked to hydralazine therapy. A 60-year-old woman was taking 75 mg hydralazine daily. She had two eposides of an influenza-like illness (85c). Ten days after the 2nd episode, she developed polyarthritis and a rash. The polyarthritis was resistant to therapy with NSAIDS. The rash took the form of erythematous indurated plaques on the neck, forearms, shouders and face. A skin biopsy showed a dense band-like infiltration of leukoeytes, mainly neutrophils, in the upper dermis. There was no evidence ofvasculitis. ANA was present in high titer. Her acetylator status is not known. Pleuritic chest pain developed and the hydralazine was stopped. The outcome is not clear from the report. The skin biopsy was consistent with a diagnosis ofneutrophilic dermatosis or Sweet sydrome, which is commonly caused by viral infections or by underlying malignant disease. However, in the authors' view, the clinical course was uncharacteristic of a viral illness which generally resolves quickly and no malignancy has become apparent. For this reason, they ascribe the syndrome to hydralazine. A 62-year-old man, taking dihydralazine (the dose is not given) delevoped an erythematous eruption confined to the nose and upper lip (86c). This resolved when dihydraiazine was stopped and recurred on 2 further occasions in response to rechallenge. No other tests were performed. Minoxidil (SED-IO, 354; SEDA-IO, 178;
SEDA-11,188) Cardiovascular, respiratory A 78-year-old woman taking minoxidil 10 mg/d developedpleural and pericardial effusions and a positive A N A
Antihypertensive drugs Chapter 21 titer. These resolved when minoxidil was stopped. The situation is difficult to interpret since immediately prior to taking minoxidil, the patient had been taking hydralazine which was discontinued when minoxidil was started (87~). However, effusions have been reported with minoxidil on earlier occasions (e.g. SED10, 354; SEDA-11,188).
Skin and appendages A 36-year-old m a n was treated with minoxidil 10 mg/d and developed a Stevens-Johnson sydrome. This resolved with discontinuation of antihypertensive therapy and treatment with steroids. It recurred promptly when minoxidil was restarted (88~). Topical minoxidil has been evaluated as a treatment for alopecia. A substantial review has recently been published (89c). Cardiovascular events seem to be rare and mostly related to small falls in blood pressure or rises in heart rate
179 which have not proved troublesome. Most reactions have been in the skin such as pruritus, scaling, flushing and hair growth at distant sites (90c). Occasional episodes of contact dermatitis, reproducible with patch testing, have been described (91 c, 92c). The overall incidence of the contact dermatitis is not yet clearly defined, but it is obviously at present a source of concern to National Centers for Adverse Reaction Monitoring.
Pinacidil (SEDA-IO, 179; SEDA-11,188) In two small trials pinacidil again appears to have primarily side effects characteristic of vasodilatation. These include edema, headache, palpitations and hirsutism (93c). There are reports of nausea, bradycardia and hypotension, but this is in the context of an invasive heinedynamic study (94c).
REFERENCES 1. VandenBurg MJ, Woodward SA, Tasker T et al (1987) Potassium channel activators: hypotensive activity and adverse effect profile - the first study with BRL 34915. In: Proceedings, Third European Meeting on Hypertension, p 586. 2. Curb JD, Maxwell MH, Schneider KA etal (1986) Adverse effects of antihypertensive medications in the Hypertension Detection and Followup Program. Prog. Cardiovasc. Dis., 29, Suppl I, 73. 3. Ames RP (1986) The effects of antihypertensive drugs on serum lipids and lipoproteins. II. Nondiuretic drugs. Drugs, 32, 335. 4. Houston MC (1986) Adverse effects ofantihypertensive drug therapy on glucose intolerance. Cardiol. Clin., 4, 117. 5. Mirmiran M, Brenner E, Van tier Gugten J, Swaab DF (1985) Neurochemical and electrophysiological disturbances mediate developmental behavioral alterations produced by medicines. Neurobehav. Toxicol. Teratol., 7, 677. 6. Redman CWG, Beilin l_J, Bonnar J e t al (1976) Foetal outcome in a trial of antihypertensive treatment in pregnancy. Lancet, 2, 753. 7. Jansen PAF, Schulte BPM, Meyboom RHB, Gribnan FWJ (1986) Antihypertensive treatment as a possible cause of stroke in the elderly. Age Ageing, 15, 129. 8. Matenga J, Kitai I (1986) Iatrogenic strokes in hypertensive patients. Cent. Aft. J. Med., 32, 130. 9. DiBianco R (1986) Adverse reactions with angiotensin converting enzyme (ACE) inhibitors. Med. ToxicoL, 1,122. 10. Carruthers SG (1986) Severe coughing during eaptopril and enalapril therapy. Can. Med. Assoc. J , 135,217. 11. Keim HJ, Beckers G (1987) Medikament6s in-
duzierter Reizhusten. Miinch. Med. Wochenschr., 129, 218. 12. Black J, Hunt TL, Godley PJ (1986) Intitiation of captopril therapy: the first dose effect. J. Clin. PhamacoL, 26, 539. 13. Jensen H, Ring-Larsen H, Garsdal P, Fruergaard P (1986) Carotid artery stenosis exposed by an adverse effect of captopril. Br. Med. J., 293, 1073. 14. Packer M, Lee WH (1986) Provocation ofhyperand hypokalemic sudden death during treatment with and withdrawal of converting-enzyme inhibition in severe chronic congestive heart failure. Am. J. Cardiol., 57, 347. 15. Walsh KP, Walsh MJ, Branagan JP (1986) Reversible severe thrombocytopaenia associated with captopril therapy. It. Med. J., 79, 43. 16. Packer M, Lee WH, Medina N et al (1987) Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann. Intern. Med., 106, 346. 17. Hirakata H, Onoyama K, Hori K, Fujishima M (1986) Participation of the renin-angiotensinsystem in the captopril-indueed worsening of anemia in chronic hemodialysis patients. Clin. Nephrol., 26, 27. 18. Greminger P, Vetter H, Steurer J e t al (1986) Captopril and kidney function in renovascular and essential hypertension. Nephron, 44, Suppl I, 91. 19. Durand D, Ader JL, Lloveras JJ et al (1986) Pr~dictabilit~ de I'insuffisance renale aigu~ post-captopril dans les hypertensions art~rielles avec st~nose de l'art~re r~nale d'un rein unique ou st~nose bilat~rale. Arch. Mal. Coeur Vaiss., 79, 888. 20. Mourad G, Ribstein J, Argiles A e t al (1986) Hypertension art&idle et st6nose de l'art~re du greffon: effets de l'inhibition de renzyme de conversion. Arch. Mal. Coeur Vaiss., 79, 892.
