Anxiety may be due to minor mal adjustments in day to day life. Such individuals complain of ‘tension’ with vague symptoms without any obvious signs of illness. In fact they do not really need drug (Anxiolytics) therapy. In pathological anxiety, behavioural and mental functions are often severely impaired. So anxiety becomes excessive, inappropriate and it interferes with the well-being of individual.
These patients may complain of digestive disorders, headache, backache lowering of sexual function, and may have continuous high blood pressure. Earlier barbiturates were used as sedative. However, they are no more used for this purpose because they cause marked sedation, respiratory depression, and drug dependence. At present, benzodiazepines are employed for this purpose. Further, anxiety can lead to augmented autonomic activity which may also be treated simultaneously.
Classification of Anxiolytics
A. Benzodiazepines Anxiolytics
B. Non-benzodiazepine anxiolytics
1. 5-HT1A partial agonist: Buspirone, ipsapirone, gepirone
2. 5-Hi’3 antagonipt: Ondansetron
3. Adrenergic beta-blocker: Propranolol (used to control somatic symptoms)
4. Tn- and tetracyclic antidepressants are used in generalized disorders, phobia and panic attacks.
5. Other sedatives: Meprobamate, hydroxy zine chlomazanon.
All the benzodiazepines have certain common pharmacological actions. They all show:
1. Calming effect (antianxiety)
2. Muscle relaxant property
3. Anticonvulsant action
4. Hypnotic-sedative effect
Mechanism of action of Anxiolytics:
Anxiolytics act on benzodiazepine (BDZ) receptors in brain. These receptors are in proximity of GABAA receptors and Cl channel. Benzodiazepines modulate the activity of GABA, an inhibitory neurotransmitter, and increase C1 conductance. BDZ receptors are blocked by flumezenil (BDZ antagonist) and is employed as antidote to benzodiazepine overdosing. Further skeletal muscle relaxant and sedative effects are useful in inducing a sense of relaxation in patients of anxiety.
Pharmacokinetics of Anxiolytics: On oral administration, most of the benzodiazepines are rapidly and completely absorbed from gut. Usually peak plasma concentrations are reached within 30— 60 mm. However, absorption following intramuscular administration is unpredictable except for lorazepam.
Secondary plasma peaks may occur due to enterohepatic circulation. Benzodiazepines are highly plasma protein bound. Many benzodiazepines are biotransformed to clinically active metabolites such as desmethyldiazepam, desalkyl flumazepam, oxazepam, etc. Renal excretion of metabolites occurs usually after hepatic glucuronidation.
Side effects of Anxiolytics: They are safe drugs. Minor side effects are sedation, lethargy, ataxia, weight gain, and skin rashes. Toxicity due to over dosage is rare. The action of benzodiazepines may be potentiated by central nervous system depressants and sedatives. Physical or psychological dependence is rarely seen with benzodiazepines.
However, the dependence on Anxiolytics can develop to short acting drugs and diazepam when taken for long duration in low doses. In such case, withdrawal symptoms occur on sudden stoppage of the drug.
Therapeutic Uses of Anxiolytics
1. Anxiety: The best results are seen in acute and recurrent anxiety reactions, and in generalized anxiety disorders. Since newer benzodiazepines do not offer arty added advantage, diazepam is the drug of choice. Alprazolam and clonazepam may be used to treat panic and phobic disorders.
2. Effective disorders in Anxiolytics: Alprazolam iseffective in mild depression associated with anxiety and insomnia. Clonazepam may be used to treat manic depression.
3. Due to anxiolytic, sedative, anmesic, and muscle relaxant actions diazepam or lorazepam is used in preanaesthetic medication.
4. Benzodiazepines have replaced barbiturates as hypnotics.
5. Diazepam and chlordiazepoxide are given i.v. in tetanus, strychnine poisoning, atropine poisoning, delirium tremens and infantile convulsions to control convulsions.
6. Diazepam and chiordiazepoxide have been used to reduce alcohol, barbiturate, cocaine and opiate withdrawal symptoms.
7. Clonazepam and clobazepam have a wide spectrum of antiepileptic effect. So they are used in major arid minor form of epilepsy. Diazepam is used i.v. in status epilepticus (initial dose 5—10 mg; repeat at 10—15 mm up to maximum of 30—35 mg).
8. Benzodiazepines are also employed in irritable bowel syndrome, peptic ulcer, and hypertension to allay anxiety.
9. Diazepam (0.25 mg/kg, i.v.) and medazolan-i (0.15 mg/kg, i.v.) have been used to induce anaesthesia.
10. Antianxiety agents (Anxiolytics) are useful, especially during acute exacerbations of myofacial pain of the masticatory muscle in dental practice. For oral therapy, timazepam is used due to its longer duration of action (10—18 hrs).
