Hypertension and Diabetes: The Choice of Antihypertensive Therapy

Dr. C.R. Kumana, BSc, MB, FRCP Reader in Medicine Clinical Pharmacologist University of Hong Kong The choice of antihypertensive therapy in diabetes mellitus constitutes a very large topic which cannot be covered comprehensively in the space of this article. Under the circumstances, there will be a focus on certain aspects of antihypertensive drug therapy with particular reference to a) the treatment of mild to moderate hypertension (not severe hypertension or emergency treatment), b) issues which are clinically relevant to general practitioners and c) popular first and second line agents (viz;- adrenergic antagonists, thiazide diuretics, and vasodilators), as are commonly used in the stepped care approach to antihypertensive treatment.

important effects on glucose tolerance and are therefore not contraindicated in diabetes. Beta-Adrenergic Blockade Anti-hypertensive treatment of diabetics with these drugs is somewhat more complex. Influence on Glucose Tolerance: In a placebo controlled study of a beta-blockade in 20 hypertensive diabetics controlled by diet and/or hypoglycaemic agents (Wright et al 1979) there were only trivial increases in mean blood sugar (fasting, pre lunch and mid afternoon) after one month's treatment with propranolol or metoprolol according to a double blind protocol. In individual patients however, considerable hyperglycaemia occurred, and these outliers were mainly responsible for the small effect on mean blood glucose. Several other studies have reported similar results. It is therefore accepted that in the majority of diabetics beta-blockade usually produces no clinically significant impairment of glucose tolerance but a few individuals experience important increases in blood glucose. As to why hyperglycaemia is occasionally encountered, there are many uncertainties (viz. the importance of selective versus non-selective betablockade, inter-relationship with the arachidonic acid cascade, and the role of 1 verses d propranolol). Beta-Blockade and Hypoglycaemia: The normal response to clinically significant hypoglycaemia is sympathetic stimulation, largely mediated through the release of adrenaline. This gives rise to widespread alpha and beta-receptor stimulation, which no doubt accounts for many of the prodromal symptoms (e.g. palpitations, tremor). Metabolic consequences (probably mediated through stimulation of alpha-2 and beta-2 receptors in the liver) include increased glycogenolysis and gluconeogenesis, both of which tend to restore the blood sugar. It is well known that diabetic patients treated with sulphonylureas or insulin are subject to hypoglycaemia, and it should be realised
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Adrenergic Antagonists
Experimental data from animals and in vitro studies suggest that insulin secretion is enhanced in the presence of beta-2 receptor stimulation and diminished when alpha-2 receptors are stimulated. One might therefore anticipate that beta-2 receptor antagonism might lead to diminished insulin release, higher blood sugars and diminished glucose tolerance, and vice versa after alpha-2 receptor antagonism. Fortunately, many adrenergic antagonists have a negligible net effect on blood sugar. This seems to be the case for:— (1) Central Adrenergic Inhibitors (which reduce peripheral sympathetic tone) e.g. alpha methyldopa, clonidine, (2) Adrenergic Neurone Blockers (which deplete presynaptic noradrenaline) e.g. reserpine, guanethidine and (3) Alpha-1 Blockers e.g. prazosin Though objective as opposed to anecdotal data about the use of these classes of drugs in diabetes are scarce, it is widely accepted that they do not have clinically

Hypertension and Diabetes
that beta-blockade can interfere with the consequences in at least 3 different ways:— 1) Beta-blockade Masks the Prodromal Symptoms of Hypoglycaemia. In particular, tremor, palpitation, hunger pangs and hyperventilation become diminished or are not experienced at all, whereas sweating (a cholinergically mediated response) may be exaggerated. Clearly, all diabetic patients receiving hypoglycaemic agents should be warned about this effect and asked to pay special attention to sweating even without the other symptoms. Perhaps,betablocking drugs should be avoided altogether in patients who are frequently prone to hypoglycaemia. 2) Non-selective Beta-blockade Delays the Restoration of Blood Sugar. Whereas the relatively selective beta-blockers (e.g. metoprolol and atenolol) usually do not have any discernable effect, propranolol tends to interfere with the compensatory metabolic responses (Figure 1). Whilst it is conceded that betablockade (especially when non-selective) slows the

Figure 1: Rate of Increase in Blood-Glucose Levels after Insulin (n = 7)
400+ Placebo

