HYPNOTIC - SEDATIVE HYPNOTIC - SEDATIVE DRUGSDRUGS

Dra. Ma. Shiela C. GuikingDra. Ma. Shiela C. Guiking

Are drugs that belong to a group of agents that depress Are drugs that belong to a group of agents that depress the CNS in a relatively nonselective dose-dependent the CNS in a relatively nonselective dose-dependent fashion, producing progressively calming or drowsiness, fashion, producing progressively calming or drowsiness, sleep, unconsiousness, surgical anesthesia, coma, fatal sleep, unconsiousness, surgical anesthesia, coma, fatal depression of the respiration and cardiovascular depression of the respiration and cardiovascular regulationregulation

major therapeutic use is to cause sedation (with major therapeutic use is to cause sedation (with concomitant relief of anxiety) or to encourage sleepconcomitant relief of anxiety) or to encourage sleep

SEDATIVES— drugs capable of producing SEDATIVES— drugs capable of producing

mild depression; decreased mild depression; decreased activity;activity; moderate excitement, and emotional moderate excitement, and emotional

calmness calmness

- reduce anxiety (anxiolytic) and exert - reduce anxiety (anxiolytic) and exert

a calming effect with little or no a calming effect with little or no

effect on motor or mental functions, effect on motor or mental functions, degree of CNS depression minimum degree of CNS depression minimum

consistent with therapeutic efficacyconsistent with therapeutic efficacy

HYPNOTICS — drugs that are used HYPNOTICS — drugs that are used primarily primarily

to induce sleepto induce sleep

- should produce drowsiness and - should produce drowsiness and encourage encourage

the onset and maintenance of a state the onset and maintenance of a state of of

sleep sleep

- involves more pronounced depression of - involves more pronounced depression of the CNSthe CNS

The Benzodiazepines are the most widely used The Benzodiazepines are the most widely used sedative hypnotics.sedative hypnotics.

Structures- 1,4, Benzodiazepines-contain a Structures- 1,4, Benzodiazepines-contain a carboxamide group in the 7 – membered carboxamide group in the 7 – membered heterocyclic ring structure.heterocyclic ring structure.

A substituent in the 7 position, such as a A substituent in the 7 position, such as a halogen or a nitro group, is required for halogen or a nitro group, is required for sedative-hypnotic activitysedative-hypnotic activity

CLASSIFICATION:CLASSIFICATION:

BENZODIAZEPINESBENZODIAZEPINESTypes:Types:

A. Hypnotic BenzodiazepinesA. Hypnotic Benzodiazepines

> Nitrazepam> Nitrazepam > Flurazepam (Dalmane) > Flurazepam (Dalmane)

B. Anxiolytic BenzodiazepinesB. Anxiolytic Benzodiazepines

> Alprazolam ( Xanax)> Alprazolam ( Xanax)> Chlordiazepoxide ( Librium )> Chlordiazepoxide ( Librium )> Chlorazepate ( Tranxene )> Chlorazepate ( Tranxene )

> Clonazepam ( Klonopin )> Clonazepam ( Klonopin )> Diazepam ( Valium )> Diazepam ( Valium )> Halazepam ( Paxipam )> Halazepam ( Paxipam )> Lorazepam ( Ativan )> Lorazepam ( Ativan )> Midazolam ( Versed )> Midazolam ( Versed )> Oxazepam ( Serax )> Oxazepam ( Serax )> Prazepam ( Centrax )> Prazepam ( Centrax )> Temazepam ( Restoril )> Temazepam ( Restoril )> Triazolam ( Halcion )> Triazolam ( Halcion )

Triazolam and Alprazolam : TriazolobenzodiazepinesTriazolam and Alprazolam : Triazolobenzodiazepines

