Benzodiazipines- Rashmi

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JJM MEDICAL COLLEGE, DEPT OF ANESTHESIA DAVANGERE. : 

JJM MEDICAL COLLEGE, DEPT OF ANESTHESIA DAVANGERE. CHAIR PERSON PRESENTED BY Dr D.B.Prakash Dr Rashmi G. M.D Date – 31/08/2010 SEMINAR ON BENZODIAZEPINES & OTHER TRANQUILIZERS

General properties of Benzodiazepines : 

General properties of Benzodiazepines Benzodiazepines are compounds with sedative, anxiolytic and anticonvulsant properties. As the dose is increased the effects observed are first anxiolytic, followed by sedation, then hypnosis and finally unconsciousness with respiratory depression. The dose-response curve for these effects is relatively flat when compared with the barbiturates which they have replaced. First clinically useful benzodiazepine, chlordiazepoxide hydrochloride, was discovered in 1957.

HISTORY : 

HISTORY 1959 Diazepam (Valium) was synthesized by Sternbach in a search for a new and better compound. It was first described for use as an IV anesthetic induction in 1965. 1961 Oxazepam (Serax), a metabolite of diazepam, was synthesized by Bell. 1971 Lorazepam (Ativan), a 2′ chloro-substitution product of oxazepam, was synthesized in an attempt to produce a more potent benzodiazepine. 1976 The next major achievement was Fryer and Walser's synthesis of midazolam (Versed), the first clinically used water-soluble benzodiazepine. Midazolam was the first benzodiazepine that was produced primarily for use in anesthesia

CLASSIFICATION : 

CLASSIFICATION Long Acting T1/2 (hrs) Flurazepam 50-100 Diazepam 30-60 Nitrazepam 30 Flunitrazepam 15-25 Short Acting Temazepam 8-12 Triazolam 2-3 Midazolam 2

Potency and pharmacokinetics : 

Potency and pharmacokinetics Long acting drugs such as nitrazepam, medazepam, flurazepam, diazepam, chorazepate and chlordiazepoxide have plasma half-lives of the parent drug plus active metabolite, which exceed 10hr. For this reason these drugs are not regarded as suitable long term treatments for insomnia without anxiety. The usual route for administration of benzodiazepines is oral, although some may also be given intravenously & intramuscular.

Slide 6: 

Gut absorption is reliable but slow for some compounds, e.g., chlordiazepoxide. The drugs are highly bound to plasma proteins. Diazepam is 96% bound to protein, mainly albumin. They have a large apparent volume of distribution because all of the drugs are highly lipid-soluble. Two compounds in clinical practice are water soluble chlordiazepoxide and midazolam. Water solubility of midazolam is pH-dependent

Slide 7: 

Below pH 6 it is freely water-soluble and forms a stable solution, but at physiological pH the ring structure closes and the drug becomes lipid-soluble, rapidly penetrating the blood-brain barrier. In general, benzodiazepines are non polar lipid-soluble drugs that are not extensively excreted unchanged in the urine. They are almost entirely eliminated from the body by hepatic metabolism which usually involves oxidative reactions, by microsomal enzymes in the hepatic endoplasmic reticulum.

Slide 8: 

These compounds have been produced by chemical modification of a basic ring structure, and many of the metabolic pathways of the benzodiazepines are closely interrelated. For instance, medazopam, ketazolam, prazepam, clorazepate and diazepam are all converted to the active compound desmethyldiazepam, which has a half-life of 72 hrs, thus converting the effective action of each of these drugs to the same duration because the metabolite is a potent sedative.

Slide 9: 

Although most of the benzodiazepines are extensively bound to plasma proteins, it is a free drug, which diffuses across membranes to produce central nervous system effects. It is also the free drug that may cross the placenta to affect the fetus. The highly lipophilic benzodiazepines cross the placenta rapidly so that concentrations of diazepam are commonly greater in the fetus than the mother. Use of these drugs in late pregnancy leads to accumulation of active metabolites in fetal tissues that cause early neonatal depression with hypothermia and hypotonia

Various types of benzodiazepine receptors : 

Various types of benzodiazepine receptors Three broad classes of benzodiazepine receptors have been described. First two classes are found in the CNS and subclassifies into type I and II. A 3rd class of receptor is the so-called non-neural elements in the CNS as well as in the kidney, heart and some elements in the blood.

