Hypnotics, Tranquilizers and Anti Pyretics

CONTENTS

 INTRODUCTION

 CLASSIFICATION

 BENZODIAZEPINES

 BARBITURATES

TRANQUILIZERS:

 INTRODUCTION

 CLASSIFICATION

 NEUROLEPTICS

ANTI PYRETICS:

 INTRODUCTION

 SALICYLATES

 ASPIRIN TOXICITY

 SELECTIVE COX II INHIBITORS

REFERENCES

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 Hypnotics, Tranquilizers and Anti Pyretics

• Chlordiazepoxide was the first BZD to be introduced in 1961.

 Pharmacological actions:

1. Sedation and hypnosis.

2. Reduction in anxiety.

3. Muscle relaxation.

4. Anticonvulsant effects.

5. Amnesia.

Drowsiness, confusion, amnesia.

 Lethargy, weakness, headache.

 Blurred vision, ataxia.

 Impaired motor co-ordination such as driving skills – therefore

BZD s are avoided while on driving.

Withdrawal symptoms:

 Milder and slower in onset because of longer plasma half life of BZDs

 Symptoms include anxiety, nervousness, tremors, Dizziness and anorexia

 When given to a pregnant mother during labour, BZDs cause hypotonia and

respiratory depression in neonate.

Insomnia

1. In anxiety

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2. As anti convulsants

3. Muscle relaxant

4. Pre anesthetic medication

5. During alcohol withdrawal

BZD ANTAGONIST:

 Flumazenil is BZD receptor antagonist which competes with BZDs for the receptor

USES:

 To reverse BZD sedation / anaesthesia

 In BZD overdosage

• These are the derivatives of barbituric acid.

 MECHANISM OF ACTION:

Barbiturates bind to a specific site on GABA receptor Cl- channel complex. They facilitate

inhibitory neuro transmission by opening chloride ion channels and hyperpolarise neural

membrane

1. Sedation and hypnosis

2. Anaesthesia

3. Anti convulsant effect

4. Depresses the respiration

5. Produces slight reduction in blood pressure and heart rate

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6. Depresses the excitability of neuro muscular junction

Pharmacokinetics:

• Well absorbed and widely distributed in the body

• Highly lipid barbiturates have fast onset of action and duration is short due to

redistribution into adipose tissues

• Metabolised in liver

• They are hepatic microsomal enzyme

• Metabolites are excreted in urine

• Hangover due to residual depression of CNS accompanied by nausea, vomiting,

vertigo, and diaorrhea, Distortions of mood

• Excitement and irritability, Hypersensitivity reactions like skin rashes, swelling of eye

lids and lips

 Barbiturates are contraindicated in porphyrias because they increase porphyrin

synthesis

• TRANQUILLIZERS

(Drugs used in Psychiatric Disorders)

INTRODUCTION:

Tranquillizer –

A Drug which reduces mental tension and produces calmness without inducing sleep or

depressing mental condition- This is the older terminology.

 Neuroleptics or antipsychotics were called major tranquillizers

 Anti anxiety drugs were called minor tranquillizers

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Schizophrenia

• Particular kind of psychosis (mental disorder) characterized mainly by a clear

sensorium but a marked thinking disturbance.

• Key symptoms include hallucinations, delusions and abnormal experiences, such as

the perception of loss of control of one’s thoughts.

• Patients lose empathy with others, become withdrawn, and demonstrate inappropriate

or blunted mood.

• Schizophrenic symptoms:

• Positive: can be regarded as an abnormality (incoherent speech, agitation).

• Negative: indicate a loss or decrease in function, such as poverty of speech or blunted

affect.

• Negative signs are more chronic and persistent and less responsive to treatment.