Glutethimide, etc : PiperidinedionesGlutethimide, etc : Piperidinediones> Meprobamate : Propanediol carbamates> Meprobamate : Propanediol carbamates> Barbiturates> Barbiturates> Alcohols : Ethanol, Chloral hydrate, Paraldehyde> Alcohols : Ethanol, Chloral hydrate, Paraldehyde> Cyclic esters> Cyclic esters> Buspirone : azaspirodecanedione> Buspirone : azaspirodecanedione> Zolpidem : Imidazopyridine> Zolpidem : Imidazopyridine> Zaleplon : Pyrazolopyrimidine> Zaleplon : Pyrazolopyrimidine> Beta – blocking drugs> Beta – blocking drugs> Clonidine> Clonidine> Antipsychotic tranqulizers, tricyclic antidepressant drugs> Antipsychotic tranqulizers, tricyclic antidepressant drugs> Antihistaminic agents (hydroxyzine, promethazine)> Antihistaminic agents (hydroxyzine, promethazine)

Since they commonly exert marked effects on the Peripheral autonomic nervous Since they commonly exert marked effects on the Peripheral autonomic nervous

system, they are sometimes referred to as “system, they are sometimes referred to as “sedative autonomicsedative autonomic” drugs” drugs

PHARMACOKINETICSPHARMACOKINETICSA. AbsorptionA. Absorption > to treat anxiety and sleep disorders: given orally > to treat anxiety and sleep disorders: given orally > oral absorption may depend on lipophilicity, with > oral absorption may depend on lipophilicity, with plasma peak concentration ranging from 0.5 to 8 hours plasma peak concentration ranging from 0.5 to 8 hours rapid: triazolam, diazepam, clorazepate rapid: triazolam, diazepam, clorazepate

slow : oxazepam, lorazepam temazepam slow : oxazepam, lorazepam temazepam > with high lipid-water distribution coefficients in the > with high lipid-water distribution coefficients in the non-ionized form non-ionized form > essentially completely absorbed > essentially completely absorbed > Bioavailability : after intramuscular injection > Bioavailability : after intramuscular injection unreliable unreliable (except lorazepam and midazolam ) (except lorazepam and midazolam )

B. DistributionB. Distribution- some reach the systemic circulation only in the form of - some reach the systemic circulation only in the form of

active metabolite ( prazepam, flurazepam)active metabolite ( prazepam, flurazepam)- rate of transport in blood depends on blood flow, - rate of transport in blood depends on blood flow,

concentration gradients and permeability concentration gradients and permeability - rate of entry into CNS depends on lipid solubility- rate of entry into CNS depends on lipid solubility

- plasma protein binding 60% to over 95% cross the - plasma protein binding 60% to over 95% cross the placental barrier and secreted into breast milkplacental barrier and secreted into breast milk

PHARMACODYNAMICS:PHARMACODYNAMICS:

Mechanism of actionMechanism of action appear to enhance GABA’s effects without directly appear to enhance GABA’s effects without directly

activating GABA receptors or opening the associated activating GABA receptors or opening the associated chloride channels.chloride channels.

The enhancement in chloride ion conductance induced The enhancement in chloride ion conductance induced by the interaction of benzodiazepines with GABA takes by the interaction of benzodiazepines with GABA takes the form of an increase in the the form of an increase in the

frequencyfrequency of channel opening events of channel opening events

Types of Benzodiazepine receptor interactions:Types of Benzodiazepine receptor interactions: 1. AGONISTS 1. AGONISTS

facilitate GABA actions, and this occurs at multiple BZ receptor sites in the facilitate GABA actions, and this occurs at multiple BZ receptor sites in the case of benzodiazepinescase of benzodiazepines

––> Zolpidem and Zaleplon – selective agonists at the BZ1 receptor subtype> Zolpidem and Zaleplon – selective agonists at the BZ1 receptor subtype

2. ANTAGONISTS2. ANTAGONISTS – – synthetic benzodiazepine derivative FLUMAZENIL, blocks the actions of synthetic benzodiazepine derivative FLUMAZENIL, blocks the actions of

benzodiazepines and zolpidem but does not antagonize the actions of benzodiazepines and zolpidem but does not antagonize the actions of barbiturates, meprobamate and ethanolbarbiturates, meprobamate and ethanol