180 21. Rodero FG, Millet VG, Iglesias JN et al (1986) Fracaso renal agudo inducido per captopril en presencia de estenosis bilateral de arteria renal. An. Med. lnterna, 3, 391. 22. Laplatte G, Gutbub AM, Baeumle D, Haegy JM (1986) Apparition d'une insuffisance r~nale au cours d'un traltement par le captopril et st~nose de i'art~re r~nale. Sem. Hdp., 62, 2491. 23. Webb DJ, Atkinson AB (1986) Enalapril following captopril-induced nephrotic sydrome. Scot. Med. J., 3l, 30. 24. Madeddu P, Ena P, Dessi-Fulgheri P et al (1986) Captopril-induced proteinuria in hypertensive psoriatic patients. Nephron, 44, 358. 25. Flageul B, Foldes C, Wallach D et al (1986) Captopril-induced fichen planus pemphigoides with pemhigus-like features. Dermatologica, 173, 248. 26. Ricci G, Silva M, Crippa D et al (1986) Un case di pemfigo indotto da captopril? (Letter to Editor). Rec. Prog. Med., 77, 86. 27. Mancuso G, Bernondoni RM (1986) Eruzione lichenoide da captopril. Chron. Dermatol., 17, 407. 28. Bhatia KK, Chaudhary SD, Gupta S (1985) Captopril (SQ 14, 225) induced pityriasis rosea like eruption. Indian J. DermatoL VenereoL LeproL, 51, 351. 29. Hauschild Tr, Bauer R, Kreysel HW (1986) Erstmanifestation einer eruptiv-exanthematischen Psoriasis vulgaris unter Captoprihnedikation. Hautarzt, 37, 274. 30. Corone S, Davido A, Corone P (1987) Une complication rare du captoprii: rulctration des muqueuses linguales et jagales. Rev. MJd. Interne, 8, 73. 31. Borders JV (1986) Captoprii and onychnlysis. Ann. Intern. Med., 105, 304. 32. Sekimoto K, Tomita H (1986) Zinc chelation capacity of hypotensive agents causing taste disturbance. Nihon Univ. J. Med., 28, 233. 33. Wood SM, Mann RD, Rawhns MD (1987) Angio-oedema and urticaria associated with angiotensin converting enzyme inhibitors. Br. Med. J., 294, 91. 34. Suarez M, Lye PW, Johnson ES, Perez G (1986) Angioneurotic edema, agranniocytosis and fatal septicemia following captopril therapy. Am. J. Med., 81, 336. 35. Hogg KJ, Hillis WS (1986) Captopril/metolazone induced renal failure. Lancet, l, 501. 36. Cleland JGF, Dargie H J, Pettigrew A et al (1986) The effect of captopril on serum digoxin and urinary urea and digoxin clearances in patients with congestive heart failure. Am. Heart J., 112, 130. 37. White WB (1986) Hypotension with postural syncope secondary to the combination of chlorpromazine and captopril. Arch. Intern. Med., 146, 1833. 38. Packer M, Lee WH, Yushak M, Medina N (1986) Comparison of captopril and enalaprii in patients with severe chronic heart failure. N. Engl. J. Med., 315, 847. 39. Gavras H (1986) A multicentre trial of enalapril in the treatment of essential hypertension. Clin. Ther., 9, 24. 40. Webb D, Benjamin N, Collier J, Robinson B
Chapter 21 J.A. Steiner (1986) Enalapril-induced cough. Lancet, 2, 1095. 41. Fennerty A, Littley M, Reid P (1986) Enalaprilinduced nasal blockage. Lancet, 2, 1395. 42. Brown P, Gross M, Harrison M (1987) Paraplegia following oral hypotensive treatment of malignant hypertension. J. NeuroL Neurosurg. Psychiatry, 50, 104. 43. Loeb G (1987) Hyperkali6mie suns inhibiteur de l'anzyme de conversion. Concours M~d., 109, 55. 44. Anonymous (1987) Warnings from the Committee on Safety of Medicines. Pharm. Int., 7, 194. 45. Guerin C, Genin C, Sabatier JC etal (1987) Evolution de la fonction r6nale chez le transplante r6nal hypertendu trait6 par enalapril. N~phrologie, 8, 19. 46. Franklin SS, Smith RD (1986) A comparison of enalapril plus hydrochlorothiazide with standard triple therapy in renovascular hypertension. Nephron, 44, Suppl 1, 73. 47. Marichal JF, Failer B, Brignon P (1986) Angioed~me apr6s administration d'enalapril chez un insuffisant r6nal chronique. Tl~rapie, 41,517. 48. Lau CP (1986) Attemptod suicide with analapril. N. EngL J. Med., 315, 197. 49. Belz GG, Lange H, Tschollar W, Neis W (1986) Cilazapdl bei essentieller Hypertonie. Med. Kiln., 81, 524. 50. Nash DT (1986) Lisinopril cough. Texas Heart Inst. J., 13, 353. 51. Niemann JT, Getzug T, Murphy W (1986) Reversal of clonidine toxicity by naloxone. Ann. Emerg. Med., 15, 1229. 52. Maynard FM (1986) Early clinical experience with clonidine in spinal spasticity. Paraplegia, 24, 175. 53. Reed MT, Hamburg EL (1986) Person-toperson transfer of transdermal drug-delivery systems: a case report. N. Engl. J. Med., 314, 1120. 54. Okada S, Miyai Y, Sate K et ai (1986) Effect of clonidine on insulin secretion: a case report. J. Int. Med. Res., 14, 299. 55. Boekhorst JC, Lustermans FAT, Van Tel RGL (1987) Transdermal administration of clonidine for treatment of mild-to-moderate essential hypertension. Curt. Ther. Res., 41, 215. 56. Dick JBC, Northridge DB, Lawson AA (1987) Skin reactions to long-term clonidine. Lancet, 1, 516. 57. Kellaway GSM (1986) A commanity-based trial of transdermal antihypertensive therapy with clonidine (Catapres-TrS). N Z Med. J., 99, 711. 58. Malbach HI (1987) Oral substitution in patients sensitized by transdermal clonidine treatment. Contact Derm., 16, 1. 59. Mehta JL, Lopez LM (1987) Rebound hypertension following abrupt cessation of clonidine and metoproiol. Arch. Intern. Med., 147, 389. 60. Leckman JF, Ort S, Caruso KA et al (1986) Rebound phenomenon in Tourette's syndrome after abrupt withdrawal of clonidine. Arch. Gen. Psychiatry, 43, 1168. 61. Huisjes HJ, Hadders-Algra M, Touwen BCL (1986) Is clonidine a behavioural teratogen in the human? Early Hum. Dev., 14, 43.
Antihypertensive drugs Chapter 21 62. World Health Organization (1986) Guidelines for the Evaluation of Drugs and Other chemicals for Behavioral Teratogenicity. Revised drain, WHO, Regional Office for Europe, Copenhagen. 63. Yust I, Frisch B, Goidsher N (1986) Antibody dependent cell-mediated cytotoxicity and phagoeytosis of autologous red blood cells in alpha methyldopa-induced haemolysis. Scand. J. HaematoL, 36, 211. 64. Itoh Y, Yuasa S (1986) Blood group specificity of an autohaemagglutinin induced by alpha methyldopa therapy. Jpn. J. Leg. Med., 40, 30. 65. Venkateswara K (1986) Cholestaticjaundice associated with methyldopa. Minnesota Med., 69, 720. 66. Power MJP, McConnell JG, Taylor IC (1986) Methyldopa-induced connective tissue disorder. Ulster Med. J., 55, 172. 67. Brody HJ, Cohen M (1986) Black tongue secondary to methyldopa therapy. Cutis, 38, 187. 68. Stanford JL, Martin EJ, Brinton LA, Hoover RN (1986) Rauwolfia use and breast cancer: a casecontrol study. J. Natl Cancer Inst., 76, 817. 69. Baez MA, Garg DC, Jallad NS, Weidler DJ (1986) Antihypertensive effect of doxazosin in hypertensive patients: comparison with atenolol. Br. J. Clin. Pharmacol., 21, 63S. 70. Lehtonen A, Himanen P, Saraste M et al (1986) Double-blind comparison of the effects of long-term treatment with doxazosin or atenolol on serum lipoproteins. Br. J. Clin. Pharmacol., 21, 77S. 71. Stannard M, Cohen M, Marrott PK, Paseucci VL (1986) Antihypertensive therapy with indoramin: risk-benefit profile in clinical practice. J. Cardiovasc. PharmacoL, 8, Suppl 2, $48. 72. Grube E, Giesing M (1986) Antihypertensive therapy in the Federal Republic of Germany: clinical practice experience with indoramin (Wydora). J. Cardiovasc. Pharmacol., 8, Suppl 2, $43. 73. Deitch MW, Allen IE, Pascucci VL (1986) Antihypertensive therapy with indoramin in the elderly. J. Cardiovasc. PharmacoL, 8, Suppl 2, $88. 74. Overlack A, Stumpe KO (1986) Comparison of the effect of indoramin and prazosin on blood pressure and lipid profiles in essential hypertension. J. Cardiovasc. Pharmacol., 8, Suppl 2, S53. 75. Chin DKF, Ho AKC, Tse CY (1986) Neuropsychiatric complications related to use of prazosin in patients with renal failure. Br. Med. J., 293, 1347. 76. Sperzel WD, Glassman HN, Jordan DC, Luther RR (1986) Overall safety of terazosin as an antihypertensive agent. Am. J. Med., 80, Suppl 5B, 77. 77. Anonymous (1987) Koorts veroorzaakt door labetalol. Bull. Bijwerk. Geneesm., 3, 13. 78. Hasegawa K, Sakamoto Y, Mitsunaga K (1980) Drug fever due to oxprenolol. Br. Med. J., 2, 27. 79. Costa FV, Borghi C, Mussi A, Ambrosioni E
