Brr 24 January 1970 MEDCAL JOuRNAL 217 TODAY'S DRUGS effects reduce the amount of the response, which is partiallv vagus dependent. Br Med J: first published as 10.1136/bmj.1.5690.217 on 24 January 1970. Downloaded from With the help of expert contributors we print in this section Other Actions notes on drugs in current use. Potentially desirable.-The basic structure of antihistamines is similar to the active part of atropine, its related alkaloids, and synthetic substances with peripheral and central atropine- Antihistamines like properties. A similar relationship can be seen to the local anaesthetics. Peripheral atropine-like properties, including dry- Antihistamines have a simple chemical structure, similar in ness of the mouth, blurring of vision, and tachycardia, are well some respects to other important classes of drugs. Their marked. The central effects, including both depression and pharmacological actions are therefore closely related to those stimulation of the C.N.S., convulsant and anticonvulsant pro- of these other drugs, and indeed it has never been possible to perties, and suppression of motion sickness and tremor, are manufacture an antihistamine without other actions. However, present to a variable extent. Local anaesthetic properties, in- many of these are useful, and, in certain circumstances, are the -cluding antidysrhythmic actions, are also present. Table I in- basis of therapeutic use. The great variety of available anti- cludes an attempt to quantify these various side-effects, but histamines is due to the many uses to which they are put and the value of such predictions is reduced by the considerable the ease with which the chemical criteria for antihistamine individual variation of response. activity can be satisfied. The few antihistamines discussed in Anticholinergic actions are least marked with mepyramine this review are selected representatives from the main classes and cyclizine. Diphenhydramine and promethazine regularly of drugs of antihistaminic action, but should be suitable for cause severe dryness of the mouth, blurring of vision, and the great majority of therapeutic needs. palpitations. Neither drug should be given to a patient with glaucoma. Urinary symptoms are less troublesome. Antihistamines share the ability of atropine alkaloids, Pharmacology especially scopolamine, to depress spontaneous activity in the electroencephalograph and reduce activation responses to light Absorption is rapid from the gastrointestinal tract and from and hypothalamic and reticular activity. However, restlessness injection sites. Effects begin within 15-30 minutes and con- can also occur, and it must be concluded that mechanisms tinue for a varying length of time, 4-6 hours for most pre- controlling spontaneous cortical activity are separate from parations. These drugs are excreted as unidentified metabolites those regulating consciousness. Stimulation of the higher in the urine, having undergone hydroxylation and glucuronide centres causes alertness and convulsions may result in higher conjugation in the liver. An enterohepatic circulation exists for dosage or in patients with a focus of cortical excitability. Anti- the hepatic metabolite of mepyramine. Caution is advised in histamines should never be given to major epileptics. giving antihistamines to patients with hepatic disease. There is There is nothing paradoxical in a drug possessing both sets every reason to expect an increased rate of metabolic break- of actions. Depression of subcortical regions results in sleep down in patients receiving barbiturates and in higher dosage respiratory depression. The stimulant actions are less frequent, tend to occur in children, and may be seen in early overdosage. Most antihistamines, notably Antihistaminic Actions promethazine and diphenhydramine, cause somnolence. Me- http://www.bmj.com/ pyramine and chlorpheniramine are said to be less By definition, antihistamines antagonise the actions of hist- sedative, but there may be personal variation of response. Pheninda- amine, and so they do by competing with histamine for mine is not sedative. the occupation of receptor sites. This is a competitive antago- Antiadrenaline and antiserotonin actions are most marked nism, quite different from the reversal of histamine effects by in promethazine, in which they perhaps contribute to the adrenaline, which acts on different receptor systems. all Not sedative effects. Cyproheptadine, structurally quite similar to the effects of histamine can be antagonized to the same extent. imipramine, has potent antiserotonin actions, and in addition Thus the smooth-muscle stimulating cause on 23 September 2021 by guest. Protected copyright. effects-the of to antihistamine actions it is useful in the carcinoid syndrome