Central-type benzodiazepine receptor : 

Central-type benzodiazepine receptor Specific high-affinity benzodiazepine-binding sites were demonstrated in the human CNS in 1978. Although mostly located on neurons within the CNS, some are located on neuroglia, the functions of these later sites are unknown. Benzodiazepine-binding sites are distributed unevenly within the CNS, the highest density being found in the cerebral cortex and limbic system a moderate density in the cerebellar cortex and a low density in the brainstem and spinal cord

Slide 12: 

A strong correlation between binding and pharmacological activity of agonists, and inverse agonists has been recorded. Two subtype of benzodiazepine receptor were originally suggested for the CNS. The BZ1subtype is found through out brain, but with a high concentration in the cerebellum. The BZ2 type is found principally in the cerebral cortex, spinal cord and hippocampus. Anxiolysis is ascribed to the BZ1 site.

GABA Receptors : 

GABA Receptors GABA was first proposed as an inhibitory neurotransmitter in the mammalian CNS in 1954. In mammalian CNS GABA is present in approximately 20-40% of synapses. GABA concentrations vary widely in the CNS.

Slide 14: 

The highest concentrations are found in the cerebellum, hippocampus, hypothalamus and basal ganglia in the brain and in Substansia gelatinosa of the dorsal horn of the spinal cord Moderately large amounts were also found in the cerebellum and retina where it is localised in the horizontal cell layer and where it is responsible for lateral inhibition.

Slide 15: 

Most GABAnergic neurons are local interneurons with short local connections. Their actions are generally inhibitory and the effect is achieved by an increase in neuronal membrane chloride conductance. This effect has been shown to occur both pre and post synaptically. GABA has been known for a long time to produce presynaptic inhibition by hyperpolarization of afferent terminals in the spinal cord.

Slide 16: 

GABAnergic interneurons release GABA onto primary afferent fibres before they make synaptic contact in the dorsal horn of the spinal cord. The subsequent hyperpolarization of primary terminals may be recorded from the cut central ends of primary afferent fibres as dorsal root potential. The effect of this hyperpolarization is to decrease neurotransmitter release from primary afferent terminals and inhibit the central propagation of the action potential

Anxiety : 

Anxiety Anxiolytic effects of GABA are recognised as a reduction in aggression and increased social behaviour and increased handlability. GABA produces this effect by an interaction with 5-hydroxytryptamine in the limbic system. This is probably a real physiological role for GABA since receptor subunit messenger RNAs have been shown to be elevated by social stress. Sedation and induction of sleep by GABA were the first properties.

Anticonvulsant effects : 

Anticonvulsant effects Many conventional drugs used in the management of epilepsy are known to interact with GABA receptors. Sodium valproate is thought to produce its anticonvulsant action by reducing the metabolism of GABA. There are other more recent drugs such as vigabatrin that are GABA analogues

GABA- benzodiazepine interaction : 

GABA- benzodiazepine interaction It is now well established that the major CNS actions of benzodiazepines are due to potentiation of the effects of GABA. Benzodiazepines lack intrinsic activity but have been shown to exert their effects by potentiation of GABA actions in numerous regions within the CNS, e.g., cerebral cortex, hypothalamus, amygdala, brainstem, cuneate nuclues, hippocampus, cerebellum and spinal cord

Slide 20: 

It has been suggested that a GABA receptor/ benzodiazepine receptor and chloride ionophore formed one macromolecular complex, inorder to explain experimental observations that benzodiazepines were not GABA-mimetic per se, but potentiated the effects of GABA binding with the receptors in operating a chloride channel. Two types of GABA receptor exist within the CNS, these are denoted subtype A and B

Peripheral-type benzodiazepine receptor : 

Peripheral-type benzodiazepine receptor These sites are located on membranes and have been called peripheral benzodiazepine binding sites. It has also been suggested that these are functional receptors- peripheral benzodiazepine receptors. Peripheral benzodiazepine receptors are different from central type because they are not coupled to GABA receptors and they have different ligand specificity

Slide 22: 

The peripheral benzodiazepine receptors are associated with mitochondria in tissues such as testis, lung, kidney, heart, skeletal muscle, liver and brain. The mitochondrial protein, has at least two subunits – 30 and 18 kDa.