181 (1986) Cadralazine and chlorthalidone as a secondstep drug with atenolol in hypertensive patients: differences in blood pressure control during exercise. Eur. J. Clin. Pharmacol., 30, 145. 80. Persson B, Granerus G, Wysocki Met al (1987) Acute systemic and renal haemodynarnic effects and long-term antihypertensive action of cadralazine in patients pretreated with beta-blockers and diuretics. Eur. J. Clin. PharmacoL, 31,513. 81. Asherson RA, Benbow AG, Speirs CJ etal (1986) Pulmonary hypertension in hydralazine induced systemic erythematosus: association with C4 null allele. Ann. Rheum. Dis., 45, 771. 82. Anandadas JA, Simpson P (1986) Cardiac tamponade, associated with hydralazine therapy, in patients with rapid acetylator status. Br. J. Clin. Pract., 40, 305. 83. Mason PD, Lockwood CM (1986) Rapidly progressive nephritis in patients taking hydralazine. J. Clin. Lab. Immunol., 20, 151. 84. Friedman E, Mandel M, Katznelson D, Sack J (1986) Pheochromocytoma and hydr alazine-induced myocardial ischaemia in a 14-year-old boy. Eur. J. Pediatr., 145, 318. 85. Sequeira W, Polisky RB, Alrenga DP (1986) Neutrophilic dermatosis (Sweet's syndrome): association with a hydralazine-induced lupus syndrome. Am. J. Med., 8l, 558. 86. Sehgal VN, Gangwani OP (1986) Hydralazineinduced fixed drug eruption. Int. J. Dermatol., 25, 394. 87. Tunkel AR, Shuman M, Popkin M e t al (1987) Minoxidil-induced systemic lupus erythematosus. Arch. Intern. Med., 147, 598. 88. Jones JK (1986) Evaluation of a case of StevensJohnson sydrome. Drug Inf. J., 20, 487. 89. Clissold SP, Heel RC (1987) Topical minoxidil: a preliminary review of its pharmacodynamic properties and therapeutic efficacy in alopecia areata and alopecia androgenetica. Drugs, 33, 107. 90. Price VH (1987) Topical minoxidil (3%) in extensive alopecia areata, including long-term efficacy. J. Am. Acad. Dermatol., 16, 737. 91. Rietschel RL, Duncan SH (1987) Safety and efficacy of topical minoxidil in the management of androgenetic alopecia. J. Am. Acad. Dermatol., 16, 677. 92. Fielder VC (1987) Topical minoxidil solution (l~o and 5%) in the treatment of alopecia areata. J. Am. Acad. DermatoL, 16, 745. 93. Zachariah PK, Sheps SG, Schirger A et al (1986) Antihypertensive efficacy of pinacidil - automatic ambulatory blood pressure monitoring. Eur. J. Clin. Pharmacol., 31, i 33. 94. Nicholls DP, Murtagh JG, Scott ME et al (1986) Acute haemodynamic effects of pinacidil in man. Br. J. Clin. Pharmacol., 22, 287.
21
Antihypertensive drugs
Since last year's chapter was written, some interesting developments have occurred. We are seeing much more of a move towards the treatment of hypertension with angiotensinconverting enzyme (ACE) inhibitors and calcium-channel antagonists (see Chapter 19) than previously. Despite initial difficulties with both captopril and enalapril, is seems clear that modern drugs, appropriately handled, provide treatment regimens which may be more acceptable to patients than older compounds which in one way or another interacted with the sympathetic nervous system. In addition, the concept of potassium-channel activators is being explored. At least one such compound is in Phase II evaluation and shows promise (P). During the year, a number of reviews have been published. In particular, further progress has been made by the Hypertension and Detection Follow-Up Program (2R). Unfortunately, as with many other large epidemiological reviews, the drugs included are rather oldfashioned. What this program does show, however (as mentioned in SEDA-11), is the high rate of patients' complaints prior to entry. This 'background noise' may be carried over into any study of side effects and the authors point out that the lack of a control group poses difficulties of interpretation. Two good reviews have appeared, one on the effects of antihypertensive drugs on lipids and looproteins (3 R) and the other on glucose tolerance (4R). In particular, it is becoming clear that many of the drugs associated with favorable lipid profiles, e.g. guanabenz, clonidine, labeta1ol, indapamide and guanfacine, may not be widely regarded as first-line therapy. It will be interesting to see the results of large-scale studies of the long-term effects of ACE inhibitors and calcium-channel antagonists on lipid and carbohydrate profiles. A review of the effects of centrally acting drugs administered neonataily to rodent pups has been published (5r). The authors claim that neonatally administered centrally acting drugs Side Effects of Drugs Annual 12 M.N.G. Dukes and L. Beeley, editors 9 Elsevier Science Publishers B.V., 1988
suppress REM sleep and cause hyperactivity, hyperanxiety, reduced sexual activity and decreased cerebral cortical size. Extrapolation to the human state seems to ignore several factors. The first is that the quantities of drugs given to these animals may be greater than would be expected either from transplacental transfer or exposure to breast milk. Secondly, the t/me of exposure in the process of development is significant. Thirdly, Redman et al have already published their findings on children exposed in utero to methyldopa and found no detectable effects (6c), although a study discussed later (60c) on clonidine does suggest some minor effects. Some more information about the association of stroke with sudden lowering of the blood pressure has been published (7~, 8"). Although, as might be expected, the elderly appear to be more vulnerable to cerebral infarction under these circumstances, it is clear that this can occur in young people as well. One novel development is the use of topical minoxidil to treat hair loss. Side effects associated with this approach will be dealt with later in this Chapter.
ANGIOTENSIN-CONVERTING ENZYME (ACE) INHIBITORS (SED-IO, 356; SEDA-9,
193; SEDA-10, 174; SEDA-11,183) An overview of the effects of some currently available ACE inhibitors has recently been published (9R). In addition, a number of other reports have appeared. Captopril (SED-IO, 356; SEDA-9, 193;
SEDA-IO, 174; SEDA-11,183)
Cough Five further cases ofcaptopril-induced cough have been reported (10 ~, 1 lC). The mechanism for this is still unknown. One interesting feature is that the onset and offset of the symptom may be quite delayed (10c).
Cardiovascular There is a further report of a first-dose effect in a 61-year-old woman with con-
Antihypertensive drugs Chapter 21 gestive heart failure (12c). Hypotension occurred twice in response to oral doses of 12.5 mg. It is not clear whether this woman was taking diuretics at the time, but her serum electrolytes were said to be within the normal range. There is a report of 2 severely hypertensive patients who developed large falls in blood pressure in response to a single dose of captopril 6.5mg (13c). Both had extensive vascular disease complicated by renal and neck artery stenosis. Both became dizzy and one became aphasic at the same time. All symptoms and signs reversed as the blood pressure rose again. The authors conclude that stenosis of vessels supplying the brain may exacerbate the neurological response to hypotension and promote focal vascular lesions. There is an interesting account of a 34-yearold man with severe congestive cardiac failure who had been treated with captopril 150 mg/d for 4 months in addition to furosemide and digoxin (14c). The eaptopril was suddenly discontinued while the rest of the treatment regimen was continued. The patient developed ventricularfibrillation 1 week later and was found to have a serum potassium of 2.8 mmol/1. Previously he had been normokalemic. The authors conclude that the hypokalemia was due to a rebound after removal of captopril. However, since furosemide was continued without potassium supplementation, this argument may be little unconvincing. It should also be borne in mind that the dose of captopril used is vastly in excess of that recommended by the manufacturers today. If one assumes a rebound phenomenon, extrapolation to current dosage regimens is tenuous. The same authors describe a patient who became hyperkalemic and had a cardiac arrest while taking digoxin, captopril 150 mg/d and potassium salt substitute. Hematological A 68-year-old man was treated with captopril 37.5 mg t.d.s, for heart failure (15c). He was admitted to hospital septicemic and was treated with antibiotics in addition to his usual heart failure therapy. He became thrombocytopenic during this illness. The thrombocytopenia resolved when captopril was stopped. No other drugs were stopped at the same time. No other hematological abnormalities were observed. In particular, there was no evidence of disseminated intravascular coagulation or platelet antibodies. This complex history is difficult to interpret.