bronchospasm-and the direct nerve-stimulating effect-the and in certain variants of migraine. cause of the flare in the triple response and of pruritus-are The valuable properties of almost completely antagonized. antihistamines in motion sickness Antihistamines also reverse the and tremor cannot be separated from ordinary vascular effects, such as the atropine-like dilation of capillaries and the in- side-effects, but limited specificity has been achieved with crease in their permeability. cyclizine and meclozine, which are potent antiemetics without The histamine-induced gastric acid production is not in- excessive atropine-like actions. Promethazine is also a potent hibited by antihistamines, though their secondary vagolytic antiemetic. Diphenhydramine and phenindamine have mod- TABLE I.-Side-effects of Antihistanines Peripheral Central Effects Local Gastro- intestinal like Anti- Anaesthetic Effects OteEfcs Effects Sedation Stimulation: Anti-emetic Parkinsonian kA %;_ ivepyramine + 0 0 ++ ++ Antazoline .. + ++ ++ Antidysrhythmic Diphenhydramine . +++ + + Chlorpheniramine .. Triprolidine ++ + Photosensitization Cyclizine .. + + ++ Meclozine . + Possibility of Promethazine + + teratogenicity + Photosensitization Phenindamine . ++ Cyproheptadine + + +++ Adrenaline antagonism ++ Serotonin antagonism KEY: + + + Wel marked effect. + + Moderate effect. + Effect present 0 Effect not present. - Information not sufficient to permit assessment, but unlikely to be striking. I1 Especially in children. 218 24 January 1970 Today's Drugs MEDICAL JOURNAL erate antitremor activity but are not the best available drugs systemically and stopping the allergen, if this is possible. When for parkinsonian tremor. a more general reaction with bronchospasm or profound hypo- All conventional antihistamines are local anaesthetics. This tension is present, as in a well developed penicillin ana- Br Med J: first published as 10.1136/bmj.1.5690.217 on 24 January 1970. Downloaded from is an unobtrusive side-effect possessed notably by prometha- phylaxis, antihistamines are less useful. They cannot reverse zine, mepyramine, and diphenhydramine. Antazoline, also a the bronchospasm, which is due to slow-reacting substance, potent local anaesthetic, has quinidine-like cardiac actions of and they only partially reverse the vascular effects (there is a therapeutic interest. non-histamine component) and at a slow rate. Thus an anti- histamine is only supplementary to the adrenaline required in Generally undesirable.-Loss of appetite, nausea, vomiting, general anaphylaxis. epigastric distress, constipation, and diarrhoea have all been Again, in serum sickness antihistamines dispel the urticaria reported. These are not all readily explicable, but doubtless but rarely benefit the arthralgia or pyrexia. Patients with high the combined effects of somnolence and lack of saliva and skin reactivity, as in neurosis or mastocytosis or with urticaria gastric secretion contribute to anorexia. Epigastric pain could pigmentosa, react excessively to minor stimuli. An antihista- well be a result of histamine release, as could diarrhoea, but mine reduces dermographism and the flushing in the skin of the more usual constipation is an atropine-like action. Cypro- the neurotic and unduly sensitive. The pruritic aspects of ex- heptadine is an appetite stimulant. anthematous drug eruptions and contact dermatitis are treat- All antihistamines seem capable of sensitizing, especially in able with an antihistamine, but in neither is the visible lesion contact with the skin, and then particularly with exudative benefited. Withdrawal of the drug in the former case and top- lesions, such as eczema. Similar risks are present with aerosols ical steroids in the latter are usually curative. and nasal sprays. Photosensitivity is common with the pheno- Excellent results are obtained in the pruritus and oedema of thiazine antihistamines and is reported with triprolidine. The insect bites. The erythematous aspects of some other lesions latter also has an interesting property of absorbing ultra- are quite well controlled, but little benefit is found in erythe- violet light, and has therefore been used as a sun-burn pro- ma multiforme and exfoliative dermatitis. Generally beneficial tective. Nevertheless, topical antihistamine lotions and creams results are obtained in angioneurotic oedema, but it must be are amongst the most common causes of iatrogenic skin erup- understood that an antihistamine is less satisfactory than tions seen in outpatient clinics by dermatologists, and their use adrenaline when the site of the angio-oedema is life- should be discouraged. endangering. Blood dyscrasias are not common, but agranulocytosis, The other situation in which immune reactions provide a thrombocytopenia,