• The dopamine (DA) hypothesis for schizophrenia is the basis for rational drug

therapy. Several lines of circumstantial evidence suggest that excessive DA-ergic

activity plays a role in this psychosis:

(1) Many antipsychotic drugs strongly block post-synaptic D2-receptors in the CNS,

especially in the mesolimbic-frontal system;

(2) Drugs that increase DA-ergic activity, such as levodopa (a precursor),

amphetamines (releasers of DA), and apomorphine (a direct DA-ergic agonist),either

aggravate schizophrenia or produce psychosis de novo in some patients;

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(3) DA receptor density has been found postmortem to be increased in the brains of

schizophrenics who have not been treated with antipsychotic drugs;

(4) positron emission tomography (PET) has shown increased DA receptor density in

both treated and untreated schizophrenics when compared with such scans of

nonschizophrenic persons;

(5) successful treatment of schizophrenic patients has been reported to increase the

amount of homo-vanillic acid (HVA), a metabolite of DA, in the cerebrospinal fluid,

plasma, and urine.

Neuroleptics

Mechanism of action:

• Several important DA-ergic systems or pathways are now recognized in the brain:

• The first pathway (the one most closely related to behaviour) is the mesocortical

tract, which projects from cell bodies neaR the substantia nigra to the limbic system

and neocortex.

• The second system (the nigrostriatal tract)consists of neurons that project from the

substantianigra to the caudate and putamen; it is involved inthe coordination of

voluntary movement.

• Five DA receptors have been described, consisting of two separate families – the D1-

and D2-like groups:

(1) The D1-receptor is coded by a gene on chromosome 5, increases cAMP by

activation of adenylylcyclase, and is located mainly in the putamen, nucleus

accumbens, and olfactory tubercle.

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• The second member of this family is D5. It is coded by a gene on chromosome 4, also

increases cAMP and is found in the hippocampus and hypothalamus

(2) The D2-receptor family includes D2, D3 and D4-receptors. D2-receptors is coded

on chromosome 11,decreases cAMP (by inhibition of adenylyl cyclase), and inhibits

calcium channels but opens potassium channels.

• It is found both pre- and postsynaptically on neurons in the caudate-putamen, nucleus

accumbens, and olfactory tubercle.

• A second member of this family, the D3-receptor,also coded by a gene on

chromosome 11, is thought to decrease cAMP and is located in the frontal cortex,

medulla, and midbrain.

• The D4-receptor also decreases cAMP.

 Pharmacological Actions:

(1) CNS.

In normal individuals antipsychotics produce neuroleptic syndrome –

indifference to surroundings,paucity of thought,psychomotor slowing, emotional

quietening, reduction in initiative.

• In psychotic patients neuroleptics reduce irrational behaviour, agitation and

aggresiveness.

• They control psychotic symptomatology. Disturbedthought and behaviour are

gradually normalized,anxiety is relieved.

• Hyperactivity, hallucinations,and delusions are suppressed.

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(2) ANS.

• Neuroleptics have varying degrees of alpha-adrenergic blocking activity and

produce hypotension (primarily postural). The hypotensive effect is more marked

after parenteral administration.

• Anticholinergic property of neuroleptics is weak.

• The phenothiazines have weak H1-antihistaminic and anti-5-

• HT actions as well. Promethazine has strong sedative, and H1-antihistaminic

action.

(3) Endocrine system.

• Neuroleptics consistently increase prolactin release by blocking the inhibitory

action of DA on pituitary gland.

• This may result in galactorrhea and gynecomastia.

• They reduce gonadotrophins, ACTH, GH and ADH secretion

• Adverse reactions – behavioral effects:

The older typical antipsychotic drugs are unpleasant to take.

• Many patients stop taking these drugs because of the adverse effects, which may be

mitigated by giving small doses during the day and the major portion at bedtime.

• A “pseudo depression” that may be due to drug-induced akinesia usually responds to

treatment with antiparkinsonian drugs.

• Other pseudodepressions may be due to higher doses; the decreasing the dose may

relieve the symptoms.

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• Toxic-confusional states may occur with very high doses of drugs that have

prominent antimuscarinic actions.

