Hypnotics are drugs which produce sleep resembling natural sleep
Sedatives are drugs which reduce excitement without producing sleep
They are 2 types of sleep
- Rapid Eye Movement (REM)
- Non Rapid Eye Movement (NREM)
- Rapid Eye Movement (REM)
Tension of the muscles can be studied
It can identified by Electromyogram
The REM comprise of 20- 25 % of sleep
It does not produce sleep spindles, eyeballs make rapid jerky movements and muscles are profoundly relaxed. This pattern is known as Rapid Eye Movement (REM) OR paradoxical sleep
Tachycardia and increase in blood pressure are seen in REM sleep also dreaming is there
- Non Rapid Eye Movement
It reveals eyeball movements
It can be identified by EOG – Electro Oculogram
It produces sleep spindles and prominent slow waves, the eye balls remain motionless and the muscles under the chain remain tense. This is known as Non – Rapid Eye Movement of orthodox sleep
The NREM sleep comprised 90% of sleep and during this period the growth hormones secretion are increased
Qualitatively hypnotics and sedatives produce depression of CNS and the
difference between them is mainly quantitative
Classification
1. Barbiturate derivatives
2. Non – barbiturate derivatives
1 .Barbiturate derivatives
A. Long acting barbiturates (8 -12 hours )
Phenobarbitone
Mephobarbitone
Methylphenobarbitone
Barbitone
B. Intermediate acting barbiturates
Amylobarbitone
Butobarbitone
Allobarbitone
Vinbarbitone
C. Short acting barbiturates
Pentobarbitone
Secobarbitone
Cyclobarbitone
Hepatobarbitone
D. Ultra short acting barbiturates
Thiobarbitone
Hexabarbitone
Methobarbitone
11. Non –barbiturate derivatives
A. Benzodiazepines
Diazepam
Oxazepam
B. Aldehydes
Chloral hydrate
Chloral formamide
Paraldehyde
C. Bromides
Potassium bromide
Sodium bromide
Ammonium bromide
D. Alcohols
Ethyl alcohol
Tribromo-ehamol
Amylene hydrate
E. Piperidine derivatives
Glutethimide
Methyprylon
Barbiturates
Barbiturates o derivatives of barbituric acid which is obtained by condensation of urea and malonic acid
Barbituric acid itself does not possess hypnotic activity but hypnotic activity is produced, if the hydrogen atoms at position 5 are replaced by alkyl or aryl groups
The barbiturates were formerly the mainstay of treatment used to sedate the patient or to induce and maintain sleep
Today , they have been largely replaced by the benzodiazepines, primarily because barbiturates induce tolerance, drug metabolizing enzymes, physical dependence and
severe withdrawal symptoms
The barbiturates in severe doses produces coma
Mechanism action of barbiturates
The sedative – hypnotic action of the barbiturates is due to their interaction with GABA A receptors which enhances GABA nergic transmission
The binding site of distinct from that of the benzodiazepines
Barbiturates potentate GABA Acton on chloride entry into the neuron by prolonging the duration of the chloride channel openings
In addition , barbiturates can block excitatory glutamate receptors
Anesthetic concentration of pentobarbital also block high frequency sodium channels
All of these molecular action lead to decreased neuronal activity
Pharmacological actions
On CNS
Barbiturates produce all degrees of CNS depression like mild sedation, hypnosis and general anesthesia
Sleep
Barbiturate induced sleep resembles natural sleep
But it decreases the time spent on rapid-eye movement sleep, also there is hangover effect after awakening
Analgesic effect
Barbiturates do not relieve pain without producing unconsciousness
They enhance the analgesic effect of salicylates and Para-amino phenol derivatives
Anesthetic effect
Thiobarbiturates and some ultra short acting oxybarbriturates produce anesthesia on intravenous administration
Anti- consultant effect
Barbiturates like phenobarbitone which have a phenyl group at the 5 th carbon atom have anticonvulsant effect
Respiration
Respiration is not affected at sedative or hypnotic dose
Large dose administered intravenously may produce death due to central respiratory paralysis
GIT
Intestinal motility is not affected at a normal dose, but gastric secretion may be depressed
Uterus
Force and frequency of uterine contractions are depressed at toxic dose
Kidney
No effect at normal dose but anesthetic dose decreases urinary output due to decrease in
glomerular filtration and release of Ach
Liver
No effect at normal dose but anesthetic dose may produce hepatic dysfunction
Enzyme induction
Barbiturates induce P450 microsomal enzymes in the liver
Chronic barbiturate administration diminishes the action of many drugs that a re dependent on P450 metabolism to reduce their concentration