Urinary system Packer et al (16c) have also reviewed their experience of 86 patients with
173 heart failure taking captopril in doses of 75150mg/d. They conclude that where renal impairment occurs in this group of patients, it is always due to an excessive fall in left ventricular filling pressure or mean arterial pressure. It should again be borne in mind that the doses used are very high and that a different interpretation may be required for similar effects occurring with lower doses of captopril. Patients with pre-existing renal impairment can be treated with captopril, but some precautions will need to be observed. Hirakata et al (17 c) report their experience of 13 patients with chronic renal failure requiring hemodialysis. These patients became slightly more anemic when treated with captopril in a mean dose of 19.3 mg/d. Angiotensin II levels fell and correlated with the reticulocyte count both before and after exposure to captopril. Plasma erythropoietin concentrations remained unchanged, but it is not clear whether they were normal or not. The authors hypothesize that reduction of circulating angiotensin II levels may contribute to the anemia experienced by patients with severe chronic renal failure. There are several further reports of reversible renalfailure in patients with renal artery stenosis (18c-22~). At present, there is some discussion as to whether a 'captopril provocation test' is sufficiently predictable to be used to make the diagnosis of renovascular disease. A 40-year-old woman with severe hypertension developed signs of the nephrotic syndrome while taking captopril 450 mg/d (23c). She did not have renovascular disease. Renal biopsy revealed mesangial prominence with basement membrane thickening, crescents and focal glomerulosclerosis. The tubules demonstrated focal cellular loss with pronounced interstitial inflammatory infiltrates. Immunofluorescence showed granular deposits of C3 and IgG along the basement membrane. The signs resolved very slowly once eaptopril was stopped. They did not recur when the patient was treated with enalapril. Madeddu et al (24 c) report their experience with 10 psoriatic patients treated for hypertension with captopri125 mg t.d.s. Three developedproteinuria which resolved when captopril was stopped. Interestingly, 3 patients also experienced a marked and unexpected improvement in their skin disorder while taking captopill. Some other aspects of the renal effects of captopril are dealt with under 'Interactions' (below).
174
Chapter 21 J.A. Steiner
Skin and appendages A number of rashes have again been reported. There are 2 cases ofpemphigus (25 r 26c), a lichenoid eruption (27r a case of pityriasis rosea (28~) and an episode of psoriasis (29c). There was also an episode of buccal mucous membrane ulceration apparently not associated with dysgeusia (30~). There was 1 case ofonycholysis in a patient with renal artery stenosis treatment with captopri150 mg/d (31r Most of these lesions resolved when captopril was stopped.
zosin became hypotensive when given captopril 12.5 mg/d (37c). Captopril alone did not have this effect and the authors postulate an interaction between captopril and chlorpromazine. This seems credible, since hypotension is a wellknown complication of antipsychotic drugs which is readily potentiated by other agents (SED-10, 96, 104).
Special senses Sekimoto and Tomita (32r suggest that zinc deficiency due to chelation of zinc by captopril or other antihypertensive agents may cause the taste disturbances which are sometimes experienced. This is based on a study of 193 patients with taste disorders while taking a variety of drugs. Fifty-six percent were zinc-deficient. Unfortunately, there is no control group for comparison.
An open study of 42 patients with heart failure taking either captopril 150mg/d or enalapri140 mg/d as a single daily dose has been presented (38c). Enalapril is said to have been associated with a more prolonged hypotensive effect than captopril, although the actual trough blood pressure values are not given. A greater fall in creatinine clearance and rise in serum potassium concentrations was observed in the enalapdl group. This has been interpreted as a response to prolonged hypotension and possibly ACE inhibition. These data are difficult to relate to normal therapeutic practice given that the dose used is so much higher than the 2.5 mg recommended by the manufacturers.
Hypersensitivity New cases of angioedema have been reported to the U.K. Committee on Safety of Medicines. Of 6 patients, 3 also developed urticaria (33r All resolved when treatment was suspended. A 49-year-old woman taking captopril 150 mg/d developed facial edema and a rash. Captopril was discontinued, but she developed agranulocytosis and septicemia of which she died (34~). In the same paper there is a description of a 55-year-old man given captopril 12.5 mg. He also developed facial edema which resolved when captopril was stopped. It is clear that drug-related angioedema may occur with relatively small doses of captopril. Interactions Administration of captopril and metolazone together has been claimed to cause a sufficient degree of renal impairment to cause problems, although the evidence comes from a ease with multiple medication and is therefore not easy to interpret. A 65-year-old woman with congestive cardiac failure was treated with captopril 25mg b.d., furosemide, digoxin, mianserin, warfarin and spironolaetone (35~). Addition ofmetolazone 5 mg produced nausea, anorexia and malaise. This was attributed to renal failure with associated digoxin toxicity. Discontinuation of captopril and metolazone led to a return to normal renal function with resolution of symptoms. Another report of 32 patients, however, demonstrates that captopril inhibits renal clearance of digoxin (36c). A 49-year-old schizophrenic taking chlorpromazine, hydrochlorothiazide, nadolol and pra-
Enalapril (SED-IO, 358; SEDA-9, 195; SEDA-IO, 176; SEDA-11,185)
Cough As with captopril, there are a number of reports of dry cough (11 c, 33~ 39c, 40c). Gavras in an open study of 276 patients, estimates the incidence to be 0.7% (39c). There was also a 45-year-old woman taking enalapril 10mg/d who presented with severe nasal obstruction (41c). The symptom reversed when enalapril was stopped and recurred on rechallenge. Nervous system A 66-year-old man developed a transient fight hemiparesis 2 hours after a single dose ofenalapril (39r His blood pressure at the time is not given. However, he was found to have bilateral carotid artery stenosis. A 41-year-old patient given enalapril 2.5 mg and atenolol 100 mg decreased his blood pressure from 200/140 to 100/60mmHg. Several hours later he became paraplegic. The authors postulate an infarction of the thoracic spinal cord secondary to hypotension (42c). Mineral and fluid balance A 75-year-old man with a creatinine clearance of 30 ml/min became hyperkalemic after being given enalapril 5 mg/d and furosemide 20 mg/d (43c). Urinary system Evidence is presented that enalapril in doses of 20-40 m u d in patients with
Antihypertensive drugs Chapter21 heart failure decreases renal function through a sustained fall in mean arterial of let~ ventricular filling pressure just as does captopril (16 c ). This sort of problem has prompted the manufacturers to limit the starting dose in this group of patients to 2.5 mg and in hypertensives to 5 mg (44r). However, enalapril also decreases renal function in post-renal-transplant patients. Six of 18 patients experienced a reversible decrease in renal function while the rest had no renal effect as estimated by creatinine clearance (45r The dose used is not mentioned. There were no obvious differences between those whose creatinine clearances deteriorated and the others. In particular, differences in blood pressure do not appear to have been important. In an intriguing study, enalapril 10-40 mg/d and hydrochlorothiazide were compared with triple therapy (hydrochlorothiazide, timolol and hydralazine) for efficacy and safety in 75 patients with documented unilateral or bilateral renal artery stenosis (46c). Ten of 49 patients taking enalapril developed a rise in serum creatinine of 0.3 mg/100 ml or greater and a fall in inulin clearance. Enalapril was associated with an increase in effective renal plasma flow as measured by PAH clearance in all patients, even those whose serum creatinine concentrations rose significantly. No patient developed clinical renal failure. This is of some interest since it suggests that enalapril may be used cautiously, if needed, in patients with renal artery
stenosis.
Hypersensitivity
New cases of angioedema have been reported to the U.K. Committee on Safety of Medicines (33c). All resolved when treatment was suspended. A case of reversible angioedema is reported in a 59-year-old man who took a single dose of 10 mg of enalapril (47c). Apparently, he had never been exposed to ACE inhibitors in the past.
Overdosage A 56-year-old woman with heart failure took enalapril 440 mg in a suicidal attempt (48c). She became severely hypotensive, uremic, acidotic, hyperkalemic and hyponatremic. ACE inhibition was virtually complete for a week and angiotensin II and aldosterone were suppressed for the same time. The patient recovered with supportive therapy.
175 compound-related and which are likely to be common to the entire group.