Endogenous benzodiazepines : 

Endogenous benzodiazepines The demonstration of specific benzodiazepine receptors within the CNS controlling GABA neurotransmission has an obvious parallel in the opiate/enkephalin story elucidated in the late 1970s and early 1980s. Stress may cause concentrations of this substance to vary in the brain possibly indication that Beta-CCB is an endogenous inverse agonist active at benzodiazepine receptors, and perhaps involved in the control of stress,

Slide 24: 

Agonist benzodiazepine ligands have also been extracted from the brain. These compounds are very similar to benzodiazepines developed for use as drugs. These compounds have been extracted from many different tissue sources with a number of different extraction procedures, thus ensuring that the endogenous benzodiazepine-like substances are a real entity. They have been shown to be released from cultured neurons and they have been implicated in the generation of hepatic encephalopathy

Slide 25: 

These compounds may modulate GABA-activated chloride conductance in isolated human cortical neurons. This diazepam-like substance also seems to be confined to synaptic vesicles. On the other side of the coin, however, benzodiazepine-like substances are found in many common foodstuffs, and these may be the source of the endozepines. However, the presence of the diazepam-like substance in synaptic vesicles and the description of an in vivo mechanism for the formation of 1-4 benzodiazepines make it likely that these are indeed endogenous ligands for the benzodiazepine/GABA receptor complexes

Advantages over barbiturates : 

Advantages over barbiturates Benzodiazepine have a high therapeutic index. Ingestion of even 50 hyptonic doses does not endanger life-there is no loss of consciousness and patient can be aroused; respiration is not so depressed as to need assistance. Hypnotic doses do not affect respiration or cardiovascular functions Benzodiazepines have practically no action on other body systems. Only on IV injection the BP falls and contractility decreases. Fall in BP in case of diazepam and lorazepam is due to reduction in cardiac output while that due to flunitrazepam and midazolam is due to decrease in peripheral resistance. The coronary arteries dilate on IV injection of diazepam

Slide 27: 

Benzodiazepines cause least distortion of sleep architecture and rebound phenomena on discontinuation of regular use are less marked. Benzodiazepines do not alter disposition of other drugs by microsomal enzyme induction They have lower abuse liability, tolerance is mild, psychological and physical dependence and withdrawal syndrome are less marked. A specific benzodiazepine antagonist flumazenil is known, which can be used in case of poisoning.

Various actions of benzodiazepines : 

Various actions of benzodiazepines Antianxiety: anxiolytic effects are seen with the lowest doses, but in severe anxiety and panic attacks, sedative or even hypnotic doses may have to be used. Sedation: there is a decreases responsiveness to a constant level of stimulation, with a decrease in spontaneous activity. Increasing dosage will eventually produce sleep and the drug have gained considerable popularity as hyptonics. Intravenously, BZDs are used extensively to produce conscious sedation during unpleasant procedures .

Slide 29: 

Diazepam and midazolam have also been used as intravenous inducing agents. Cardiovascular stability is a feature of such use, but the drugs are not as reliable and predictable as thiopental for induction and there is wide variation between patients in the dose required to produce the desired effect. Midazolam, however, potentiates propofol in the technique of co-induction.

Slide 30: 

Anticonvulsants: like most classes of sedative hypnotics, BZDs are capable of preventing and terminating convulsive activity. Clonazepam and diazepam are effective in status epilepticus, while the former is also of use in petit mal epilepsy. Muscle relaxation: benzodiazepines reduce muscle tone and this is mediated via an interneurons in the spinal cord.

