Antianxiety Drugs

Antianxiety Drugs

Anxiety

It is an emotional state, unpleasant in nature, associated with uneasiness, discomfort and concern or fear about some defined or undefined future threat. Some degree of anxiety is a part of normal life. Treatment is needed when it is disproportionate to the situation and excessive. Some psychotics and depressed patients also exhibit pathological anxiety.

Cardiac neurosis (unfounded fear of heart disease— palpitation, functional precordial pain); g.i. neurosis (fixation on bowel movement, distention, eructation, reflux, acidity); social anxiety (fear of being observed and evaluated by others); obsessivecompulsive disorder (OCD), posttraumatic stress disorder and various forms of phobias are some specific types of anxiety disorders.

Antianxiety Drugs

These are an ill-defined group of drugs, mostly mild CNS depressants, which are aimed to control the symptoms of anxiety, produce a restful state of mind without interfering with normal mental or physical functions. The anxiolytic-sedative drugs differ markedly from antipsychotics, and more closely resemble sedative-hypnotics. They:

ü Have no therapeutic effect to control thought disorder of schizophrenia.

ü Do not produce extrapyramidal side effects.

ü Have anticonvulsant property.

ü Produce physical dependence and carry abuse liability.

ü Do not selectively block conditioned avoidance response in animals.

Classification

1. Benzodiazepines

Diazepam

Chlordiazepoxide

Oxazepam

Lorazepam

Alprazolam

2. Azapirones

Buspirone

Gepirone

Ispapirone

3. Sedative antihistaminic

Hydroxyzine

4. β blocker

Propranolol

In addition to the above drugs, antidepressants, especially the selective serotonin reuptake inhibitors (SSRIs) are effective in obsessive compulsive disorder (OCD), phobias, panic and many types of severe generalized anxiety disorders.

Benzodiazepines

The pharmacology of benzodiazepines (BZDs) as a class is described in Ch. No. 29.

Some members have a slow and prolonged action, relieve anxiety at low doses without producing global CNS depression. They have a selective taming effect on aggressive animals and suppress induced aggression. They also suppress the performance impairing effect of punishment. In contrast to barbiturates, they are more selective for limbic system and have proven clinically better in both quality and quantity of improvement in anxiety and stress-related symptoms.

At antianxiety doses, cardiovascular and respiratory depression is minor.

Because anxiety is a common complaint and is a part of most physical and mental illness, and because the BZDs—

(i) have little effect on other body systems,

(ii) have lower dependence producing liability: withdrawal syndrome is milder and delayed due to their long half lives,

(iii) are relatively safe even in gross overdosage,

they are presently one of the most widely used class of drugs. Potent BZDs like lorazepam and clonazepam injected i.m. have adjuvant role in the management of acutely psychotic and manic patients.

BZDs act primarily by facilitating inhibitory GABAergic transmission, but other additional mechanisms of action have been suggested. Higher doses induce sleep and impair performance.

Adverse Effects of BZDs noted in their use as hypnotics are described in Ch. No. 29. Side effects that occur in their use to relieve anxiety are— sedation, lightheadedness, psychomotor and cognitive impairment, vertigo, confusional state (especially in the elderly), increased appetite and weight gain, alterations in sexual function. Rashes are uncommon. Some women fail to ovulate while on regular use of BZDs. The major constraint in their long-term use for anxiety disorders is their potential to produce dependence.

Differences between individual BZDs recommended for anxiety are primarily pharmacokinetic: choice of one over the other is largely empirical.

Chlordiazepoxide

It was the first BZD to be used clinically. Oral absorption is slow: produces a smooth long lasting effect; preferred in chronic anxiety states; often combined with other drugs in psychosomatic diseases. Its t½ is 5–15 hours but active metabolites are produced which extend the duration of action. It has poor anticonvulsant action.

Daily dose: 20–100 mg; LIBRIUM 10, 25 mg tabs; EQUILIBRIUM 10 mg tab.

Diazepam

It is quickly absorbed; produces a brief initial phase of strong action followed by prolonged milder effect due to a two phase plasma concentration decay curve (distributive phase t½ 1 hr, elimination phase t½ 20–30 hours). The biological effect t½ is still longer due to production of active metabolites. It is preferred in acute panic states and anxiety associated with organic disease.

Daily dose: 5–30 mg; VALIUM, PLACIDOX 2, 5, 10 mg tabs; CALMPOSE 5, 10 mg tab, 2 mg/5 ml Syr.

Oxazepam

It is slowly absorbed; being relatively polar, its penetration in brain is also slow. The plasma t½ is about 10 hours; no active metabolite is produced—duration of action is relatively shorter. It may be preferred in the elderly and in those with liver disease, because its hepatic metabolism is not significant and duration of action is short. It has been used mainly in short lasting anxiety states.

Daily dose: 30–60 mg in 2–3 divided portions; SEREPAX 15, 30 mg tab.

Lorazepam

Has slow oral absorption. Being less lipid-soluble than diazepam, its rate of entry in brain is slower. The plasma t½ is shorter (10–20 hours); no active metabolite is produced. However, it is quite sedative and capable of producing marked amnesia when injected i.v. Injection site complications are few— is the only BZD recommended for i.m. use. It has been preferred for short lasting anxiety states, panic, obsessive compulsive neurosis and tension syndromes, as well as psychosomatic diseases.

Daily dose: 1–6 mg; LARPOSE, ATIVAN 1, 2 mg tab.