S 300-•

Metoprolol

Propranolol

100

20

40

60

80

100

120

140

160

180

200

Time (min) from nadir

Modified Figure 2, Lger et al 1979, Lancet 1, 458-62

recovery from hypoglycaemia by inhibiting glycogenolysis and gluconeogenesis, this effect is seldom important clinically, except when there is additional hypoglycaemic provocation, e.g. severe exercise, and end stage renal failure. 3) Exaggerated Hypertensive Responses. Many well controlled studies in normal volunteers and hypertensive patients show that infusion of adrenaline (which stimulates alpha-receptor mediated vasoconstriction as well as beta receptor mediated vasodilatation) reduces net peripheral resistance (Figure 2). This is usually associated with a fall in diastolic and mean blood pressure and an increase in heart rate. After giving a non-selective beta-blocker such as propranolol (which inhibits beta-2 receptor
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mediated vasodilatation), adrenaline administration results in unopposed alpha receptor mediated vasoconstriction becoming unmasked, resulting in a rise of peripheral resistance. Consequently, diastolic and mean blood pressure increases and heart rate decreases (presumably due to a reflex effect). After administration of a relatively selective antagonist like metoprolol, vascular beta- receptors appear relatively spared and the haemodynamic response to adrenaline resembles that in the control state. Not surprisingly, after insulin induced hypoglycaemia which also releases adrenaline, diastolic blood pressure generally falls. Furthermore, many studies have confirmed that after pre-treatment with propranolol, similar degrees of hypoglycaemia elevate diastolic pressure (Figure 3). Moreover, though the mean haemodynamic responses

(turn to page 3554)

Hypertension and Diabetes
Figure 2: Haemodynamic Responses to Adrenaline on and off Beta-Blockers
Mean artenal blood pressure mm Hg

Heart rate beats/min 80-r
6040-

are generally small, they tend to be relatively larger in the presence of non-selective as opposed to selective beta-blockade and individual patients receiving nonselective drugs like propranolol can experience very serious elevations in blood pressure. Thiazide Diuretics It is well known that thiazide (and loop) diuretics are diabetogenic. This effect may be partly attributed to diminished release and reduced sensitivity to insulin. In part this may result from the slight lowering of plasma potassium levels induced by these drugs. Moreover, diazoxide (a non-diuretic thiazide vasodilator) commonly gives rise to hypokalaemia and hypoglycaemia and very rarely thiazides have been implicated in causing pancreatitis. Though the hypokalaemic effect of diuretics is generally considered to be trivial, in several recent studies (MRFIT, MRC trial in mild hypertension) many reservations have been aired concerning its epidemiological significance. Interestingly, the use of potassium supplements can correct the diabetogenic effect of these drugs. It is interesting to compare the adverse effects and relative contraindications of thiazide diuretics and beta

9070-

Peripheral resistance U
70 n

Diastolic blood pressure mm Hg

100-1
5030-

75-

10-

50-

Before

During Adr infusion metoprolol: 10 mg i.v. propranolol: 5 mg i.v. control

Before

During Adr infusion

Modified from Johnsson 1975, Acta Pharm et Tox, 36 Suppl V, 59

Figure 3: Blood Pressure Responses to Insulin/ Hypoglycaemia in Seven Diabetic Patients
180 160 . , 140

Placebo Mean ± SEM

Metoprolol

Propranolol

100 .

80 . 60 .

"E.
5 min Nadir 5 min Nadir 5 min Nadir Modified Figure 4, Lager et al. 1979, Lancet 1, 458-62

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Vol. 10 No. 12 December 1988

blockers pertinent to their use in diabetes (Table 1). As has already been mentioned, beta-blockers are relatively contraindicated in patients subject to hypoglycaemia (brittle diabetes). In considering some of the other listed side effects and contraindications, it is useful to refer to the results of the MRC trial in mild hypertension (1985). The latter was a randomised single blind placebo controlled trial carried out in general practice and involved more than 17,000 mild hypertensives screened from clinic patients and excluded diabetics. Compared to the placebo group, withdrawal of trial medication due to diabetes (about 0.75% of cases) in patients receiving bendrofluazide was threefold more common, and due to impotence in men (about 1.5% of cases) eight-fold greater. Correspondingly withdrawal from propranolol due to Raynauds phenomenon or peripheral vascular insufficiency though rare (about 0.5%), was at least 14 fold more common than on placebo. In this investigation, possible symptoms due to vasomotor instability (dizziness, nausea, headache) were no more common in patients taking diuretics as opposed to beta-blockers, but in patients with diabetics with autonomic neuropathy, it is likely that diuretics would produce such side effects more readily. According to the MRC trial and other studies, propranolol therapy definitely has an unfavourable influence in smokers.