Slide 31: 

Amnesia: Intravenous benzodiazepines will reliably produce antegrade amnesia. Following midazolam this is very intense for 20-30 minutes and hence a very useful property when performing short unpleasant endoscopic procedures. Longer amnesia, upto 6 hr, has been reported following lorazepam. The amnesic effects of the benzodiazepines when given intramuscularly or orally is much more variable. The mechanism of the amnestic action is not known

Pharmacokinetics of benzodiazepines : 

Pharmacokinetics of benzodiazepines Short acting BZDs such as midazolam may be given intravenously or intramuscularly as an induction agent: the onset of action is rapid but the drug is quickly cleared from the body under most clinical circumstances. Other relatively short-acting BZDs, such as temazepam or oxazepam, are used to revive insomnia. They induced sleep for the first few hours, the patients then continuing to sleep and awake refreshed and drug free, without hangover effects.

Slide 33: 

Short-acting BZDs, at lower doses, may also be used to provide demand relief of acute symptoms of anxiety, such as panic attacks and phobias. Long acting BZDs, such as diazepam and chlordiazepoxide have a slower onset of action following oral administration and subsequently, a prolonged pharmacological action. At modest doses, administered just once or twice daily, they provide sustained relief from persistent symptoms of anxiety, the expectation being that such treatment may be required continously over several days or weeks.

Slide 34: 

Sedation and sleep may ensure sleep, particularly if this has been denied by anxiety or concurrent illness and particularly if higher doses are administered. Because of their persistent pharmacological action the long-acting BZDs may be used in some form of epilepsy and will find a use in preventing the increased muscle tone of tetanus infection.

Slide 35: 

Benzodiazepines are metabolized in liver by dealkylaytion and hydroxylation to many metabolites, some of which are active. The biological half-life of these drugs may be much longer than the plasma t1/2 of the administered compound. Benzodiazepines and their phase I metabolites are excreted in urine as glucoronide conjugates.

Other adverse effects : 

Other adverse effects At the time of maximal effect from a hypnotic dose of benzodiazepines, dizziness, lassitude, vertigo, disorientation, amnesia, increased reaction time with motor incoordination, impairment of mental coordination occur. Weakness, blurring of vision, dry mouth and urinary incontinence are sometimes complained. Paradoxical stimulation, irritability and sweating may occur in an occasional patient, specially with flurazepam. Increase in nightmares and behavioural alterations are also seen in some

Slide 37: 

There are a no. of psychological effects that may accompany the use of short acting benzodiazepines in insomnia. Normal pattern of sleep, no. of episodes of REM sleep are frequently disturbed. Defect in overall production of REM sleep can lead to persistent tiredness or hangover effect. With repeated medication, some tolerance to these effects develops, to the extent that proportion of REM returns to normal.

Interactions : 

Interactions Benzodiazepines synergise with alcohol and other CNS depressants leading to excessive impairment. Drug interaction due to displacement from protein binding or microsomal enzyme induction are not significant. Cimetidine, isonizid and oral contraceptives have been shown to retard benzodiazepine metabolism

Uses of benzodiazepines : 

Uses of benzodiazepines As hypnotic: Used to shorten sleep latency Used to reduce nocturnal awakening Impaired performance the next day is largely related to dose and pharmacokinetics of the drug. Though effect of drugs on the EEG stages of sleep, including REM sleep, could be physiologically important, most important is the subjects own assessement of having slept restfully with no impairment the following day Insomnia arises under a variety of circumstances. Could be long term, short term or transient problem

Other uses : 

Other uses As anxiolytic and for day time sedation As anticonvulsants, specially emergency control of status epilepticus As centrally acting muscle relaxant For preanaesthetic medication and IV anaesthesia Alcohol withdrawal in dependent subjects Along with analgecis, NSAIDs. Spasmolytics, anti-ulcer and many other drugs

Diazepam : 

Diazepam Physical characteristics It is insoluble in water Solution for injection contains several organic solvents, mainly propylene glycol, ethanol & sodium benzoate in benzoic acid. Should not be mixed with other drugs

Pharmacology : 

Pharmacology CNS- Diazepam is a benzodiazepine, which is a potent tranquilizer, muscle relaxant and anticonvulsant. These properties are due to its effect on the ascending reticular activating system and spinal internuncial neurons as well as the effect on the limbic system. It can be given in doses that cause a state of extreme drowsiness but in which the patient is still accessible and there is marked amnesia. When combine with other drugs as premedicant, the incidence of amnesia is increased.