CALMESE 1, 2 mg tabs, 4 mg/2 ml inj.

Alprazolam

A high potency anxiolytic BZD which in addition has some mood elevating action in mild depression: is particularly useful in anxiety associated with depression. Good response has been obtained in panic disorders with severe anxiety and autonomic symptoms. Its plasma t½ is about 12 hours, but an active metabolite is produced. Alprazolam is claimed to cause less drowsiness, but some patients experience anxiety in between doses.

Dose: 0.25–1.0 mg TDS; upto 6 mg/day in panic disorder; ALPRAX 0.25, 0.5, 1.0 mg tabs., 0.5, 1.0, 1.5 mg SR tabs; ALZOLAM 0.25, 0.5, 1.0 mg tabs; 1.5 mg SR tab, ALPROCONTIN 0.5, 1.0, 1.5 mg CR tabs. RESTYL 0.25, 0.5, 1.0 mg tabs, RESTYLSR 0.5, 1.0, 1.5 mg SR tabs.

Other Antianxiety Drugs

Buspirone

It is the first azapirone, a new class of antianxiety drugs, distinctly different from BZDs.

·    Does not produce significant sedation or cognitive/functional impairment.

·    Does not interact with BZD receptor or modify GABAergic transmission.

·    Does not produce tolerance or physical dependence.

·    Does not suppress BZD or barbiturate withdrawal syndrome.

·    Has no muscle relaxant or anticonvulsant activity.

Buspirone relieves mild to moderate generalized anxiety, but is ineffective in severe cases, in those showing panic reaction and in OCD. The therapeutic effect develops slowly: maximum benefit may be delayed up to 2 weeks. The mechanism of anxiolytic action is not clearly known, but may be dependent on its selective partial agonistic action on 5HT_1A receptors. By stimulating presynaptic 5HT_1A autoreceptors, it reduces the activity of dorsal raphe serotonergic neurones. Antagonism at certain postsynaptic 5HT_1A receptors has also been demonstrated. After chronic treatment, adaptive reduction in cortical 5HT₂ receptors may occur. Buspirone has weak dopamine D2 blocking action but no antipsychotic or extrapyramidal effects. A mild mood elevating action has been noted occasionally—may be due to facilitation of central noradrenergic system.

Buspirone is rapidly absorbed; undergoes extensive first pass metabolism; (bioavailability <5%), one metabolite is active and excretion occurs both in urine and faeces; t½ is 2–3.5 hrs. Side effects are minor: dizziness, nausea, headache, lightheadedness, rarely excitement. It may cause rise in BP in patients on MAO inhibitors, but does not potentiate CNS depressants. Though most patients on buspirone remain alert, those operating machinery/motor vehicles should be cautioned.

Dose: 5–15 mg OD–TDS: ANXIPAR, BUSPIN, BUSCALM 5, 10 mg tab.

Hydroxyzine

An H₁ antihistaminic with sedative, antiemetic, antimuscarinic and spasmolytic properties. It is claimed to have selective anxiolytic action, but accompanying sedation is quite marked; may be used in reactive anxiety or that associated with marked autonomic symptoms. Due to antihistaminic and sedative property, it is effective in pruritus and urticaria.

Daily dose 50–200 mg; ATARAX 10, 25 mg tab, 10 mg/ 5 ml syr, 25 mg/2 ml inj.

Blockers

Many symptoms of anxiety (palpitation, rise in BP, shaking, tremor, gastrointestinal hurrying, etc.) are due to sympathetic overactivity, and these symptoms reinforce anxiety. Propranolol and other nonselective β blockers help anxious patients troubled by these symptoms, by cutting the vicious cycle and provide symptomatic relief. They do not affect psychological symptoms such as worry, tension and fear, but are valuable in acutely stressful situations (examination fear, unaccustomed public appearance, etc.). They may be used for performance/situational anxiety or as adjuvant to BZDs.

Treatment Of Anxiety

Anxiety is a universal phenomenon, and to experience it in appropriate circumstances is the normal response. It may serve to enhance vigilance and drive. However, if anxiety symptoms are frequent and persist in a severe form, they are a cause of distress/suffering and markedly impair performance. It should be treated with drugs only when excessive and disabling in its own right.

The established drugs are BZDs which should be used in the smallest possible dose. The dose has to be found out for each patient by titration with symptoms of anxiety. Acute anxiety states generally respond better. The drug should be withdrawn as soon as it is no longer required. But when large doses have been used for longer periods—withdrawal should be gradual. Long-term use of BZDs is of questionable value.

The usual practice is to give ½ to 2/3 of the daily dose at bed time to ensure good nightly rest; the remaining is divided in 2–3 doses given at day time. Though the t½ of BZDs used in anxiety are longer, divided day time doses are required to avoid high peaks.

Buspirone is a non-sedating alternative to BZDs for less severe forms of generalized anxiety. The SSRI and some atypical antidepressants are now being increasingly used in many forms of severe anxiety disorders, but are not good for acute anxiety. They produce a delayed but often gratifying response and can be combined with BZDs. The SSRIs are now drugs of choice for social anxiety in which BZDs, though effective, carry abuse potential on long-term use.

Patients with hypertension, peptic ulcer, ulcerative colitis, irritable bowel, gastroesophageal reflux, thyrotoxicosis, angina pectoris are often given low doses of BZD in addition to specific therapy, though anxiety may not be a prominent manifestation.

Fixed dose combination of tranquillizers with vitamins has been banned.