3. INVERSE AGONISTS 3. INVERSE AGONISTS act as negative allosteric modulators of GABA receptor function ( B-act as negative allosteric modulators of GABA receptor function ( B-

carbolines eg. N-butyl-B-carboline-3-carboxylate (B-CCB) )carbolines eg. N-butyl-B-carboline-3-carboxylate (B-CCB) )

FLUMAZENIL

> A specific benzodiazepine antagonist> Available only for intravenous administration - half-life is 1 hourDuration - 30 to 60 mins.Primary indication: management of benzodiazepine overdose & reversal of its sedative effects

Dosage:1 mg given over 1-3 minutescummulative dose of 1 to 5 mg given over 2 to 10 minsadditional course within 20-30 mins should sedation reappear.May cause seizures

ORGAN LEVEL EFFECTSORGAN LEVEL EFFECTS 1. Sedation:1. Sedation:

defined as a suppression of responsiveness to a constant level of defined as a suppression of responsiveness to a constant level of stimulation, with decreased spontaneous activity and ideationstimulation, with decreased spontaneous activity and ideation

2. Hypnosis: 2. Hypnosis: - induction of sleep- induction of sleep

A. The latency of sleep onset is decreasedA. The latency of sleep onset is decreased

B. The duration of stage 2 NREM sleep is increasedB. The duration of stage 2 NREM sleep is increased

C. The duration of REM sleep is decreasedC. The duration of REM sleep is decreased

D. The duration of stage 4 NREM slow-wave sleep is D. The duration of stage 4 NREM slow-wave sleep is decreased decreased

3. Anesthesia3. Anesthesia

> diazepam and midazolam, are used IV but have not proved > diazepam and midazolam, are used IV but have not proved to be fully successful as agents capable of producing surgical to be fully successful as agents capable of producing surgical anesthesiaanesthesia

4. Anticonvulsant effects4. Anticonvulsant effects

> clonazepam, nitrazepam, lorazepam and diazepam > clonazepam, nitrazepam, lorazepam and diazepam have selective actions that are clinically useful in the have selective actions that are clinically useful in the management of seizure statesmanagement of seizure states> they are capable of inhibiting the development and spread > they are capable of inhibiting the development and spread of epileptiform activity in the CNSof epileptiform activity in the CNS

5. Muscle relaxation5. Muscle relaxation

> they exert inhibitory effects on polysynaptic reflexes > they exert inhibitory effects on polysynaptic reflexes and internuncial transmissionand internuncial transmission> high doses may also depress transmission at the skeletal > high doses may also depress transmission at the skeletal neuromuscular junctionneuromuscular junction

6. Respiratory System:- hypnotic dose -* slight depression of alveolar

ventilation similar to natural sleep changesdose dependent depression of alveolar ventilation

and pO2 -p CO2 narcosis and respiratory acidosis

7. Cardiovascular System- minimal decrease in blood pressure, cardiac

output and systemic vascular resistance- increased coronary blood flowdecrease both cerebral blood flow and cerebral 02 utilization

8. Gastrointestinal Tract - improve anxiety related GI disorders decrease nocturnal gastric secretion

UNTOWARD EFFECTS:

tolerance - lightheadednessphysiologic & psychologic dependence - ataxiadrowsiness - chest painimpaired judgement - incontinencediminished motor skills - nauseahypersensitivity reactions - headacheimpairment of sexual function - vertigo

DRUG INTERACTIONS:

- Additive effect - alcohol, opioid analgesics, anticonvulsants, and phenothiazines

- Delays hepatic clearance & prolongs elimination half time of diazepam & metabolites - cimetidine

- Enhanced CNS depression effects - antihistamines, antihypertensives and tricyclic

antidepressants

Types:Types:

A. Long Acting Barbiturates:A. Long Acting Barbiturates: > Phenobarbital (Luminal sodium)> Phenobarbital (Luminal sodium)