Slide 43: 

Respiratory system: IV injection of 0.14mg/kg depress the sensitivity of the respiratory centre CVS: IV injection of 0.2mg/kg at the rate of 10mg/minute, the only significant change is tachycardia, which may persist for some time. There is no effect on cardiac output or any marked effect of blood pressure

Indications : 

Indications As a premedicant To induce anaesthesia Used intravenously in sub-anaesthetic doses as a sedative for pts with dental phobia to cover unpleasantness in ICU and to accustom pts to artificial ventilators Used as a sole agent to cardioversion As a sedative during carotid angiography Orally in treatment of psychosomatic illness

Slide 45: 

Reduce fasciculation after scoline. In radio-diagnostic procedures for pediatric patients. Reduce hallucination & emergence delirium after Ketamine anesthesia. Reduces dose requirement of muscle relaxants. To treat tachycardia, systolic hypertension & anxiety neurosis. Used as anti-convulsant in status epilepticus, eclampticus & tetanus.

Dosage and administration : 

Dosage and administration Can be given in tablet form, syrup and by IV Pre-medication- 10 to 20mg, 1-1.5 hr before operation Acute sedation- 0-2mg/kg To induce unconsciousness- 0.6mg/kg Tetanus treatment- 5mg/kg/24hr

Precautions : 

Precautions Consumption of alcohol should be avoided by pts under treatment It cannot be diluted and precipitates when mixed with most other agents Painful when injected intramuscularly

Midazolam : 

Midazolam It is water soluble benzodiazepine whose solubility is pH dependent. Chemically designated as 8 chloro 6 (2 fluro-phenyl) 1 methyl-GH-imidazo benzodiazopine. Mol wt.  325.8 Below 6.0 it is water soluble & forms a stable solution.

Pharmacokinetics : 

Pharmacokinetics At body pH, it is highly lipophillic and is rapidly redistributed after intravenous injection. MOA- interferes with reuptake of inhibitory neurotransmitter GABA thereby causing accumulation of GABA. Elimination half-life of 2-3hr. Entirely metabolized by liver and less than 1% is excreted unchanged in urine

Pharmacology : 

Pharmacology CNS: Its actions are qualitatively similar to those of other benzodiazepines and are exerted by its attachment to benzodiazepine receptors. It blocks EEG arousal from stimulation of the brain stem and reticular system. Effect when given IV varies from mild sedation to full GA, depending on dosage used. Drug is highly protein bound and slight variation in plasma concentration can have a marked influence on the pharmacodynamically active free drug levels in the plasma

Slide 51: 

CVS: It is less depressant to CVS. It causes a slight fall in systemic vascular resistance and arterial blood pressure with little change in cardiac output RS: In healthy pts, in a dose of 0.075mg/kg IV produces only a transitory and non-significant depression of the carbon dioxide response curve

Indications : 

Indications Has largely replaced diazepam in anaesthetic practice. To produce sedation in unpleasant procedures such as upper intestinal endoscopy, bronchoscopy, dental work carried out under local anaesthesia and major surgery performed with the aid of regional anaesthesia. When used for sedation it is frequently combined with small doses of fentanyl & other opioids. Used for induction of anesthesia

Slide 53: 

Co-induction: combination of sedative drugs with intravenous anaesthetic agents have a synergic action, although the exact mechanism is unknown. Several studies have shown that this also occurs between midazolam and propofol.

Dosage and administration : 

Dosage and administration IM a dose of 0.07-0.08mg/kg produces satisfactory anxiolysis and sedation when used for pre-medication For conscious sedation: 0.07-0.1mg/kg Available for injection either in 1ml ampoules at a concentration of 5mg/ml or 5ml ampoules containing 1mg/ml.

