Adverse reactions to antihypertensive therapy.

A large number of antihypertensive agents are available today. They belong to different drug classes and permit the treating physician to choose the drug he deems best suited for the treatment of an individual patient. Because hypertension is usually asymptomatic yet requires long-term therapy, consideration of potential undesirable effects of drugs used for its treatment is important for making the appropriate choice. In this context, a precise understanding of the typical adverse reaction profiles of the different drugs is essential. This article provides a short review of the adverse reaction profiles of the main classes of antihypertensive drugs and refers to topics such as the recent controversy regarding calcium channel blockers and comparative investigations between different antihypertensive agents. Furthermore, the effects of antihypertensives on metabolic parameters, differences between their effects in subgroups of patients and in patients with different concomitant diseases, and the potential of antihypertensives for interactions with other drugs are briefly discussed. Even with a good knowledge of all of these aspects, however, no fixed plan for drug treatment of hypertension suitable for every patient can be established. A high percentage of adverse drug reactions can, however, be avoided by appropriate drug selection and dosage, carried out after careful consideration of the known adverse reaction profiles as well as the known spectrum of pharmacological actions of the different compounds. Low doses are often effective and well tolerated. Instead of increasing the dose, it is usually preferable to add a low dose of a second agent with a different mode of action if one drug given alone does not sufficiently lower blood pressure. This procedure avoids many adverse drug reactions attributable to an exaggerated pharmacological response, and, if chosen carefully, this combination may also reduce counterregulatory reactions secondary to the fall in blood pressure.

Clinical pharmacology, physiology and pathophysiology of superficial veins--1.

1. Venous resistance contributes very little to total peripheral resistance; more than half of the total blood volume, however, is contained in the extrathoracic veins. Owing to marked differences between venous and arterial anatomy and physiology, studies on veins and arteries usually require different methodological approaches. Whereas for arteries the most relevant parameters are resistance, pressure and flow, for veins volume and compliance are most important. For studies of general aspects of the peripheral circulatory system, venous occlusion plethysmography is probably the most useful method. The determination of both the rate of rise in limb volume and the total volume rise after inflating a proximally applied occlusion cuff to a subdiastolic pressure permits the concomitant estimation of both arterial flow and venous compliance. 2. Studies of direct pharmacological or physiological effects on veins, interactions of various pharmacological or physiological stimuli, or pathophysiological changes in venous responsiveness have been facilitated by the development of investigational techniques relying on direct measurements of the compliance of single human veins in vivo. One of these, relying on the use of a linear variable differential transformer (LVDT) for determining changes in the compliance of superficial veins at a standardized congestion pressure, has been found very suitable for the practical application in both patients and healthy subjects. 3. Physiological studies were carried out on the effect of age, exercise, temperature, and the menstrual cycle on venous compliance and venous responsiveness to various stimuli. In addition, interindividual variability in venous responsiveness in monozygotic and dizygotic twins and in unrelated subjects was investigated, and studies on the function of the endothelium were carried out in man in vivo. 4. Pathophysiological studies using this technique were reported from patients with hypertension, orthostatic hypotension, myocardial infarction, varicosis, cystic fibrosis, asthma, diabetes, systemic sclerosis, and cluster headache. 5. Clinical pharmacological studies represent a most important field for the use of this method. Studies were carried out on the effects of a large number of constrictor and dilator agents, and also on drug interactions on human veins in vivo. Venoconstriction was observed after local administration of alpha-adrenoceptor and 5-HT-receptor agonists, ergot derivatives, angiotensinogen, angiotensin I and II, and several prostaglandins. 6. Owing to the low venous tone present under effects can usually be quantified only on veins e.g. noradrenaline or 5-hydroxytryptamine. Under these conditions dilatation was observed after the administration of beta-adrenoceptor agonists, cholinergic (muscarinic) agonists, nitrates, calcium antagonists, bradykinin, substance P and several prostaglandins.

Pharmacokinetic investigation of oral and i.v. dihydroergotamine in healthy subjects.