ADME
Barbiturates can be administered by oral and parenteral routes
They are distributed in all tissues and body fluids
They cross placental barrier and also are excreted in milk
They are chiefly metabolized in the liver and to a small extent in kidney and brain
Excretion is through urine both in free form and as glucuronic acid conjugate
Adverse reaction
Intolerance like nausea, headache and diarrhea
Fetal respiratory depression if administered during labor
Drug automatism due to repeatedly taking the drug owing to forgetfulness
Tolerance because of increased inactivation in the liver
Dependence and withdrawal symptoms
Therapeutic uses
1. Sedation in case of anxiety or tension
2. Hypnosis to relieve insomnia
3. Anticonvulsant effect in case of tetanus or status epilepticus
4. Pre anesthetic medication and to produce basal anesthesia
5. Potentiation of analgesics like salicylates
6. In psychiatric practice and in neonatal jaundice
Phenobarbitone
Phenobaarbitone is a short acting barbiturate with sedative, hypnotic and anticonvulsant effects
It depresses sensory cortex, decreases motor activity , alters cerebella function and produces drowsiness, sedation and hypnosis
Its anticonvulsant property is exhibited at high doses
Dose
It is available in tab and injection
It is available in 30 , 60 and 100mg
Sedative dose - 15 – 30mg ( 3 – 4 times / day )
Hypnotic dose - 100- 200 mg (100 – 200 mg / day)
Phenobarbitone inj - 200 mg - Hypnotic dose - 60 – 200 mg
Drug interactions
Additive sedative effect with alcohol and other CNS depressants
Adverse drug reactions
Sedation, depression, confusion, headache ataxia, hypothermia and mood changes and impairment of memory
Benzodiazepines
These are very important class of hypnotics and sedatives because of their high therapeutic index
The important Benzodiazepines are
Diazepam
Flurazepam
Nitrazepam
Lorazepam
Oxazepam
Mechanism of action
The GABA (Gamma amino butyric acid ) is acts as an inhibitory neurotransmitter in the body
It acts on GABA receptors
But the benzodiazepine receptor are associated with GABA receptors
These benzodiazepines acts on GABA and stimulate the GABA receptors , leading to increase in the GABA activity
GABA activating the chloride channels leading to increase in the Cl conductance and hence decrease firing of the regions
Benzodiazepines produce increase in pre-synaptic inhibition , decrease in turnover of 5HT, nor adrenaline and dopamine
These also posses GABA agonistic activity
Therapeutic uses
In anxiety and insomnia
As a pre-anesthetic medication
Treatment of epilepsy and seizure states or muscular relaxation in spastic conditions
In control of ethanol and sedative- hypnotic withdrawal symptoms
As diagnostic aid for treatment in psychiatry
Adverse effects
Drowsiness, confusion, impaired motor in co-ordination, tolerance and dependence to the less extent and reparatory depression
Chloral hydrate
Chloral hydrate is a trichlorinated derivative of acetaldehyde .
It is converted to the active metabolite , trichloroethanol, in the body
The drug is an effective sedative and hypnotic that induces sleep in about thirty minutes and lasts about six hours
Chloral hydrate is irritating to the gastrointestinal tract and causes epigastric distress
It also produces an unusual, unpleasant taste sensation
It synergizes with ethanol
It does not have the analgesic activity but may produce excitement and delirium in presence of pain
Adverse effects
Nausea, vomiting, gastric irritation, respiratory and vasomotor depression , myocardial depression and arrhythmia
Paraldehyde
It is nauseating and volatile, liquid hypnotic which is harmless and quick in Acton
It is more potent than the chloral hydrate and polymer of acetaldehyde
During labor it causes analgesic effect but it can cross placenta and may delay respiration in new born
Higher doses may cause hypotension, respiratory depression and coma
It can be used as anticonvulsant , hypnotic and basal anesthetic
It is absorbed thorough the oral and parental administration
It is excreted through the lungs with offensive smell
It reacts with plastic materials so cannot administer with the plastic syringes
Rectal administration cause irritation to mucosa of rectum an may cause ulceration
Ethyl alcohol
It has antianxiety and sedative effects , but its toxic potential outweighs its benefits
Alcoholism is a serious medical and social problem
Ethanol is a CNS depressant producing sedation and ultimately hypnosis with increasing dosage
It is readily absorbed orally and has a volume of distribution close to that of total body water