CUazapril In a study of 27 patients, cilazapril caused dizziness in one patient (49c). Another patient developed a r/se in serum creatinine concentration. This was reversible and did not reappear on rechallenge.
Lisinopril Four cases of dry cough have been reported with lisinopril (50c). Two resolved when therapy was stopped and one resolved despite continuing therapy. One patient had a cough prior to therapy which persisted thereafter and may not have been drug-related. D R U G S A C T I N G ON THE SYMPATHETIC NERVOUS SYSTEM: PRESYNAPTIC ~ - A D R E N O C E P T O R AGONISTS (SED-IO, 361; SEDA-9, 197;
SEDA-IO, 179; SEDA-11, 186)
Clonidine (SED- I O, 361; SEDA-9, 197; SEDA-IO, 179; SEDA-I 1,186) Cardiovascular A patient suffering from a myocardial infarct was given clonidine 0.5 mg to control sudden severe hypertension (51~). He developed prolonged hypotension and was treated with naloxone with a prompt rise in blood pressure. Nervous system
Clonidine has been evaluated in the treatment of spinal spasticity in 12 patients (52c). A number of these experienced dizziness and lethargy or drowsiness, as would be expected. Three patients had episodes of autonomic hyperreflexia. In 2 of these, the spells were associated with involuntary neck and face movements which had not occurred previously. The situation is difficult to evaluate since the subjects had also taken antihistamines at the time, but the drug has long been known to have effects on the nervous system (SED-10, 362). An infant aged 9 months accidentally received clonidine from a transdermal patch (53 ~ He became irritable, drowsy, anorexic and polydipsic. The symptoms resolved promptly when the patch was removed.
Endocrine, metabolic
Other ACE inhibitors
In the past, clonidine has variously exhibited hyperglycemic or hypoglycemic effects, depending on the situation in which it was used (SED-10, 363).
As the number of ACE inhibitors increases, so it becomes clearer which adverse effects are
A 52-year-old woman suffering from non-insulindependent diabetes mellitus was given clonidine
176 0.225 mg/d in addition to methyldopa and metoprolol. Her blood glucose and hemoglobin AI levels had previously been controlled with diet and an oral hypoglycemic agent but became abnormal once clonidine was started (54c). The authors demonstrated that when she was taking clonidine, her insulin responseto a glucose load diminished compared with her response a~er clonidine was stopped. Skin and appendages A number of trials of transdermal clonidine have been published. In all, the main adverse event was contact derraalitis (55c-57r This seems mainly due to the adhesive in the patch (58 c) and on occasion has been severe enough to warrant stopping of therapy. Even systemic clonidine is however known to produce rash (SED-10, 362). Withdrawal effects The cardiovascular response to clonidine withdrawal is well documented (SED-10, 362). Labetalol continues to be a useful treatment for this condition (59"). However, a study of the effects of abrupt withdrawal of clonidine in Giles de la Tourette syndrome has now been published (60c). Five of 7 young patients showed marked worsening of their tics. Increases in motor restlessness, blood pressure and pulse rate were also observed. When clonidine was reinstituted, it took 2 weeks to 4 moaths to control the tic symptoms again. The authors postulate that the neurological expressions of withdrawal may be due to increased CNS catecholamine turnover.
Second-generationeffects Twenty-two children have been studied whose mothers were treated with clonidine in pregnancy (6P). Eighteen were full-term deliveries. They were compared with 22 matched controls 3-91/2 years after birth. The children treated with clonidine showed an excess of disturbed sleep patterns as assessed by a comprehensive questionnaire. No other neurological or developmental differences were found between the two groups. It is not clear whether the sleep disturbances resolved as the children grew older. This type of'behavioral' effect in the second generation can be difficult to study, but approaches to it are now being better defined than in the past (62R). DRUGS I N T E R F E R I N G WITH NEUROTRANSMITTERS
Methyldopa (SED-IO, 358; SEDA-9, 198; SEDA-IO, 180; SEDA-11,187) Hematological Hemolytic anemia is a wellknown complication of methyldopa therapy.
Chapter 21 J.A. Steiner Seven patients with a positive direct antiglobulin test were examined (63c). Two of these had signs of hemolysis. In these 2 patients, ehiates from red cells contained antibodies of the IgG subclass and supported antibodydependent mononuclear-cell-mediated phagocytosis and cytotoxicity of the patients' red cells even after remission. This was not found in the 5 patients without hemolysis. Another patient with hemolytic anemia was studied by a Japanese group (64c). In this case, an IgG kappa antibody was eluted which agglutinated 44 different groups of red cell specimens but did not agglutinate Rh null red cells. Liver A 40-year-old male patient taking methyldopa and hydrochlorothiazide developed signs and laboratory signs of mild cholestasis (65c). A liver biopsy was not performed. Both drugs were suspended and the jaundice resolved promptly. Clearly it is difficult to assess which of the two drugs may have been responsible, but methyldopa has been associated with a range of hepatic complications in the past (SED-10, 359) while thiazides very rarely cause such problems, if at all (SED-10, 377).
Autoimmune effects A 78-year-old woman treated with methyldopa 500 mg t.d.s., cyclopenthiazide and naftidrofuryl oxalate developed a lupus-like syndrome (66c). Antinuclear antibodies were present in a titre of 1:320. Methyldopa was stopped and some of her signs resolved. However, on the next visit she had developed some of the features of scleroderma. It is difficult to assess whether this illness is drug-related or not. Miscellaneous A 48-year-old man treated with methyldopa 250 mg b.d. developed hyperpigmentation of the tongue. Biopsy was refused. The signs resolved slowly once methyldopa was suspended (67c).
Rauwolfia alkaloids (SED- I O, 364; SEDA-9, 199; SEDA-IO, 181) A case-control study of 1362 rauwolfia users and 1250 controls was conducted in a multicenter breast cancer screening program (67r Allowing for other variables such as age, menopausal status and family history, prolonged rauwolfia use was associated with about a 4-fold increase in relative risk of developing breast cancer. This conflicts with the results of some previous studies (SEDA-6, 205) but not others (SED-10, 364).
Antihypertensive drugs Chapter 21 ~q-ADRENOCEPTOR A N T A G O N I S T S
(SED-IO,361; SEDA-9, 197; SEDA-IO, 179) Doxazosin Doxazosin, a member of the quinazoline family to which prazosin belongs, has been compared double-blind to atenolol and placebo in a small study (69c). Symptoms which were attributed to it were postural dizziness, headache,
abdominal discomfort, blurred vision, edema, lack of energy, chest discomfort, sedation, constipation and dry mouth. It should be said that all of these also occurred with atenolol at about- the same frequency and, to a lesser extent, with placebo. In another study (70r total serum cholesterol was lowered in comparison to atenolol by about 10% of baseline values and LDL cholesterol by about 20%. HDL cholesterol rose marginally. The lipid effects are thus comparable in type to those seen with prazosin. lndoramin (SED- I O, 361) Newer work on indoramin largely confirms the preliminary impressions recorded in these volumes as early as 1984. Two large open studies of the use of indoramin in Step II antihypertensive therapy have been published. The first (70 ~) included hypertensive patients taking indoramin 50-200 mg/d and diuretic. By far the most common side effect was drowsiness ( 1 9 ~ ) which also caused the largest number of withdrawals. Other common side effects were dizziness ( 8.3 ~o), headache ( 5.2 % ), lack of energy (4.3 %), dry mouth (2.8 %), depression (2.7 %), nausea (1.9%), weight gain (1.7%), ejaculator), failure (2.5 %) and impotence (1.9 %). Another study (72c) included 3708 patients taking fl-adrenoceptor antagonists and diuretics in addition to indoramin 50-125 mg/d. The most common side effects were tiredness (8.3 %), dizziness (5.6%), dry mouth (4.0%), nausea (3.4%) and headache (2.8%). A similar profde has been obtained in the elderly (73c). Like other drugs of this class, indoramin appears to lower total serum cholesterol concentrations (74c). Prazosin (SED- I O, 360; SEDA-9, 197;
SEDA-IO, 179; SEDA-II, 187) Nervous system Mental changes with prazosin have been reported sporadically in the past, but sufficiently convincingly to show that a minority of patients will experience them.