A new radioimmunoassay (RIA) for the specific measurement of dihydroergotamine (DHE), sufficiently sensitive for the determination of low plasma concentrations, has been used to investigate the pharmacokinetics of unchanged DHE. In a randomized cross-over trial, eight healthy male volunteers received single doses of DHE 5 mg, 10 mg and 20 mg orally and 0.1 mg and 0.5 mg intravenously. It was possible to determine plasma concentrations and urinary excretion of DHE over the following 48 h. A long terminal plasma elimination phase of unchanged DHE (half-life 15 h) was found. A similar terminal elimination half-life was also calculated from urine data. The multi-exponential decline in plasma DHE with a long terminal half-life suggests that distribution into a deep compartment contributes to the long-lasting effect of the drug. Plasma protein binding was 93%. Despite extensive tissue distribution (Vz = 33 l/kg) and a high plasma clearance (CLP = 2 l/min), dose-independent linear pharmacokinetics was observed. The present assay was at least 20-times more specific than the polyvalent RIA used previously and appears suitable to explore the pharmacokinetics of unchanged DHE in patients on low-dose therapy. The long terminal elimination half-life of DHE only reported previously in studies using 3H-labelled drug, and considered to be due to metabolites, was also true for the parent compound. This, in addition to the sustained pharmacological activity of the 8'-hydroxy metabolite already shown, provides a further explanation for the long duration of action of DHE in animals and man.

Superficial hand and foot veins show no difference in sensitivity to constrictor agents.

Potential differences in responsiveness of superficial veins from different regions to locally and systemically administered constrictor agents were investigated in healthy male volunteers. Compliance was determined by measuring venous diameter at a constant occlusion pressure. Dose-response curves for locally infused norepinephrine were established in five subjects on superficial hand and foot veins. Slopes of regression lines for norepinephrine log dose-response curves and doses required to produce equal reductions of diameter were virtually identical in both areas. In 12 subjects, 0.5 mg dihydroergotamine and placebo were administered intramuscularly in a double-blind randomized order; the venoconstrictor effect of dihydroergotamine was almost identical on hand and foot veins. Thus despite the marked differences in hydrostatic pressure to which they are exposed, superficial hand and foot veins react in a similar way to the constrictor agents investigated. The findings indicate that the responses of hand veins appear to be representative for superficial veins in other areas of the body.

Is the ISA of pindolol beta 2-adrenoceptor selective?

1. Pindolol is a beta-adrenoceptor blocking drug with ISA (also called partial agonist activity). This means that in addition to blocking the effects of beta-adrenoceptor agonists, it produces some stimulation of beta-adrenoceptors. 2. In vitro studies with pindolol show that its maximum stimulant action is similar to that of isoprenaline in tissues possessing mainly beta 2-adrenoceptors, but is negligible in tissues possessing mainly beta 1-adrenoceptors. This suggests selective stimulation of beta 2-adrenoceptors. 3. In man the arteriodilator effects observed after intra-arterially infused pindolol at concentrations within the same range as those producing an antihypertensive effect also suggest a stimulant action on vascular beta 2-adrenoceptors. 4. The fact that pindolol prevents the reduction of resting heart rate and cardiac output observed after drugs lacking ISA at first sight suggests stimulation of cardiac beta 1-adrenoceptors. However, human atria possess not only beta 1- but also beta 2-adrenoceptors, stimulation of which would produce the same effect. 5. Although all beta-adrenoceptor antagonists lower blood pressure, recent experiments have shown that those agents with combined beta 1-adrenoceptor blocking activity and ISA at those receptors are less effective. This observation lends weight to the thesis that pindolol does not stimulate beta 1-adrenoceptors since it lowers blood pressure as effectively as drugs lacking ISA. 6. The evidence available therefore suggests that although pindolol blocks both beta 1- and beta 2-subtypes, it selectively stimulates beta 2-adrenoceptors.

Clinical pharmacological studies with the long-acting beta-adrenoceptor blocking drug bopindolol.

Bopindolol is a potent beta-adrenoceptor antagonist with mild intrinsic sympathomimetic activity that exhibits a long duration of action. The cardiac beta-adrenoceptor blockade produced by an oral dose of 1 mg bopindolol is of similar intensity as that seen after atenolol 100 mg p.o. or pindolol 10 mg p.o. Like other beta-adrenoceptor antagonists, bopindolol is effective in inhibiting resting and stimulated plasma renin activity. In contrast to compounds lacking ISA, bopindolol does not produce undesirable changes in plasma lipoprotein composition during chronic therapy. Its bioavailability after oral administration amounts to about 70%. In the studies reviewed, bopindolol was well tolerated even after an oral dose of 12 mg, which, as far as beta-adrenoceptor blockade is concerned, would be equivalent to a single oral dose of about 1.2 g of atenolol. The onset of action of bopindolol is relatively slow, a feature that to a certain extent might account for the good tolerance of the drug observed in experimental and therapeutic studies. The delayed onset of action of the drug has facilitated the elucidation of the relationship between plasma levels and pharmacological effects during the period immediately after oral administration. Analysis of the temporal relationship between drug plasma levels and beta-adrenoceptor blockade provides evidence suggesting that the cardiac beta adrenoceptors lie outside the plasma compartment.