> Barbital (Veronal) > Barbital (Veronal)> Mephobarbital ( Mebaral)> Mephobarbital ( Mebaral)> Metharbital (Gemonil)> Metharbital (Gemonil)

B. Intermediate Acting Barbiturates:B. Intermediate Acting Barbiturates: > Amobarbital (Amytal)> Amobarbital (Amytal)

> Butarbital (Butisol) > Butarbital (Butisol)

C. Short Acting Barbiturates:C. Short Acting Barbiturates: > Pentobarbital (Nembutal sodium)> Pentobarbital (Nembutal sodium)

> Secobarbital (Seconal)> Secobarbital (Seconal)

D. Ultra – Short Acting BarbituratesD. Ultra – Short Acting Barbiturates > Thiopental (Penthotal)> Thiopental (Penthotal)

> Hexobarbital (Sombulex)> Hexobarbital (Sombulex)> Methohexital ( Brevital )> Methohexital ( Brevital )> Thiamylal (Surital)> Thiamylal (Surital)

PHARMACOKINETICS:

A. Absorption - rapid & complete absorption after oral intakeDistribution - redistribution from brain to highly perfused tissues such as skeletal muscle and subsequently to poorly perfused adipose tissue

> crosses the placental barrier

- thiobarbiturates very lipid soluble - rapid entry into CNS- readily cross placental barrier- intravenous route -+ for induction of anesthesia & management of status epilepticus - cummulative with repeated administration

Biotransformation - complete metabolism or conjugation in the liverElimination half life : Seco- 18 hrs

Pento – 48 hrs Pheno – 4-5 daysExcretion - mainly unchanged in the urineelimination rate significantly increased by alkalinization of the urine

PHARMACODYNAMICS

> Barbiturates depress neuronal activity at the midbrain reticular formation, facilitating and prolonging the inhibitory effects of GABA and glycine

Barbiturates increase the duration of GABA-mediated chloride ion

channel opening

Organ Level Effects:

1. Sedation> Barbiturates have euphoriant effects

2. Hypnosis> Barbiturates alter the stages of sleep in

the dose-dependent manner > they decrease sleep latency, decrease number of awakenings and decrease body movements

3. Anesthesia> Thiopental and methohexital are very

lipid soluble, penetrating brain tissue rapidly following IV administration > which are therefore useful in anesthesia practice

44. Anticonvulsant Effects:. Anticonvulsant Effects:> Phenobarbital and metharbital (converted > Phenobarbital and metharbital (converted

to phenobarbital in the body) are effective in the to phenobarbital in the body) are effective in the treatment of generalized tonic-clonic seizurestreatment of generalized tonic-clonic seizures

5. Respiration:5. Respiration: > Depress both respiratory drive & the > Depress both respiratory drive & the mechanisms responsible for the rhythmic mechanisms responsible for the rhythmic character of respirationcharacter of respiration

> Diminish neurogenic drive & in higher > Diminish neurogenic drive & in higher doses, suppress hypoxic & chemoreceptor drivedoses, suppress hypoxic & chemoreceptor drive

> Laryngospasm – chief complaint of > Laryngospasm – chief complaint of barbiturate anesthesiabarbiturate anesthesia

6. Cardiovascular System6. Cardiovascular System

> Cardiovascular reflexes are obtunded by partial inhibition of > Cardiovascular reflexes are obtunded by partial inhibition of ganglionic transmission –slight fall or no change in BPganglionic transmission –slight fall or no change in BP> Decrease in renal plasma flow and in cerebral blood flow > Decrease in renal plasma flow and in cerebral blood flow with a marked fall in CSF pressurewith a marked fall in CSF pressure

7. Liver7. Liver> Combine with cytochrome 450 & competitively > Combine with cytochrome 450 & competitively

interfere with the biotransformation of a number of drugsinterfere with the biotransformation of a number of drugs> Chronic administration causes a marked increase in the > Chronic administration causes a marked increase in the protein and lipid content of the hepatic smooth endoplasmic protein and lipid content of the hepatic smooth endoplasmic reticulumreticulum