It is metabolized primarily in the liver, first to acetaldehyde by alcohol dehydrogenate and then to acetate by aldehyde dehydrogenate
Elimination is mostly through the kidney, but a fraction is excreted through the lungs
Ethanol synergizes wit h many other sedative agents and can produce severe CNS depression with antihistamines or barbiturates
Chronic consumption can lead to severe liver disease, gastritis and nutritional deficiencies
Cardiomyopathy is also a consequence of heavy drinking
The treatment of choice for alcohol withdrawal are the benzodiazepines
Carbamzepine is effective in treating convulsive episodes during withdrawal
Antianxiety drugs
Def
Antianxiety drugs (anxiolytics) are CNS depressants which control symptom of anxiety
They produce a calming effect in anxiety states
1. Benzodiazepines
Diazepam
Oxazepam
Lorazepam
Alprazolam
2. Azapirones
Buspirone
Gipirone
Benzodiazepines
These are the commonly used antianxiety drugs
They have anxiolytic, hypnotic, muscle relaxant and anticonvulsant actions
They are less toxic and addiction liability is very low
Classification
These are classified on the basis of duration of action & therapeutic action
A. Classification on duration of action
- Ultra short acting BZDs
Half life – 2- 4 hrs, Duration of action – less than 6 hrs
Ex – Triazolam, Midazolam
- Short acting BZDs
Half life – 10 – 15 hrs, Duration of action – less than 6 hrs
Ex – Oxazepam, Temazepam
- Intermediate BZDs
Half life – 20 – 30 hrs, Duration of action – 8 – 10 hrs
Ex – Nitrazepam
- Long acting BZDs
Half life – 20 – 40 hrs, Duration of action – More than 24 hrs
Ex – Diazepam , flurazepam , Clonazepam
B. Classification according to therapeutic uses
1. Anxiolytic benzodiazepines
Diazepam, Oxazepam, Lorazepam, Alprazolam
2. Hypnotic benzodiazepines
Nitrazepam, Temazepam, Estazolam
3. Antiepileptic benzodiazepines
Clonazepam
4. Anesthetic benzodiazepines
Midazolam
Mechanism of action
It is believed that these agents facilitate the effects of GABA receptor activation in the CNS
It potentates GABA ergic inhibition
Side effects
Sedation
Lethargy
Ataxia
Weight gain
Confusion
Tolerance
Dependence
Diazepam
It is an important benzodiazepine compound
Like all other benzodiazepines, it has a hypnotic, anxiolytic, muscle relaxant and anticonvulsant actions
It is quickly absorbed on oral administration
Uses
Acute panic states
Anxiety associated with organic disease
Status epileptic us
Dose
2- 5 mg twice a day
Oxazepam
It is active metabolites of diazepam
This benzodiazepine is slowly absorbed on oral administration also
It also penetration slow
It has a short duration of action
So it is used mainly in short lasting anxiety states
Dis-advantages
It is short acting
It is not well absorbed
Dose
10 mg /day
Lorazepam
This benzodiazepine is slowly absorbed on oral administration
It also penetration in brain is slow
It has a short duration of action
So it is used mainly in short lasting anxiety states
Dose
1-4mg
Alprazolam
It is a recently introduce antianxiety drug
In addition to anxiolytic effect
It has a mood elevating action
It also produces less drowsiness
Use
Anxiety states associated with depression
Dose
0.25-1 mg three times daily
Meprobamate
The drug produces calmness In as individual
It reduces tension and hostility
Reactions of the patient to his environment become – congenial
Unlike phenothiazines it dies not abolish conditioned reflexes
Adverse reaction
Drowsiness
Angioneurotic edema and other r allergic manifestations
Blood dyscrasias
Disadvantages
Tolerance develops
IT produces drug
Dependence
Uses
Anxiety
Neurosis
Chlordiazapoxide
Though it is a benzodiazepine, its actions resemble barbiturates
It produces calmness
It also produces sedation
It produces skeletal muscle relaxation
It stimulates appetite
Adverse reaction
Drowsiness, lethargy and ataxia
Hypotension is produce in few
Disadvantages
Tolerance develops
It induces physical dependence , withdrawal symptoms are produced on its stoppage
Use
Anxiety and neurosis
It is used to suppress withdrawal symptoms of alcohol
As preanaesthestic medication
Buspirones
It is new antianxiety drug
It does not have sedative, hypnotic, muscle relaxant and anticonvulsant effects as
produced by benzodiazepines
It has a slow action and the effect is delayed for even two weeks
Mechanism of action
It acts by stimulating presynaptic 5-HT 1A auto receptors
Use
Mild to moderate anxiety
Dose
10-30 mg daily is divided doses
Flumazinil
It is a benzodiazepine antagonist
It binds competitively with benzodiazepine receptors and blocks many of the pharmacological actions of benzodiazepines
Use