177 Three patients are described all with chronic renal impairment who developed mental abnormalities while taking prazosin (75c). In 2 eases, these consisted of psychotic symptoms and in the 3rd drowsiness, confusion and disinhibited behavior. In 2 of these patients, abnormal EEGs with diffuse slow-wave activity were obtained. One of these returned to normal when prazosin was stopped. The mental abnormalities resolved in all 3 cases alter stopping prazosin. The authors attributed the side effect to reduced prazosin clearance or decreased protein binding of prazosin in patients with chronic renal failure. Terazosin (SEDA-I 1,187) Approximately 1000 patients who have been enrolled in terazosin studies have been reported upon (76c). Of these, 567 received terazosin in placebo-controlled studies and the rest in open studies. Side effects in these 567 patients were dizziness (29.1 ~ ), asthenia (13.6 % ), somnolence (6.2 ~o),peripheral edema (6.0 ~ ) , nausea (5.1 ~o), palpitations (4.6%) and blurred vision (1.6%). These incidences all exceeded those in the placebo group considerably. In the entire group, the main side effects were dizziness (29.0%), headache (28.8%), asthenia (21.3~), nasal congestion (12.0 ~o) and cold symptoms (11.5 ~ ) . The dose ofterazosin was up to 40 mg/d. It may be that the increased frequency of side effects in the group as a whole is due to a greater average dose ofterazosin than in controlled trials alone, but it is difficult to define this from the publication. None of the symptoms, however, seem at all unexpected in view of experience with prazosin.
Ct- AND fl-ADRENOCEPTOR ANTAGONISTS Labetaloi (SED- I O, 328; SEDA-9 , 178;
SEDA-11,166) Pyrexia as a reaction to beta-blockers must be very rare; 1 case with oxprenolol was reported in 1980 (77 c) and there are now 2 exceptionally well-documented case-reports with labetalol
(78cr).
The Netherlands Centre for Monitoring of Adverse Reactions to Drugs has published details of 2 cases in which labetalol caused fever. One was a woman of 61 with hypertension and a history of myocardial infarct who had earlier developed cold feet when treated with metoprolol and an itching rash with urticaria when treated with pindolol; the rash disappeared when she was transferred to labetalol (300 mg/d) and other concurrent medication was continued, but 3 weeks later
Chapter 21 J.A. Steiner
178 she developed pronounced pyrexia (39.80 ~C) without shivering or pain. The fever disappeared when labetalol was withdrawn but reappeared on 2 different attempts at rechallenge, the latter with a dose of only 100 mud. The second patient, a woman of 67, showed a very similar reaction to 300 mud oflabetaloi and to rechailenge with 100 mud.
D I R E C T V A S O D I L A T O R S (SED-IO, 352;
SEDA-8,206; SEDA-9, 195; SEDA-IO, 177; SEDA-11, 187) Cadralazine (SEDA-I O, 178; SEDA- I1,187) In two small studies of the use ofcadralazine, typical vasodilator side effects were found (79 r 80r These included headache, edema, weight
gain, flushing and palpitations. Hydralazine (SED-IO, 353; SEDA-9, 195;
SEDA-IO, 177; SEDA-11,188) Nearly a decade after a full review of lupuslike-complications to hydralazine in these volumes (SED-9, 318, 319) new features continue to be observed. A 52-year-old woman developed a lupus-like syndrome with some interesting features after having taken hydralazine 150 mud for 18 months (81c). The rare manifestations were pulmonary hypertension, lesions on the lung scan presumed to be pulmonary vasculitis and, in addition to slow acetylator status and HLADR4 antigen, a null allele for CA. In addition, she had antibodies to double-stranded DNA, lupus erythematosus (LE) cells and antinuclear antibodies (ANA). The syndrome resolved completely when hydralazine was stopped and prednisolone given. Another patient also presented with unusual cardiovascular features (82c). This was a 53-year-old woman taking hydralazine 200 mg/d as well as a number of other antihypertensive medications. She presented with a chronicpericardial effusion. She was negative for LE cells and ANA and was a fast acetylator. Antibody titers to doublestranded DNA were elevated. She was HLA-DR4 negative. A number of coagulation function tests were abnormal. Interestingly, she had elevated antibody titers for respiratory syncytial (RS) virus. The effusion was drained and did not recur once hydralazine was stopped. The authors argue that the effusion was unlikely to be due to the RS virus since so many features of the case are unusual for such an infection. Urinary system Two cases of rapidly progressive nephritis are reported (83c). These occurred without the usual signs of the lupus-like syn-
drome although A N A was present and both patients were slow acetylators. Both cases had rapidly progressive renal failure, proteinuria, hematuria and granular casts. In one renal biopsy there was a focal segmental proliferative pattern, positive for IgM and C3 on immunofluorescence. In the other, there was a crescentic nephritis with focal mesangial deposits of IgG and IgM. Both patients were taking hydralazine 150 mg/d which was stopped. Both responded well to cyelophosphamide and prednisolone. Risk situations A 14-year-old boy known to have apheochromocytoma was given hydralazine 6.25 mg i.m. to control a hypertensive crisis (84c). He became very hypotensive and developed angina pectoris and signs of isehemia in the anteroseptal E C G leads. These fortunately resolved without sequelae with the passage of time. Skin and appendages There are 2 reports of cutaneous manifestations, possibly linked to hydralazine therapy. A 60-year-old woman was taking 75 mg hydralazine daily. She had two eposides of an influenza-like illness (85c). Ten days after the 2nd episode, she developed polyarthritis and a rash. The polyarthritis was resistant to therapy with NSAIDS. The rash took the form of erythematous indurated plaques on the neck, forearms, shouders and face. A skin biopsy showed a dense band-like infiltration of leukoeytes, mainly neutrophils, in the upper dermis. There was no evidence ofvasculitis. ANA was present in high titer. Her acetylator status is not known. Pleuritic chest pain developed and the hydralazine was stopped. The outcome is not clear from the report. The skin biopsy was consistent with a diagnosis ofneutrophilic dermatosis or Sweet sydrome, which is commonly caused by viral infections or by underlying malignant disease. However, in the authors' view, the clinical course was uncharacteristic of a viral illness which generally resolves quickly and no malignancy has become apparent. For this reason, they ascribe the syndrome to hydralazine. A 62-year-old man, taking dihydralazine (the dose is not given) delevoped an erythematous eruption confined to the nose and upper lip (86c). This resolved when dihydraiazine was stopped and recurred on 2 further occasions in response to rechallenge. No other tests were performed. Minoxidil (SED-IO, 354; SEDA-IO, 178;
SEDA-11,188) Cardiovascular, respiratory A 78-year-old woman taking minoxidil 10 mg/d developedpleural and pericardial effusions and a positive A N A
Antihypertensive drugs Chapter 21 titer. These resolved when minoxidil was stopped. The situation is difficult to interpret since immediately prior to taking minoxidil, the patient had been taking hydralazine which was discontinued when minoxidil was started (87~). However, effusions have been reported with minoxidil on earlier occasions (e.g. SED10, 354; SEDA-11,188).
Skin and appendages A 36-year-old m a n was treated with minoxidil 10 mg/d and developed a Stevens-Johnson sydrome. This resolved with discontinuation of antihypertensive therapy and treatment with steroids. It recurred promptly when minoxidil was restarted (88~). Topical minoxidil has been evaluated as a treatment for alopecia. A substantial review has recently been published (89c). Cardiovascular events seem to be rare and mostly related to small falls in blood pressure or rises in heart rate
179 which have not proved troublesome. Most reactions have been in the skin such as pruritus, scaling, flushing and hair growth at distant sites (90c). Occasional episodes of contact dermatitis, reproducible with patch testing, have been described (91 c, 92c). The overall incidence of the contact dermatitis is not yet clearly defined, but it is obviously at present a source of concern to National Centers for Adverse Reaction Monitoring.
Pinacidil (SEDA-IO, 179; SEDA-11,188) In two small trials pinacidil again appears to have primarily side effects characteristic of vasodilatation. These include edema, headache, palpitations and hirsutism (93c). There are reports of nausea, bradycardia and hypotension, but this is in the context of an invasive heinedynamic study (94c).