8. Kidney8. Kidney> Severe oliguria or anuria in acute barbiturate poisoning, > Severe oliguria or anuria in acute barbiturate poisoning, largely as a result of the marked hypotensionlargely as a result of the marked hypotension

UNTOWARD EFFECTS:

After-effects:- drowsiness for only a few hours- residual CNS depression up to 10-22 hrs.- distortions of mood- impairment of judgement & fine motor skills- other residual effects: vertigo, nausea, vomiting, diarrhea, over excitement - awakes slightly intoxicated, euphoric & energeticirritability and temper

Paradoxical Excitement:- common among geriatric & debilitated patients- phenobarbital & N-methylbarbiturates

Pain:- prescribed for localized or diffuse myalgic, neuralgic, or arthritic pain- may cause restlessness, excitement & delirium in presence of pain Hypersensitivity:- may occur in patients with asthma, urticaria, angioedema- localized swelling,erythematous dermatitisexfoliative dermatitis -- phenobarbital

ABSOLUTE CONTRAINDICATION:

ACUTE INTERMITTENT PORPHYRIA –

barbiturates enhance porphyrin synthesis

DRUG INTERACTIONSA. increased CNS-depressant effects:

1. other CNS depressants (ethanol)2. isoniazid3. methylphenidate4. monoamine oxidase inhibitors

B. induction of microsomal hepatic enzymes -> accelerated disappearance of drugs & endogenous substances

accelerated metabolism of vitamins D & Khamper bone mineralization & lower Ca`+

absorption (phenobarbital)

* coagulation defects in neonates whose mothers are

taking phenobarbital> enhance metabolism of steroid hormones -*

endocrine disturbances> enhance metabolism of oral contraceptives -

unwanted pregnancyC. induce hepatic generation of toxic metabolites of chlorocarbon anesthetics & carbon tetrachloride - ~ promote lipid peroxidation - facilitates the periportal necrosis of the liver

MISCELLANEOUS HYPNOTIC-SEDATIVE DRUGS:

a.Buspironee. Alcohols: g. Clomethiazoleb.Zolpidem i. Paraldehyde h. etomidatec.Zaleplon ii. Chloral Hydrated.Carbamates iii. Ethchlorvynoli. Meprobamate f. Piperidinedionesii.Ethinamate i. Gluthetimideii. Methyprylon

Buspirone Relieves anxiety without marked sedative or euphoric effects

No hypnotic, anticonvulsant or muscle relaxant property

Mechanism of action: partial agonist at 5-HT1A receptors

less psychomotor impairment than diazepamsuitable for generalized anxiety states

- > Pharmacokinetics:

rapid oral absorption- extensive first-pass metabolism & form active metabolites elimination half-life: 2-4 hrs -> prolong in liver dysfunction

-—+ reduced with rifampicin (cytochrome P450 inducer)increased plasma levels with erythromycin & ketoconazole ( inhibitors of CYP3A4)

untoward effects: tachycardia, palpitations, nervousness, GIT distress, paresthesias,dose-dependent pupillary constrictionBP elevations on patients taking MAO inhibitors

Zolpidem

An imidazopyridine derivative with hypnotic actions

Mechanism of action: binds selectively to BZ, (omega, ) subtype of benzodiazepine receptors and facilitates GABA-mediated neuronal inhibition

Actions antagonized by flumazenil

Minimal muscle relaxing and anticonvulsant effectShort-term treatment of insomniaMinor effects on sleep patterns but suppress REM sleep at higher doses.Less tolerance & dependence with extended use than with benzodiazepines

Pharmacokinetics: rapidly metabolized in the liver to inactive metaboliteselimination half-life ---> 1.5 – 3.5 hours

Precautions: patients with hepatic dysfunction, elderlies & cimetidine

Drug interaction: rifampicin — decreases half-life of zolpidemEthanol & other CNS depressants — respiratory depression

Zaleplon

Resembles zolpidem

Mechanism of action: binds selectively to BZ, receptor subtype, facilitating inhibitory actions of GABA

Decreases sleep latencyLittle effect on total sleep time or on sleep structure.