• Neurologic effects:

Extrapyramidal reactions occurring early during treatment with older agents include

typical

• Parkinson's syndrome, akathisia (uncontrollable restlessness), and acute dystonic

reactions(spastic retrocollis or torticollis).

• Parkinsonism can be treated, with conventional antiparkinsonian drugs of the

antimuscarinic type or, in rare cases,with amantadine.

• Parkinsonism may be self-limiting,so that an attempt to withdraw antiparkinsonian

drugs should be made every 3–4 months.

• Akathisia and dystonic reactions also respond to such treatment, but many prefer to

use a sedative antihistamine with anticholinerg Tardive dyskinesia

- persistent involuntary movements of mouth, tongue or face.

• Autonomic nervous system effects

Antimuscarinic (atropine-like)

• Adverse effects:

• urinary retention, dry mouth, midriasis.

• Alpha-blockade:

• Orthostatic hypotension or impaired ejaculation should be managed by switching to

drugs with less marked adrenoceptor-blocking actions.

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• Ocular complications

Deposits in the anterior portions of the eye (cornea and lens) are a common

complication of Chlorpromazine therapy. They may accentuate the normal

processes of aging of the lens.

• Thioridazine is the only antipsychotic drug that causes retinal deposits,which in

advanced cases may resemble retinitis pigmentosa. The deposits are usually

associated with “browning” of vision.

• The maximum daily dose of thioridazine has been limited to 800 mg to reduce the

possibility of this complication.

• Metabolic and endocrine side effects

• Weight gain is very common, especially with clozapine and olanzapine, and requires

monitoring of food intake, especially carbohydrates.

• Hyperglycemia may develop.

• Hyperprolactinemia in women results in the

• amenorrhea – galactorrhea syndrome and infertility;in men loss of libido,

impotence, and infertility may result.

• Toxic or allergic reactions

Agranulocytosis, cholestatic jaundice, and skin eruptions occur rarely with the high-

potency antipsychotic drugs currently used.

• INTRODUCTION:

• Analgesics are the drugs that selectively relieves pain by acting in CNS or peripheral

pain mechanism, without significantly acting on consciousness.

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• Analgesics relieve pain as a symptom without affecting its cause.

• These are divided into two groups :

• Opioid / narcotic /morphine like analgesics.

• Non opioid / non narcotic / ANTI PYRETIC/ non steroidal inflammatory drugs

(NSAIDs).

• Antipyretic – analgesics and NSAIDs are most commonly employed for dental pain

because tissue injury and inflammation due to tooth abscess ,caries , tooth extraction .,

etc are the main causes of acute dental pain.

• During inflammation , Arachidonic acid is liberated from membrane phospholipids is

converted to prostaglandins (PGs), catalysed by the enzyme cyclo-oxygenase (COX).

• These PGs produce hyperalgesia.

• NSAIDs inhibit PGs synthesis by inhibiting COX

• There are two forms of COX:

• COX 1- found in most of the normal cells (constitutive)& maintains tissue

homeostasis.

• COX 2 is induced in inflammatory cells by cytokines & other mediators.

• These catalyse synthesis of prostanoids which are the mediators of inflammation.

• Salicylates are the salts of salicylic acid.

• Ex : Methyl salicylate, sodium salicylate, acetyl salicylic acid (aspirin).

• Aspirin is taken as the prototype.

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• Pharmacological actions:

1. Analgesia :

 Aspirin is a good analgesic and relieves pain of inflammatory origin.

 This is because PGs are formed during inflammation and they sensitize the tissues to

pain and aspirin inhibits PG synthesis and there by acts as an analgesic.

 Pain originating from integumental structures like muscles , bones , joints and pain in

connective tissue is relieved.

2.Anti pyretic action:

 In presence of fever, salicylates bring down the temperature to normal level.

 In fever, pyrogen – a protein circulates in the body and this increases the synthesis of

PGs in hypothalamus, thereby raising its temperature. The thermostatic mechanism of

hypothalamus is thus disturbed.