Adverse reactions & Complications : 

Adverse reactions & Complications Disadvantage of carcinogenicity & mutagenicity. Not used in Lactational mothers Extremes of age. Potentiates effects of Narcotic analgesics. Hypotensive effects of β blockers. Diuretics, CCB, MgSO4 & nitrates. Pain during injection, phlebitis, drowsiness, bronchospasm, impaired co-ordination, diminished reflexes etc

LORAZEPAM : 

LORAZEPAM PHYSICAL CHARACTERISTIC Insoluble in water Parenteral use-dissolved in polyethylene glycol & propylene glycol PHARMACOLOGY CNS Similar to diazepam Produces anterograde amnesia No analgesic properties

Slide 57: 

RS Enhanced ventilatory response to CO2 challenge suggesting stimulant effect on respiration. CVS No marked change in BP, PR or SVR. MUSCULOSKELETAL Has muscle relaxant property, probably of central origin.

Slide 58: 

FATE IN BODY: Absorption of orally administered lorazepam is rapid, max blood concentration occuring 2-4 hrs & it’s action persists for 12-18 hrs. 80% dose recovered in urine as glucuronide

Slide 59: 

INDICATIONS: For sedation Relief of anxiety Post op abolition of emergence reactions when given i.v after ketamine anaesthesia DOSAGE & ADMINISTRATION Intermediate duration of action 5 times as potent as diazepam Oral dose : for anxiety is 1-3 mg (bd) Doses upto 5 mg orally or i.v are used for preanaesthetic medication

Slide 60: 

PRECAUTIONS Potentiates effect of other CNS depressants & may have prolonged action I.V inj produces thrombosis & thrombophlebitis Long term use has high incidence of dependence and withdrawal symptoms

NITRAZEPAM : 

NITRAZEPAM It has hypnotic action & same as Diazepam. Less soluble in water Used for night sedation & premedication. Given in dose of 5-10mg orally. Action lasts 6-8hrs. C/I  COPD.

TRANQUILIZERS : 

TRANQUILIZERS

CHLORPROMAZINE : 

CHLORPROMAZINE 3 ringed structure, linked by sulphur & nitrogen. Greenish white crystalline powder with slightly pungent odour. Water soluble. 5% solution has pH of 4.5

PHARMACOLOGICAL ACTIONS : 

PHARMACOLOGICAL ACTIONS CNS It depresses Hypothalamus. Meso-diencephalic neurons. Central vomiting center. Stimulation of Epileptiform foci (anticonvulsant action). It controls  BMR

Slide 65: 

It decreases Secretion of Anterior Pituitary gland. Body temperature Vasomotor tone Dosage of CNS depressants, Hypnotics, Analgesics, Alcohol & IV anesthetic agents. It produces Sleep & wakefulness. Drowsiness, loss of interest in surroundings. Euphoria.

Slide 66: 

ANS α adrenergic blocking effect. Moderate inhibition of actions of Ach & 5-HT. Central depressant action on Hypothalamic center controlling sympathetic activity postural hypotension  Tachycardia.

Slide 67: 

CVS Dilatation of peripheral blood vessels. ↑coronary blood flow. ↑contractile force of heart & ↓irritability. RS ↑respiratory rate. (irregular) ↓tidal volume & min volume. Stimulates respiration as a whole.

Slide 68: 

LIVER ↑viscosity of bile Stasis & Intrahepatic canalicular obstruction. KIDNEY Sodium & water excretion is slightly increased. METABOLIC SYSTEM Reversible inhibition of cellular activity. ↓BMR. ↓secretion of all endocrine glands.

Slide 69: 

MISCELLANEOUS EFFECTS Depresses central temp regulating center prevents Shivering. ↑effects of both DMR & NMDRs. Local analgesic. Produces sedation DOSAGE 2-3mg/kg IV/IM/Oral.

ABSORPTION, FATE & EXCRETION : 

ABSORPTION, FATE & EXCRETION Well absorbed on oral & parenteral doses. Distributed in all body tissues with high conc in liver, lungs & adrenals. Metabolized in liver by Hydroxylation & subsequent Glucuronide conjugation, sulfaxilation & deaminoethylation. Metabolites are observed 6-12hrs in urine.

THERAPEUTIC USES : 

THERAPEUTIC USES Treatment of Psychosis (Major & Senile) Treatment of Schizophrenia. Anti-emetic & Anti-hiccup Induction of Hypothermia. Treatment of Pre-eclamptic toxemia & Eclampsia in Lactic-cocktail regime. Treatment of intractable pain. As pre-anesthetic medication As anti-rigidity agent in tetanus.