in treating them with calcium channel blockers. However, those with autonomic neuropathy may experience excessive postural symptoms (headaches, palpitations, flushing and oedema) due to the vasodilator properties of these drugs. Based on experimental data there are also concerns that calcium antagonists alter glucose homeostasis. Increases in blood glucose stimulate pancreatic beta cells to release insulin by a process that is calcium influx dependent. Therefore, on theoretical grounds calcium antagonists may interfere with the pancreatic response to increases in blood glucose. Clinical information regarding this possibility remains meager, partly because the various calcium antagonists in current use are dissimilar. Moreover, the "studies" often referred to are of questionable design (non-blind, non-randomised, anecdotal, small numbers). Nevertheless, most suggest that there is no important effect but a minority of investigators have reported considerable elevations in blood glucose levels after treatment with nifedipine. However the latter effects may be related to the duration of therapy and the doses involved. With respect to the risks of developing atheromatous complications in hypertensive diabetics, in contrast to some of the commonly used thiazide diuretics and betablockers (Table 2), calcium channel antagonists do not seem to exert an unfavourable influence on plasma lipid profiles. Despite this apparent advantage it should be appreciated that calcium channel blockers (as opposed to beta-blockers) have not yet been shown to improve outcome from cardiovascular disease. Conclusion Regarding the choice of antihypertensive drug therapy in diabetes it is clear that many drugs have altered risk/adverse effect profiles in diabetic patients. However, any additional unfavourable influence from these drugs due to diabetes is usually minimal. In a small minority of diabetic individuals, certain risks/adverse effects could assume clinical significance. Whilst no antihypertensive drug is completely contraindicated in diabetes, it is useful to take account of individual patient characteristics when considering therapy. In patients with brittle diabetes or peripheral vascular disease, beta blocking drugs (especially nonselective agents like propranolol) are relatively 3555 (turn to page 3558)

Beta-Blockers Raynauds & Peripheral Vascular Disease Hypoglycaemia (brittle diabetes) Smoking

Thiazide Diuretics Diabetes Impotence (men) Ventricular tachyarrhythmia Hypokalaemia Dizziness, Nausea, Headache

Adapted from MRC Mild Hypertension trial, 1885, BMJ, 291, 97-104.

Table 1: Adverse Effects/Relative Contraindications Pertinent to Diabetes Calcium Antagonists Since diabetic patients are subject to both hypertension and angina, there is considerable interest

Hypertension and Diabetes

Total Cholesterol Beta-Blockers Non-selective Relatively /}, selective Non-selective with ISA Diuretics Hydrochlorothiazide (50-100 mg/day) Chlorthalidone (12.5-100 mg/day) Clopamide (5 mg/day) Indapamide

LDL

HDL

Triglyceride

+ ±

Mean duration of treatment = 13-26 weeks, ± = No significant change, + = Increase, — = Decrease Table 2: Plasma Lipid Changes Following Antihypertensive Treatment with Beta-Blockers and Diuretics contraindicated. In those whose diabetes is poorly controlled or who experience impotence or postural symptoms, it may be prudent to avoid thiazides. As a general rule diabetics starting antihypertensive' drug treatment need to be carefully monitored. If appropriate, they may require adjustment of their diet and/or antidiabetic drug dosage. Rarely, it may be necessary to select an alternative antihypertensive drug. Further Reading
McKenney JM, Goodman RP, Wright JT: 1985 Clinical Pharmacy 4 649-56. Use of Antihypertensive Agents in Patients with Glucose Intolerance. Editorial Review: 1985 Journal of Hypertension 3 297-306. Antihypertensive Treatment and Serum Lipoproteins. Kendall MJ, Horton RC, Chellingsworth MC: 1986 Journal of Clinical & Hospital Pharmacy, 11 175-80. Calcium Antagonists and Glycaemic Control. Kumana CR: 1987 Drugs for Heart Disease, 2nd Edition, (edited by J. Hamer), publishers Chapman & Hall Ltd, Chapter 2, 29-75 on 'Beta Adrenergic Blocking Drugs'.

NOTICE

The Federation of Medical Societies of Hong Kong is preparing the 4th edition of 'The Medical Directory of Hong Kong'. Doctors who wish to be listed in the Directory have to fill in and return a prescribed form before 30th December 1988. Members who have not yet received such a form from the Federation are urged to apply to the Federation for one (tel: 5-278898). Doctors who have sent in their forms before the deadline are eligible for a free copy of the Directory.

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