REFERENCES 1. VandenBurg MJ, Woodward SA, Tasker T et al (1987) Potassium channel activators: hypotensive activity and adverse effect profile - the first study with BRL 34915. In: Proceedings, Third European Meeting on Hypertension, p 586. 2. Curb JD, Maxwell MH, Schneider KA etal (1986) Adverse effects of antihypertensive medications in the Hypertension Detection and Followup Program. Prog. Cardiovasc. Dis., 29, Suppl I, 73. 3. Ames RP (1986) The effects of antihypertensive drugs on serum lipids and lipoproteins. II. Nondiuretic drugs. Drugs, 32, 335. 4. Houston MC (1986) Adverse effects ofantihypertensive drug therapy on glucose intolerance. Cardiol. Clin., 4, 117. 5. Mirmiran M, Brenner E, Van tier Gugten J, Swaab DF (1985) Neurochemical and electrophysiological disturbances mediate developmental behavioral alterations produced by medicines. Neurobehav. Toxicol. Teratol., 7, 677. 6. Redman CWG, Beilin l_J, Bonnar J e t al (1976) Foetal outcome in a trial of antihypertensive treatment in pregnancy. Lancet, 2, 753. 7. Jansen PAF, Schulte BPM, Meyboom RHB, Gribnan FWJ (1986) Antihypertensive treatment as a possible cause of stroke in the elderly. Age Ageing, 15, 129. 8. Matenga J, Kitai I (1986) Iatrogenic strokes in hypertensive patients. Cent. Aft. J. Med., 32, 130. 9. DiBianco R (1986) Adverse reactions with angiotensin converting enzyme (ACE) inhibitors. Med. ToxicoL, 1,122. 10. Carruthers SG (1986) Severe coughing during eaptopril and enalapril therapy. Can. Med. Assoc. J , 135,217. 11. Keim HJ, Beckers G (1987) Medikament6s in-
duzierter Reizhusten. Miinch. Med. Wochenschr., 129, 218. 12. Black J, Hunt TL, Godley PJ (1986) Intitiation of captopril therapy: the first dose effect. J. Clin. PhamacoL, 26, 539. 13. Jensen H, Ring-Larsen H, Garsdal P, Fruergaard P (1986) Carotid artery stenosis exposed by an adverse effect of captopril. Br. Med. J., 293, 1073. 14. Packer M, Lee WH (1986) Provocation ofhyperand hypokalemic sudden death during treatment with and withdrawal of converting-enzyme inhibition in severe chronic congestive heart failure. Am. J. Cardiol., 57, 347. 15. Walsh KP, Walsh MJ, Branagan JP (1986) Reversible severe thrombocytopaenia associated with captopril therapy. It. Med. J., 79, 43. 16. Packer M, Lee WH, Medina N et al (1987) Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure. Ann. Intern. Med., 106, 346. 17. Hirakata H, Onoyama K, Hori K, Fujishima M (1986) Participation of the renin-angiotensinsystem in the captopril-indueed worsening of anemia in chronic hemodialysis patients. Clin. Nephrol., 26, 27. 18. Greminger P, Vetter H, Steurer J e t al (1986) Captopril and kidney function in renovascular and essential hypertension. Nephron, 44, Suppl I, 91. 19. Durand D, Ader JL, Lloveras JJ et al (1986) Pr~dictabilit~ de I'insuffisance renale aigu~ post-captopril dans les hypertensions art~rielles avec st~nose de l'art~re r~nale d'un rein unique ou st~nose bilat~rale. Arch. Mal. Coeur Vaiss., 79, 888. 20. Mourad G, Ribstein J, Argiles A e t al (1986) Hypertension art&idle et st6nose de l'art~re du greffon: effets de l'inhibition de renzyme de conversion. Arch. Mal. Coeur Vaiss., 79, 892.
180 21. Rodero FG, Millet VG, Iglesias JN et al (1986) Fracaso renal agudo inducido per captopril en presencia de estenosis bilateral de arteria renal. An. Med. lnterna, 3, 391. 22. Laplatte G, Gutbub AM, Baeumle D, Haegy JM (1986) Apparition d'une insuffisance r~nale au cours d'un traltement par le captopril et st~nose de i'art~re r~nale. Sem. Hdp., 62, 2491. 23. Webb DJ, Atkinson AB (1986) Enalapril following captopril-induced nephrotic sydrome. Scot. Med. J., 3l, 30. 24. Madeddu P, Ena P, Dessi-Fulgheri P et al (1986) Captopril-induced proteinuria in hypertensive psoriatic patients. Nephron, 44, 358. 25. Flageul B, Foldes C, Wallach D et al (1986) Captopril-induced fichen planus pemphigoides with pemhigus-like features. Dermatologica, 173, 248. 26. Ricci G, Silva M, Crippa D et al (1986) Un case di pemfigo indotto da captopril? (Letter to Editor). Rec. Prog. Med., 77, 86. 27. Mancuso G, Bernondoni RM (1986) Eruzione lichenoide da captopril. Chron. Dermatol., 17, 407. 28. Bhatia KK, Chaudhary SD, Gupta S (1985) Captopril (SQ 14, 225) induced pityriasis rosea like eruption. Indian J. DermatoL VenereoL LeproL, 51, 351. 29. Hauschild Tr, Bauer R, Kreysel HW (1986) Erstmanifestation einer eruptiv-exanthematischen Psoriasis vulgaris unter Captoprihnedikation. Hautarzt, 37, 274. 30. Corone S, Davido A, Corone P (1987) Une complication rare du captoprii: rulctration des muqueuses linguales et jagales. Rev. MJd. Interne, 8, 73. 31. Borders JV (1986) Captoprii and onychnlysis. Ann. Intern. Med., 105, 304. 32. Sekimoto K, Tomita H (1986) Zinc chelation capacity of hypotensive agents causing taste disturbance. Nihon Univ. J. Med., 28, 233. 33. Wood SM, Mann RD, Rawhns MD (1987) Angio-oedema and urticaria associated with angiotensin converting enzyme inhibitors. Br. Med. J., 294, 91. 34. Suarez M, Lye PW, Johnson ES, Perez G (1986) Angioneurotic edema, agranniocytosis and fatal septicemia following captopril therapy. Am. J. Med., 81, 336. 35. Hogg KJ, Hillis WS (1986) Captopril/metolazone induced renal failure. Lancet, l, 501. 36. Cleland JGF, Dargie H J, Pettigrew A et al (1986) The effect of captopril on serum digoxin and urinary urea and digoxin clearances in patients with congestive heart failure. Am. Heart J., 112, 130. 37. White WB (1986) Hypotension with postural syncope secondary to the combination of chlorpromazine and captopril. Arch. Intern. Med., 146, 1833. 38. Packer M, Lee WH, Yushak M, Medina N (1986) Comparison of captopril and enalaprii in patients with severe chronic heart failure. N. Engl. J. Med., 315, 847. 39. Gavras H (1986) A multicentre trial of enalapril in the treatment of essential hypertension. Clin. Ther., 9, 24. 40. Webb D, Benjamin N, Collier J, Robinson B
Chapter 21 J.A. Steiner (1986) Enalapril-induced cough. Lancet, 2, 1095. 41. Fennerty A, Littley M, Reid P (1986) Enalaprilinduced nasal blockage. Lancet, 2, 1395. 42. Brown P, Gross M, Harrison M (1987) Paraplegia following oral hypotensive treatment of malignant hypertension. J. NeuroL Neurosurg. Psychiatry, 50, 104. 43. Loeb G (1987) Hyperkali6mie suns inhibiteur de l'anzyme de conversion. Concours M~d., 109, 55. 44. Anonymous (1987) Warnings from the Committee on Safety of Medicines. Pharm. Int., 7, 194. 45. Guerin C, Genin C, Sabatier JC etal (1987) Evolution de la fonction r6nale chez le transplante r6nal hypertendu trait6 par enalapril. N~phrologie, 8, 19. 46. Franklin SS, Smith RD (1986) A comparison of enalapril plus hydrochlorothiazide with standard triple therapy in renovascular hypertension. Nephron, 44, Suppl 1, 73. 47. Marichal JF, Failer B, Brignon P (1986) Angioed~me apr6s administration d'enalapril chez un insuffisant r6nal chronique. Tl~rapie, 41,517. 48. Lau CP (1986) Attemptod suicide with analapril. N. EngL J. Med., 315, 197. 49. Belz GG, Lange H, Tschollar W, Neis W (1986) Cilazapdl bei essentieller Hypertonie. Med. Kiln., 81, 524. 50. Nash DT (1986) Lisinopril cough. Texas Heart Inst. J., 13, 353. 51. Niemann JT, Getzug T, Murphy W (1986) Reversal of clonidine toxicity by naloxone. Ann. Emerg. Med., 15, 1229. 52. Maynard FM (1986) Early clinical experience with clonidine in spinal spasticity. Paraplegia, 24, 175. 53. Reed MT, Hamburg EL (1986) Person-toperson transfer of transdermal drug-delivery systems: a case report. N. Engl. J. Med., 314, 1120. 54. Okada S, Miyai Y, Sate K et ai (1986) Effect of clonidine on insulin secretion: a case report. J. Int. Med. Res., 14, 299. 55. Boekhorst JC, Lustermans FAT, Van Tel RGL (1987) Transdermal administration of clonidine for treatment of mild-to-moderate essential hypertension. Curt. Ther. Res., 41, 215. 56. Dick JBC, Northridge DB, Lawson AA (1987) Skin reactions to long-term clonidine. Lancet, 1, 516. 57. Kellaway GSM (1986) A commanity-based trial of transdermal antihypertensive therapy with clonidine (Catapres-TrS). N Z Med. J., 99, 711. 58. Malbach HI (1987) Oral substitution in patients sensitized by transdermal clonidine treatment. Contact Derm., 16, 1. 59. Mehta JL, Lopez LM (1987) Rebound hypertension following abrupt cessation of clonidine and metoproiol. Arch. Intern. Med., 147, 389. 60. Leckman JF, Ort S, Caruso KA et al (1986) Rebound phenomenon in Tourette's syndrome after abrupt withdrawal of clonidine. Arch. Gen. Psychiatry, 43, 1168. 61. Huisjes HJ, Hadders-Algra M, Touwen BCL (1986) Is clonidine a behavioural teratogen in the human? Early Hum. Dev., 14, 43.