ADVERSE REACTIONS & COMPLICATIONS : 

ADVERSE REACTIONS & COMPLICATIONS Causes nasal stuffiness, dryness of mouth & sometimes palpitation. Intolerance skin eruptions, photophobia. ANS anticholinergic action  blurring of vision, tachycardia, constipation, paralytic ileus etc. Haemopoietic system & liver  agranulocytosis in 0.5%. Rarely thrombocytopenia & aplastic anemia.

Slide 73: 

CNS  10-40% may show Extrapyramidal symptoms of parkinsonism. Behavioural reactions like drowsiness, restlessness. Tremors, muscle rigidity, excess salivation, akinesia. May produce Epileptic seizures.

Slide 74: 

Endocrine & Metabolic disturbances Gynaecomastia, lactational & menstrual irregularities. There are chances of aggravation of DM, Impotence & weight gain due to increased food intake. Interaction with other drugs Prolong the effect of narcotic analgesics & anaesthetic drugs. Incompatible with MAO inhibitors.

PROMETHAZINE : 

PROMETHAZINE Synthetic agent of Phenoperidine group. Marked sedative & Anti-histaminic property Potent depressor of Upper respiratory tract reflexes, RAS & Hypothalamus. Potentiates effects of sedatives, hypnotics, anesthetic & narcotic analgesics. Reduces incidence of PONV due to its action on CTZ. Has local anesthetic property.

Slide 76: 

Uses Premedication To treat allergic episodes. To treat motion sickness. Dosage 25-50 mg bolus or 1mg/kg.

TRIMEPRAZINE : 

TRIMEPRAZINE Phenothiazine derivative. Potent central sedative, powerful anti-histaminic, anti-emetic, spasmolytic & anti-pruritic. Has less anti-cholinergic & no CVS actions. Uses  anti-pruritic & sedative. Dosage  1-1.5 mg/kg.

TRIFLUOPROMAZINE : 

TRIFLUOPROMAZINE Phenothiazine derivative. Marked anti-emetic & sedative property Intensifies & prolong the action of Barbiturates, narcotic analgesics & anesthetic agents. Causes hypotension, dryness of mouth etc. Uses premedicant & anti-emetic. Dosage  0.2 mg/kg.

Slide 79: 

PROPLOMAZINE Potent sedative & antiemetic. Dosage 20-40 mg parenterally. PROMAZINE 1/3 as potent as Chlorpromazine. Dosage  25-50mg parenteral. PROCHLORPERAZINE Widely used as antiemetic. Sometimes used in treatment of Migraine & Psychiatry. Dosage  0.2mg/kg.

HALOPERIDOL : 

HALOPERIDOL Valuable in patients with delirium. MOA: Dopamine receptor antagonist (D2). Blocks cholinergic, β1 adrenergic and histaminic receptors. Dosage: PO – 0.5-5 mg per day (max 100mg/day). Peak 3-6 hr, t1/2 17 hr IM – 2-5 mg q1-8h Peak 10-20 min, t1/2 17 hr CI: Severe toxic CNS depression, comatose states from any cause, Parkinson’s disease Adverse reactions: EPS, neurolept malignant syndrome, seizures, tachycardia, agranulocytosis

DROPERIDOL : 

DROPERIDOL A butyrophenone, a fluorinated derivative of phenothiazines. METABOLISM & PHARMACOKINETICS: Biotransformed in liver into 2 primary metabolites Clearance is 14 ml / kg/ min & elimination half life is 1 ½ -2 hrs Elimination half life is relatively short  103-134 min.

Slide 82: 

PHARMACOLOGY CNS Potent cerebral vasoconstrictor, producing 40% reduction in CBF No significant change in CMRO2 RS 0.044 mg/kg given to pt produces slight reduction in RR. 3 mg i.v has low significant effect on tidal volume CVS Produces vasodilation with decrease in BP as a result of moderate alpha adrenergic blockade. Possesses some antiarrythmic effect like quinidine

Slide 83: 

USES: Used as an NLAN component & as an antiemetic in G.A. – at the dose of 10-20 mcg /kg i.v. As an adjunct with opioids in epidural analgesia Produces CNS depression characterised by marked apparent tranquility & cataleptic immobility.