Pharmacokinetics: rapidly absorbed from GITrapid onset & short duration of actionelimination half-life of about 1 hour.metabolized mainly by hepatic aldehyde oxidase & partly cytochrome P450> Amnesic effects & next-day psychomotor impairment may occur

Alcohols:

ParaldehydeRapid acting hypnotic —> sleep ensues in 10-15 minRapidly absorbed & widely distributed70-80% metabolized in the liver> elimination half-life is 4-10 hrs> excreted in expired air & urine

untoward effects = acidosis,bleeding gastritisfatty changes in liver & kidney (toxic

hepatitis & nephrosis)toxic dose: 25-150 gm

Chloral Hydrate

Has little analgesic activityDecreases sleep latency, awakenings & slow wave sleep> Metabolized in the liver to trichloroethanol>Excreted mostly in urine as urochoralic acid Untoward effects:

Irritating to skin & mucous membraneUnpleasant taste, epigastric distress, nausea, occ.

VomitingCNS: lightheadedness, malaise, ataxia, nightmares

"Hangover"idiosyncratic - disoriented, incoherent, paranoid behavior

Icterus -acute poisoning Delirium & seizures

Ethchlorvynol

a hypnotic-sedative with rapid onset & short duration of action> has anti-convulsant & muscle relaxant propertyacts within 15-30 minutes> distribution half-life is 1-3 hours > elimination half life is 10-25 hrs.untoward effects:mintlike aftertastedizziness, nausea & vomiting hypotension, facial numbness mild "hangover"hypersensitivity - urticaria, fatal thrombocytopenia, cholestatic jaundiceacute intoxication - severe respiratory depression, bradycardiaidiosyncratic - mild stimulation to marked excitement & hysteriacontraindicated in patients with porphyria> drug interaction: enhance metabolism of oral anticoagulants> toxic dose: 10-25 gram

PiperidinedionesGluthetimide

Rarely recommended for continued use because of its addiction liability, severity of withdrawal symptoms & certain features of acute intoxicationExhibits pronounced anticholinergic activity> Absorbed from GIT, 50% bound to plasma proteins, 95% metabolized in the liverHalf-life is 5-22 hoursUntoward effects:"hangover" excitementblurring of vision, gastric irritation, headache, skin rashesthrombocytopenia, aplastic anemia, leukopeniaacute intoxication - less severe respiratory depressionantimuscarinic actions - xerostomia, ileus, urinary bladder atony, long lasting mydriasis, hyperpyrexiaabstinence syndrome - tremulousness, tachycardia, fever, tonic muscle spasms &generalized convulsions

> Toxic dose: 10-20 gms

Methyprylon,HypnoticMetabolized in the liver & eliminated almost entirely by urinary excretionPlasma half-life is 4 hrs > Should be avoided in patients with intermittent porphyriaUntoward effects:"hangover" nausea, vomiting, diarrhea, esophagitis and headacheidiosyncratic excitementacute intoxication - hypotension, shock, pulmonary edemacoma - may last up to 5 daysToxic dose: 6 gm

CarbamatesMeprobamate

Introduced as antianxiety agent in 1955Causes widespread depression of CNS but not anesthesia> Also acts as anticonvulsant> Well absorbed when administered orallyMetabolized in the liver & eliminated in the urineHalf-life is 6-17 hoursUntoward effects:Major - Drowsiness & ataxiaImpairment of learning & motor coordination, prolonged reaction timeAcute intoxication- severe or fatal respiratory depression, hypotension, shock, heart failure Abrupt discontinuation - withdrawal syndrome (anxiety, tremors, insomnia, hallucinations, generalized seizures)Toxic dose: 36 grams