Antihypertensive drugs Chapter 21 62. World Health Organization (1986) Guidelines for the Evaluation of Drugs and Other chemicals for Behavioral Teratogenicity. Revised drain, WHO, Regional Office for Europe, Copenhagen. 63. Yust I, Frisch B, Goidsher N (1986) Antibody dependent cell-mediated cytotoxicity and phagoeytosis of autologous red blood cells in alpha methyldopa-induced haemolysis. Scand. J. HaematoL, 36, 211. 64. Itoh Y, Yuasa S (1986) Blood group specificity of an autohaemagglutinin induced by alpha methyldopa therapy. Jpn. J. Leg. Med., 40, 30. 65. Venkateswara K (1986) Cholestaticjaundice associated with methyldopa. Minnesota Med., 69, 720. 66. Power MJP, McConnell JG, Taylor IC (1986) Methyldopa-induced connective tissue disorder. Ulster Med. J., 55, 172. 67. Brody HJ, Cohen M (1986) Black tongue secondary to methyldopa therapy. Cutis, 38, 187. 68. Stanford JL, Martin EJ, Brinton LA, Hoover RN (1986) Rauwolfia use and breast cancer: a casecontrol study. J. Natl Cancer Inst., 76, 817. 69. Baez MA, Garg DC, Jallad NS, Weidler DJ (1986) Antihypertensive effect of doxazosin in hypertensive patients: comparison with atenolol. Br. J. Clin. Pharmacol., 21, 63S. 70. Lehtonen A, Himanen P, Saraste M et al (1986) Double-blind comparison of the effects of long-term treatment with doxazosin or atenolol on serum lipoproteins. Br. J. Clin. Pharmacol., 21, 77S. 71. Stannard M, Cohen M, Marrott PK, Paseucci VL (1986) Antihypertensive therapy with indoramin: risk-benefit profile in clinical practice. J. Cardiovasc. PharmacoL, 8, Suppl 2, $48. 72. Grube E, Giesing M (1986) Antihypertensive therapy in the Federal Republic of Germany: clinical practice experience with indoramin (Wydora). J. Cardiovasc. Pharmacol., 8, Suppl 2, $43. 73. Deitch MW, Allen IE, Pascucci VL (1986) Antihypertensive therapy with indoramin in the elderly. J. Cardiovasc. PharmacoL, 8, Suppl 2, $88. 74. Overlack A, Stumpe KO (1986) Comparison of the effect of indoramin and prazosin on blood pressure and lipid profiles in essential hypertension. J. Cardiovasc. Pharmacol., 8, Suppl 2, S53. 75. Chin DKF, Ho AKC, Tse CY (1986) Neuropsychiatric complications related to use of prazosin in patients with renal failure. Br. Med. J., 293, 1347. 76. Sperzel WD, Glassman HN, Jordan DC, Luther RR (1986) Overall safety of terazosin as an antihypertensive agent. Am. J. Med., 80, Suppl 5B, 77. 77. Anonymous (1987) Koorts veroorzaakt door labetalol. Bull. Bijwerk. Geneesm., 3, 13. 78. Hasegawa K, Sakamoto Y, Mitsunaga K (1980) Drug fever due to oxprenolol. Br. Med. J., 2, 27. 79. Costa FV, Borghi C, Mussi A, Ambrosioni E
181 (1986) Cadralazine and chlorthalidone as a secondstep drug with atenolol in hypertensive patients: differences in blood pressure control during exercise. Eur. J. Clin. Pharmacol., 30, 145. 80. Persson B, Granerus G, Wysocki Met al (1987) Acute systemic and renal haemodynarnic effects and long-term antihypertensive action of cadralazine in patients pretreated with beta-blockers and diuretics. Eur. J. Clin. PharmacoL, 31,513. 81. Asherson RA, Benbow AG, Speirs CJ etal (1986) Pulmonary hypertension in hydralazine induced systemic erythematosus: association with C4 null allele. Ann. Rheum. Dis., 45, 771. 82. Anandadas JA, Simpson P (1986) Cardiac tamponade, associated with hydralazine therapy, in patients with rapid acetylator status. Br. J. Clin. Pract., 40, 305. 83. Mason PD, Lockwood CM (1986) Rapidly progressive nephritis in patients taking hydralazine. J. Clin. Lab. Immunol., 20, 151. 84. Friedman E, Mandel M, Katznelson D, Sack J (1986) Pheochromocytoma and hydr alazine-induced myocardial ischaemia in a 14-year-old boy. Eur. J. Pediatr., 145, 318. 85. Sequeira W, Polisky RB, Alrenga DP (1986) Neutrophilic dermatosis (Sweet's syndrome): association with a hydralazine-induced lupus syndrome. Am. J. Med., 8l, 558. 86. Sehgal VN, Gangwani OP (1986) Hydralazineinduced fixed drug eruption. Int. J. Dermatol., 25, 394. 87. Tunkel AR, Shuman M, Popkin M e t al (1987) Minoxidil-induced systemic lupus erythematosus. Arch. Intern. Med., 147, 598. 88. Jones JK (1986) Evaluation of a case of StevensJohnson sydrome. Drug Inf. J., 20, 487. 89. Clissold SP, Heel RC (1987) Topical minoxidil: a preliminary review of its pharmacodynamic properties and therapeutic efficacy in alopecia areata and alopecia androgenetica. Drugs, 33, 107. 90. Price VH (1987) Topical minoxidil (3%) in extensive alopecia areata, including long-term efficacy. J. Am. Acad. Dermatol., 16, 737. 91. Rietschel RL, Duncan SH (1987) Safety and efficacy of topical minoxidil in the management of androgenetic alopecia. J. Am. Acad. Dermatol., 16, 677. 92. Fielder VC (1987) Topical minoxidil solution (l~o and 5%) in the treatment of alopecia areata. J. Am. Acad. DermatoL, 16, 745. 93. Zachariah PK, Sheps SG, Schirger A et al (1986) Antihypertensive efficacy of pinacidil - automatic ambulatory blood pressure monitoring. Eur. J. Clin. Pharmacol., 31, i 33. 94. Nicholls DP, Murtagh JG, Scott ME et al (1986) Acute haemodynamic effects of pinacidil in man. Br. J. Clin. Pharmacol., 22, 287.