INNOVAR : 

INNOVAR It’s a combination of droperidol & fentanyl in ratio of 5:1 (2.5 mg/ml & 50 mcg/ml respectively) This combination is simply an additive effect Lactic acid is added for adjustment of pH to 3.5 Consciousness returns within 3-5 min after cessation.

Slide 85: 

PHARMACOLOGY RS Produces respiratory depression Peripheral effects involve truncate rigidity & central depression at respiratory centre is by fentanyl. Both RR & tidal volume are reduced CVS Decrease in arterial BP because of droperidol HR decreases as a result of fentanyl induced increase in vagal tone. But innovar doesn’t significantly reduce cardiac output.

Slide 86: 

USES NLAN Droperidol should be administered first in the dose of 5-150 mcg /kg followed by incremental dose of fentanyl in 50-100 mcg. Induction dose: 0.1 – 0.15 ml/kg DROPERIDOL produces hypnosis ,sedation ,antiemesis. FENTAYL produces analgesia

Slide 87: 

SIDE-EFFECTS Due to DROPERDOL: Hypotension Prolonged somnolence Extra pyramidal complications like dyskinesia esp; of face,neck & pharyngeal muscles with & swallowing difficulties, grimacing, trismus,occulogyric spasms & torticollis Due to FENTANYL: Muscle rigidity Respiratory depression Rare complication of innovar is malignant neroleptic syndrome chracterised by hyperthermia,muscle rigidity,autonomic instability

DEXMEDETOMIDINE : 

DEXMEDETOMIDINE It’s highly selective alpha 2 adrenergic agonist. It’s a specific stero isomer which is available as parenteral formulation. Metabolism By dehydrogenation or glucuronidation

Slide 89: 

Pharmacology CNS Alpha 2 agonist produce their sedative hypnotic effect by their action on alpha 2 receptor in locus ceruleus & Analgesic action at alpha 2 receptors within locus ceruleus & SPINAL CORD RS Dose of 1-2 mcg /kg induces mild increase in PaCO2 & rightward shift of CO2 response curve. Decrease RR & TV.

Slide 90: 

CVS Decreased HR, systemic vascular resistance, myocardial contractility, cardiac output & systemic BP. Shows biphasic response

Slide 91: 

USES Sedation As premedicant, at I.V doses of 0.33-0.67μg/kg, given 15min prior to surgery. Reduces thiopental doses by 30% Reduces requirement of volatile anesthetics by 25% Maintenance of Anaesthesia Starting with loading dose of 170ng/kg/min for 10min followed by infusion of 10ng/kg/min

NON-BENZODIAZEPINE HYPNOTICS : 

NON-BENZODIAZEPINE HYPNOTICS

Slide 93: 

ZOPICLONE Cyclopyrrolone hypnotic, agonist at GABA receptor & potentiates GABA by binding to site other than that of BZDs. Does not alter REM sleep & tends to prolong stages 3 & 4. Doesn’t develop hangover, withdrawal phenomenon or alteration of sleep architecture. Its t1/2 is 5-6hrs Use  short term treatment of insomnia. S/E  metallic or bitter taste. Impaired judgement, Psychological disturbances Dry mouth & rarely dependence. Dose  7.5mg at night.

ZOLPIDEM : 

ZOLPIDEM Imidazopyridine which acts on ω1 subtype of BZD receptors. Hypnotic effect is pronounced. Sleep latency is shortened & duration prolonged in insomniacs. Advantages relative lack of effect on sleep stages. minimal residual day time sedation or fading of hypnotic action on repeated nightly use. near absence of tolerance or physical dependence. Completely metabolized in liver (t1/2 2.5hr) & has short duration of action. Dosage  10-20 mg at bedtime.

REFERENCES : 

REFERENCES Miller`s Anaesthesia- 7th ed. Barash Clinical Anesthesia- 6th ed. Stoelting`s Principles of Anesthesiology-3rd ed. Collin`s Anesthesiology Goodman Gillman`s Textbook of Pharmacology- 11th ed. K.D Tripathi`s Essentials of Medical Pharmacology 5th ed.

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