Venoconstrictor effects of dihydroergotamine after intranasal and intramuscular administration.

A parenteral formulation of dihydroergotamine (DHE) is the only galenical form now available for the treatment of acute attacks of migraine in which a rapid onset of action is required. A recently developed nasal spray of DHE has been compared with intramuscular DHE for its venoconstrictor activity. In a randomised double-blind, cross-over trial, 9 healthy male volunteers received a single dose of DHE 1 mg intranasally, DHE 0.5 mg i.m. or placebo (intranasally and i.m.) on three different occasions, with an interval of at least 1 week between doses. Both active treatments, but not placebo, produced marked venoconstriction as shown by reduced compliance of superficial hand veins. The effect persisted for more than 8 h. The maximum venoconstrictor effect of 1 mg DHE intranasally was 40 +/- 12% (mean +/- SEM) and after 0.5 mg i.m. it was 52 +/- 15%. The time course of the venoconstrictor effect was similar after both routes of administration. Blood pressure and heart rate changes in these normotensive subjects were almost identical after dihydroergotamine and placebo. The results suggest that the nasal spray could be used as an alternative to parenteral DHE, permitting self-administration of the drug for the treatment of acute attacks of migraine.

Relationship between plasma concentrations and cardiac beta-adrenoceptor blockade--a study with oral and intravenous bopindolol.

Bopindolol, an esterified beta-adrenoceptor blocking drug, was administered to nine healthy male volunteers in oral (1 mg and 4 mg) and intravenous (1 mg) doses. Plasma concentrations determined using a radio-receptor assay (RRA) and high pressure liquid chromatography (h.p.l.c.) yielded almost identical results, indicating that hydrolysed bopindolol, the major metabolite, is responsible for the pharmacological activity of the drug. After intravenous administration the half-life for the formation of the hydrolysis product was about 0.3 h. The elimination of hydrolysed bopindolol from the plasma, determined with a one-compartment model occurred with a half-life of about 4 h. There were indications for a longer beta phase of elimination with a half-life of about 8 h, which, owing to the relative insensitivity of the method for concentrations present after more than 24 h, could not be determined exactly. The absolute bioavailability of the active compound is about 70%. Cardiac beta-adrenoceptor blockade was determined as the reduction in exercise-induced tachycardia. With oral doses the maximum effect was reached after 3 h (-29 beats min-1 after 1 mg, -40 beats min-1 after 4 mg). After intravenous administration most of the effect was present after 0.5 h but the maximum effect (-33 beats min-1) was only reached at 3 h. Bopindolol possesses a long duration of action: after 48 h 33% of the maximum effect of the oral dose of 4 mg was still present.(ABSTRACT TRUNCATED AT 250 WORDS)

Contrasts between pindolol and propranolol concentration-response relationships.

The plasma concentration-response relationships of oral and intravenous pindolol and propranolol have been studied in a group of eight healthy male subjects who received each dosage form in a randomized single-blind cross-over manner. Despite similar elimination half-lives, the duration of action of pindolol was longer than that of propranolol. This longer duration of action was associated with a flatter concentration-response curve for pindolol and may be related to the partial agonist activity of pindolol. Propranolol concentration-response curves were dependent on the route of drug administration whereas pindolol curves were similar following oral and intravenous routes of administration.

Pharmacological experiments in healthy volunteers with bopindolol, a long-acting beta-adrenoceptor blocking drug with partial agonist activity.

Bopindolol is a potent and specific beta-adrenoceptor antagonist with partial agonist activity. In animal experiments it blocks both beta 1- and beta 2-adrenoceptors and possesses a long duration of action. In the present study in healthy volunteers bopindolol was about ten times more potent than pindolol in reducing isoprenaline-induced and exercise-induced tachycardia. In experiments on exercise-induced tachycardia an oral dose of 2 mg produced a near maximum reduction of exercise heart rate, occurring within 2 to 3 h of administration. With higher doses (up to 12 mg) the maximum effect was reached earlier (between 1 and 2 h). The long duration of action of bopindolol observed in animal studies was confirmed in man. Twenty-four hours after 4 and 10 mg bopindolol more than 2/3 of the maximum effect was still present. After 48 h 38% of the maximum effect of 4 mg and 50% of that of 12 mg remained. Even at 72 and 96 h exercise-induced tachycardia was still significantly lowered after both doses of the drug. When bopindolol was administered once daily for 5 days there was a slight increase in the maximum reduction of exercise-induced tachycardia during treatment with 1 mg/day but not with 4 mg/day, which produced a near maximum effect.