 Aspirin inhibits PGs synthesis in hypothlamus and rests thermostat at normal level

bringing down temperature.

 Enhanced sweating and cutaneous vasodiltation promote heat loss and assist in anti

pyretic action.

 3.Anti inflammatory action:

 At higher doses of 4-6 gms/day ,aspirin acts as an anti inflammatory agent.Signs of

inflammation like tenderness, swelling, erythema and pain are reduced.But,

progression of disease in rheumatoid arthritis is not affected.

4. Respiration:

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 In therapeutic doses of 4-6gms/day salicylates increase consumption of oxygen by

skeletal muscles. As a result there is increased carbon dioxide production. This

increased CO2 stimulates respiratory centre. These directly stimulate the medullary

respiratory centre. Both these actions increase rate and depth of respiration.

5. Acid base and electrolyte balance:

 Salicylates produce significant respiratory stimulation – CO2 is washed out resulting

in respiratory alkalosis; pH becomes alkaline.

 This is compensated by increased excretion of HCO3- in urine accompanied by Na , K

and water. This stage is known as compensated respiratory alkalosis.

6.Metabolic effects:

 Salicylates enhance cellular metabolism due to uncoupling of oxidative

phosphorylation.

7.Gastro – intestinal tract:

 Aspirin is a gastric irritant. Irritation of gastric mucosa leads to epigastric distress,

nausea and vomiting.

8.Blood:

 Even in small doses aspirin irreversibly inhibits platelet cyclooxygenase and thereby

TXA2 synthesis by platelets.It therefore interferes with platelet aggregation and

prolongs bleeding time

 Headache, tinnitus, dizziness, hearing impairment – dim vision

 Confusion and drowziness

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 Sweating and hyperventilation

 Nausea, vomiting, Marked acid-base disturbances

 Hyperpyrexia, Dehydration

 Cardiovascular and respiratory collapse, coma convulsions and death

 Decrease absorption - activated charcoal, emetics, gastric lavage

 Enhance excretion - alkalinize urine, forced diuresis, hemodialysis

 Supportive measures - fluids, decrease temperature, bicarbonate, electrolytes, glucose,

etc…

 Phenylbutazone: additional uricosuric effect. Aplastic anemia.

 Indomethacin: Common ADR’s. CNS most common: halucinations, depression,

seizures

 Propionic acids: better tolerated. Differ in pharmacokinetics

 Acetaminophen: differes in effects and ADR’s from rest. Main toxicity: hepatitis due

to toxic intermediate which depletes glutathione. Treat with N-acetylcysteine.

 Selective COX-II Inhibitors

 Anti-inflammatory with less adverse effects, especially GI events.

 Potential toxicities: kidney and platelets - increased risk of thrombotic events

 Role in Cancer prevention

 Role in Alzheimer’s disease

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REFERENCES:

1. Tripathi KD, Essentials of medical pharmacology.7thed.Clayton, panama city: Jaypee

medical publishers; 2013.

2. Uday kumarP ,Textbook of pharmacology for dental and allied health sciences. 2 nd ed.

Clayton: Jaypee medical publishers; 2005.

3. Sembulingam K, Sembulingam P, Essentials of medical physiology. 3 rd ed, Clayton:

Jaypee brothers medical publishers; 2005

4. Mohan H, Textbook of pathology for dental students. 4th ed,; Jaypee brothers medical

publishers 2012.

5. Greaves A. The use of Midazolam as an Intranasal Sedative in Dentistry. SAAD DIGEST

2016 ;32:46-49.

6. Kai-Fang H et al. Antipsychotic medications and dental caries in newly diagnosed

schizophrenia: A nationwide cohort study. J psychres:2016.

7. Kashefimehr A, Babaloo A, Ghanizadeh M, Ghasemi SH, Mollazadeh H. Effect of

prophylactic administration of Novafen for periodontal surgery on postoperative pain relief.

Saudi Med J 2017;10(2) :127-130.

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