11. Midazolam (i.v. or i.m.) is used by dent ist to induce anterograde amnesia; to depress gag reflex; and to manage seizures due to over dose of local anaesthetic.
Benzodiazepine antagonist is flumazenil. It is given parenterally to treat benzodiazepine overdosage, to counteract benzodiazepine sedation and to reduce drowsiness and coma associated with hepatic encephalopathy and alcohol intoxication.
Optimal clinical benefit of Anxiolytics. Important side effects are headache, dizziness, insonmia, dysphoria and gastrointestinal upsets. It is useful in general anxiety neurosis and is given in a dose of 15—30 mg daily.
1. Buspiron : It is a new non-benzodiazepine Anxiolytics agent. It is a partial agonist at 5-HT1A receptors and reduces 5-HT release since these receptors are autoreceptors. It does not have sedative, hypnotic, muscle relaxant and anticonvulsant properties. It causes less impairment of memory and has a very low dependence potential. However, its onset of action is slow. It takes 4—6 weeks to show its
2. Ondansetron: It is 5-HT3 receptors antagonist which are heteroreceptors.These receptors modulate dopaminergic and cholinergic activity. Its profile of action and advantages are similar as that of buspiron. Its onset of clinical response is quick. It does not have central nervous system stimulant effect. It is particularly useful to control anxiety associated with withdrawal of addicting drugs such as morphine, barbiturates, cocaine and benzodiazepines being able to reduce central dopaminergic activity.
3. Propranolol is a non-specific betaadrenoceptor antagonist. It reduces the peripheral autonomic manifestations of anxiety. It may also have central activity. Dose: 40—160 mg 6 hourly.
4. Meprobamate, hydroxyzine and chiormezanon are old Anxiolytics drugs. They are no more used because of severe sedation and high addiction liability.
i. The use of Anxiolytics, alcohol, and phenothiazine shall be avoided while taking these drugs as the sedative effect is potentiated.
ii. Anxiolytics should not ordinarily be given to patients of kidney or liver disease.
iii. When used with opioid analgesics reduce dose of opioid by one-third.
iv. Use lower doses of Anxiolytics in elderly patients because they are more prone to orthostatic hypotension.
1. A dental student must learn pharmacokinetic and pharmacodynamic properties of benzodiazepines thoroughly because these are commonly used drugs in dentistry as:
a. Sedative and hypnotic
b. Anxiolytics agent alprazolam (clonazepam)
c. Preanaesthetic medication (diazepam, lorazeparn)
d. Induction of general anaesthesia (diazepam and midazolam)
2. Avoid use of antiallergic drugs along with benzodiazepines because they potentiate the sedative effect.
3. Ordinarily avoid use of benzodiazepines in presence of kidney and liver disease because these organs are involved in biotransformation arid excretion. However, if these drugs are to be used in presence of liver disease oxazepam and lorazepam may be used because these are metabolized by phase II conjugation reactions which are least affected by hepatic disease.
4. Use lower doses of benzodiazepines in elderly because they are more prone to orthostatic hypotension.
To Remember aboutAnxiolytics
1. Anxiety may be due to minor maladjustments in day to day life. Such individuals complain of tension with vague symptoms and do not really need drug therapy.
2. In pathological anxiety, behaviour and mental functions are often severally impaired. So it becomes excessive, inappropriate, and interferes with the well being of individual. It is treated with Anxiolytics.
3. Barbiturates are no more used to treat anxiety because they cause marked sedation, respiratory depression arid Anxiolytics dependence.
4. Common pharmacological actions of Anxiolytics are: (a) calming effect (antianxiety), (b) muscle relaxant, (c) anticonvulsant and (d) hypnotic sedative effects.
5. Benzodiazepines act on benzodiazepine (BDZ) receptors in brain and modulate activity of GABA, an inhibitory neurotransmitter and increase C1 conductance.
6. Flumezenil is BDZ antagonist which is employed as antidote to benzodiazepine overdosing.
7. Important therapeutic uses of Anxiolytics are: (a) anxiety (diazepam), (b) panic and phobic disorders (aiprazolam or clonazepam), (c) mild depression with anxiety and insomnia (alprazolam), (d) manic depression (clonazepam), (e) preanaesthetic medication (diazepam or brazepam), (f) anticonvulsarit (diazepam or chlordiazepoxide), (g) antiepileptic (clonazepam or clobazepam), (h) status epilepticus (diazepam) and (i) sedative and hypnotic (BDZ).
8. Buspiron is a new non-benzodiazepine Anxiolytics agent which is a partial agonist at 5-HT1A receptors and reduces 5-HT release being autoreceptors.
9. Ondansetron is a 5-HT3 receptor antagonist which modulates dopaminergic and cholinergic activity. It is useful to control anxiety associated with withdrawal of addicting drugs (Anxiolytics).