Methods for studying drug effects on superficial human veins.

Direct effects of vasoactive substances on superficial human veins in vivo can be investigated by measuring changes in the diameter of a superficial vein at a standardized congestion pressure which reflect changes in venous tone before and after local infusion of the drugs. The diameter of a superficial hand vein is measured with the aid of a linear variable differential transformer mounted directly on the back of the hand. The central core of the transformer positioned over the summit of the vein moves simultaneously with changes in venous diameter and allows continuous recording of these alterations. A series of ergot alkaloids were investigated with this technique and found to elicit a direct constrictor action when infused locally. Studies on the mode of action of the venoconstrictor effects of ergot alkaloids suggest that they are mediated by stimulation of alpha- and 5-HT-receptors. Similarly, guanfacine, a centrally-acting antihypertensive drug, reduces venous compliance after direct local administration as a result of alpha-adrenoceptor stimulation. The venodilator effect of isoprenaline can be shown in veins preconstricted with noradrenaline, whereas with nitroglycerine, venodilatation is observed by local infusions in veins not preconstricted. This method is therefore useful for studying the direct effects of venoconstrictor and venodilator drugs in man. The technique can also be used to study interactions between different agents and thus to investigate the mode of action of drugs. Drugs can be infused locally at doses which do not elicit systemic effects.

Direct effects of vasoactive substances on superficial human veins in vivo.

Direct effects of vasoactive substances on superficial human veins in vivo can be investigated by measuring changes in the diameter of a superficial hand vein at a standardized congestion pressure before and after local infusion of the drugs. Changes in diameter at a given occlusion pressure reflect changes in venous tone. Experiments have been performed in healthy male volunteers; the diameter of a superficial hand vein was measured by means of a linear variable differential transformer. A series of ergot alkaloids (dihydroergotamine, ergotamine, methysergide and bromocriptine) were found to elicit a direct constrictor action when infused locally. Dihydroergotamine also produced marked and long-lasting venoconstriction after systemic i.v. and after oral administration. Studies on the mode of action of the venoconstrictor effect of ergot alkaloids suggest that alpha- and 5-TH-receptors are involved. Pizotifen and methysergide, both characterized as 5-HT-antagonists, were found to produce a marked, dose-dependent reduction of venous compliance when locally infused into superficial hand veins, suggesting partial agonist activity on 5-HT-receptors. The centrally-acting antihypertensive drug guanfacine was found to produce venoconstriction after local administration, probably due to its alpha-adrenoceptor stimulant effect. The venodilator effect of isoprenaline can be shown in veins preconstricted by noradrenaline. With nitroglycerin, venodilatation was observed by local infusions in veins not preconstricted.(ABSTRACT TRUNCATED AT 250 WORDS)

Investigation of the venoconstrictor effect of 8' hydroxydihydroergotamine, the main metabolite of dihydroergotamine, in man.

The time course of the venoconstrictor effect of dihydroergotamine and its main metabolite 8' hydroxy-dihydroergotamine was investigated in a placebo-controlled study in seven healthy male volunteers, after direct local infusion of 0.08 and 0.4 micrograms into superficial hand veins. Both dihydroergotamine and 8' hydroxy-dihydroergotamine elicited a similar, marked venoconstrictor effect. The time course of the venoconstrictor action was similar for both compounds; about one third of the effect was present at the end of the infusion, which lasted for 10 min, and it took about a further 20 min for the effect to reach its maximum. The effect then remained fairly constant for the rest of the period of observation of 180 min from the start of the infusion. The data indicate that the pharmacological activity of oral dihydroergotamine is due not only to the unchanged drug but also to its main metabolite, 8' hydroxy-dihydroergotamine, which occurs in plasma in concentrations about 5-7 times higher than those of dihydroergotamine itself. The absolute bioavailability of unchanged dihydroergotamine, therefore, does not reflect the markedly higher bioavailability of pharmacologically active drug.

Influence of pizotifen and ergotamine on the venoconstrictor effect of 5-hydroxytryptamine and noradrenaline in man.