To reverse benzodiazepine anesthesia
In Benzodiazepine overdose
Hepatic coma and alcohol intoxication
Centrally acting muscle relaxants
Skeletal muscle relaxation without altering consciousness or normal voluntary movement is necessary during unwanted muscular spasms and rigidity and during operative procedures
The classes of drugs which can be used fro skeletal muscle relaxation are centrally acting drugs and drugs acting peripherally at neuromuscular junction
1. Mephenesin group
Mephenesin
Carisoprodol
Chlorzoxazone
Chlormezamone
Methocarbamol
2 .Benzodiazepines
Diazepam and others
3. GABA derivative
Baclofen
4. Central alpha 2 agonists
Tizanidine
Mepaenesin
It is the first centrally acting muscle relaxant which was introduced in 1946 still being widely used today
It relaxes normal and spastic skeletal muscles without interfering within neuro-muscular transmission
In moderate dose it reduces muscle tone and motor activities
But large doses produce hypotension, respiratory paralyses and death
The drug is will absorbed orally and parent rally ,but duration of action is short
It is used to treat acute spasm of skeletal muscle in tetanus and status epileptic us
It is used to produce muscular relaxation during operative procedures
Use to reduce agitation in chronic alcoholism an to relieve muscular rigidity and tremors in parkinsonism
Dose
Orally 1 gram to 3 grams
Parentally 100mg to 1 gram
Mephenesin carbamate an ester of mephanesin has a longer duration of action and hence is preferred
Dose – 1 to 1.2 gram per day orally
Methocarbamol
This chemically elated to mephenesin carbamate
It acts both as muscle relaxant and sedative
It is orally active with a longer duration of action and milder side effects
Uses
Same as mephenesin
Dose
0.5 grams per day orally
It can also be given by I.M or I.V route
Carisoprodol
It is chemically related to meprobamate
It produces muscle relaxation and sedative effects
It is used in cerebral palsy to produce muscular relaxation
Unwanted side effects are drowsiness, vertigo, weakness and allergic reactions on skin
Dose
350 mg oral
Metaxalone
Dose - 0 3.2 rams per day in divided doses
Serious side effects are leucopenia and jaundice
Muscle relaxants are contra-indicated in pregnant women , in the presence of renal damage and myasthenia gravis
Muscle relaxants acting at neuromuscular junction
The contraction of skeletal muscle is initiated by acetyl choline at the neuromuscular junction
Acetyl choline acts on the receptor of the muscle producing contraction
But there are drugs which block the action f acetyl choline on skeletal muscle receptors thereby producing muscle relaxation
They are of two types namely
1. Competitive blockers
2. Depolarization blockers
1. Competitive Blockers
The drugs which act by this mechanism are d-tubocurarine and gallamine
They compete with the acetylcholine to reach the muscle receptors
D-Tubocurarine
This is the dextro rotatory alkaloid obtained from the strychnos species
Curare was mainly used as an arrow poison in South America
It competes with acetyl choline to reach the receptors and thus blocks the action of acetylcholine at the neuromuscular junction and produces muscle relaxation
It is inactive orally, but is active parent rally
The drug is given intravenously for muscle relaxation during operative procedures
Dose -- 6 to 10 mg given with general anesthetic
Disadvantage - It is that it causes release of histamines from the tissues
Gallamine
It is a synthetics quaternary ammonium compound with curare like action
It also acts as a skeletal muscle relaxant by competitive blockade of acetylcholine
But is less potent than d – tubocurarine
It does not release histamine
It is not active orally
Hence given parent rally
It is also used to produce muscular relaxation during operative procedures
Dose
100 mg by I.V injection
Depolarization blockers
Here the drugs act by depolarizing the receptor motor end plate of the muscle which becomes resistance to further stimulation
The drug which stimulation
The drug which acts by this process and relaxing skeletal muscles is succinyl chloride
It has very short duration of action
Its action can be enhanced by anti-choline esterasis like neostigmine
It does not release histamine
It is used in anesthesiology to produce muscle relaxation by continuous I. V infusion
Other drugs which act this process is decamethonoum
1 comments:
It does not produce sleep spindles, eyeballs make rapid jerky movements and muscles are profoundly relaxed.
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GHRP 6 5mg
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