The influence of locally infused pizotifen (80 ng) and ergotamine (16 ng and 4 ng) on the compliance of superficial hand veins in man, and their interactions with the venoconstrictor effects of noradrenaline and 5-hydroxytryptamine (5-HT), were investigated in a placebo-controlled study in healthy volunteers. Pizotifen alone reduced venous compliance and produced a parallel displacement to the right of the 5-HT dose-response curve suggestive of competitive antagonism. The venoconstrictor effect of noradrenaline was not influenced by pizotifen. This confirms the selective antagonism of 5-HT by pizotifen and supports the existence of specific 5-HT receptors on human veins. After infusion of 16 ng ergotamine, which by itself reduced venous compliance, the venoconstrictor effects of the lower doses of 5-HT and of all doses of noradrenaline were larger but still never exceeded the arithmetic sum of the separate effects of noradrenaline or 5-HT and ergotamine. A lower dose of ergotamine (4 ng) induced only a small venoconstriction and did not influence the constrictor effect of noradrenaline. Therefore, in contrast to previous observations, no potentiation of the venoconstrictor effect of noradrenaline by ergotamine was observed under the present experimental conditions. The additive effect of noradrenaline and ergotamine may well explain its therapeutic action in the treatment of migraine.

Clinical pharmacology of beta-adrenoceptor blocking drugs possessing partial agonist activity, with special reference to pindolol.

Despite their common property of competitive beta-adrenoceptor blockade, beta-adrenoceptor blocking drugs differ in the presence or absence of several ancillary properties. One of these is partial agonist activity [intrinsic sympathomimetic activity (ISA)]. Drugs of this type are as effective in inhibiting beta-adrenoceptor stimulation as are drugs devoid of ISA, but unlike the latter they produce some stimulation of beta-adrenoceptors. This stimulating activity is sufficient to compensate partly or totally for the loss of resting sympathetic drive resulting from blockade of beta-adrenoceptors. Increases in heart rate during physic and psychic stress, however, are reduced to practically the same extent by all beta-adrenoceptor blocking drugs, whether they possess ISA or not. With pindolol the maximum stimulatory activity is reached at very low doses. Over a dose range wider than that used in clinical practice, the effect of pindolol on resting heart rate is therefore not dependent on the dose but on the heart rate before drug administration. Pindolol is a drug with sufficient ISA to compensate for blockade of sympathetic drive at rest. It therefore does not influence or only slightly reduces normal resting heart rate and cardiac output, and thus does not give rise to reflex increases in total peripheral resistance. During chronic oral treatment of hypertension with pindolol, peripheral resistance is usually reduced.

Clinical pharmacology of pindolol.

Beta-adrenoceptor blockade is responsible for the therapeutic action of beta-adrenoceptor-blocking drugs in the treatment of hypertension and angina pectoris. Many aspects of their effects can therefore be studied in relatively simple clinical pharmacologic experiments. Cardiac beta-adrenoceptor blockade can be measured in terms of the reduction of isoprenaline-induced and exercise-induced tachycardia. Based on these experimental procedures pindolol is, on a weight-for-weight basis, about 20 times more potent than propranolol. The duration of action of pindolol, measured by the reduction in exercise-induced tachycardia, is longer than that of many other beta-adrenoceptor-blocking drugs such as propranolol, alprenolol, and slow-release oxprenolol tested at equipotent beta-adrenoceptor-blocking doses. Pindolol is a beta-adrenoceptor-blocking drug with partial agonist activity (intrinsic sympathomimetic activity [ISA]). Drugs of this type are as effective in inhibiting beta-adrenoceptor stimulation as drugs devoid of this property, but unlike the latter they produce some stimulation of beta adrenoceptors. The ISA of pindolol is sufficient to counterbalance the diminution in resting sympathetic tone that results from beta-adrenoceptor blockade. In hemodynamic studies pindolol does not alter or only slightly reduces normal cardiac output. This is in contrast to drugs lacking ISA, which consistently depress cardiac output. In addition, propranolol has been shown to markedly reduce blood flow in the calf, whereas pindolol and placebo do not differ from one another in their effect on this parameter. A linear correlation exists between the logarithm of plasma concentrations of pindolol and cardiac beta-adrenoceptor blockade expressed as a reduction of exercise-induced tachycardia. The high systemic availability of pindolol after oral administration, due to good oral absorption and low first-pass effect, is revealed not only in pharmacokinetic studies but also in pharmacodynamic experiments; beta-adrenoceptor blockade 75 minutes after intravenous administration was equivalent to that observed 2 hours after the same doses given orally.

Pharmacokinetic comparison of pindolol 30 mg retard and 15 mg normal tablets.

In a cross-over pharmacokinetic study in 8 healthy volunteers a retard formulation containing pindolol 30 mg was compared with the normal 15 mg. pindolol tablet. The pindolol 30 mg retard tablet led to the same maximum plasma level as a single dose of the normal pindolol tablet. A plasma concentration higher than half of the maximum was maintained twice as long after the retard than after the normal 15 mg pindolol tablet. The bioavailability of the two forms was practically identical.