EthinamateEthinamate

is a urethaneis a urethane

Rapid onset & short duration of actionRapid onset & short duration of actionInactivated in the liver & excreted as glucoronide Inactivated in the liver & excreted as glucoronide in the urinein the urineUntoward effects:Untoward effects:Nausea, occasional vomiting, rashNausea, occasional vomiting, rashIdiosyncratic excitement Fever, Idiosyncratic excitement Fever, thrombocytopeniathrombocytopenia

Other Other Sedative-Hypnotics:Sedative-Hypnotics:

EtomidateEtomidate

Used as an intravenous anestheticUsed as an intravenous anesthetic

Advantages: lacks pulmonary and vascular Advantages: lacks pulmonary and vascular depressant activity Negative inotropic effectdepressant activity Negative inotropic effect

Used as sedative-hypnotics in ICU's, during Used as sedative-hypnotics in ICU's, during intermittent positive-pressure breathing and in intermittent positive-pressure breathing and in epidural anesthesiaepidural anesthesia

Clomethiazole

- Has sedative, muscle relaxant and anticonvulsant properties

- Used for hypnosis of elderly & institutionalized patients, for preanesthetic sedation, management of ethanol withdrawal

SEDATIONSEDATION HYPNOSISHYPNOSIS

DRUG DOSAGEDRUG DOSAGE DRUG DOSAGE (at DRUG DOSAGE (at bedtime)bedtime)

Alprazolam 0.25-0.5mgAlprazolam 0.25-0.5mg

2-3x daily2-3x daily

Chloral hydrate 500-1000 mgChloral hydrate 500-1000 mg

Buspirone 5-10 mg Buspirone 5-10 mg

2-3x daily2-3x daily

Estazolam 0.5-2 mgEstazolam 0.5-2 mg

Chlordiazepoxide 10-20 mg Chlordiazepoxide 10-20 mg

2-3x/d2-3x/d

Flurazepam 15-30 mgFlurazepam 15-30 mg

Clorazepate 5-7.5 mg 2x/dClorazepate 5-7.5 mg 2x/d Lorazepam 2-4 mgLorazepam 2-4 mg

Diazepam 5 mg twice Diazepam 5 mg twice

dailydaily

Quazepam 7.5-15 mgQuazepam 7.5-15 mg

Drug DosageDrug Dosage Drug Dosage(at bedtimeDrug Dosage(at bedtime

Halazepam 20-40 mgHalazepam 20-40 mg

3-4x/d3-4x/d

Secobarbital 100-200 mgSecobarbital 100-200 mg

Lorazepam 1-2 mgLorazepam 1-2 mg

once or twice/donce or twice/d

Temazepam 7.5-30 mgTemazepam 7.5-30 mg

Oxazepam 15-30 mgOxazepam 15-30 mg

3-4x/d3-4x/d

Triazolam 0.125-0.5 mgTriazolam 0.125-0.5 mg

Phenobarbital 15-30 mgPhenobarbital 15-30 mg

2-3x/d2-3x/d

Zaleplon 5-20 mgZaleplon 5-20 mg

Prazepam 10-20 mgPrazepam 10-20 mg

2-3x/d2-3x/d

Zolpidem 5-10 mgZolpidem 5-10 mg

CLINICAL PHARMACOLOGY of SEDATIVE-HYPNOTICS:

1. Treatment of anxiety states

Benzodiazepines -* most common anxiolytic drug (generalized anxiety disorder)

alprazolam = panic disorders & agoraphobia major depressive disorders

Phenobarbital, meprobamate, antihistaminesBeta-blockers> clonidine

2.Treatment of sleep disorders

Benzodiazepines Zolpidem Zaleplon

3.Preoperative medication4.anticonvulsant5.treatment of delirium tremens6.induction of anesthesia7. skeletal muscle relaxation in specific N-M disorders meprobamatebenzodiazepines8.diagnostic aid or treatment in psychiatry

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THE ALCOHOLSTHE ALCOHOLS

Ethanol Pharmacokineticswater soluble molecule that is absorbed rapidly from the GIT.After ingestion in the fasting state, peak blood concerntrations are reached within 30 minsPresence of food delay absorptionRapid distribution with tissue levels approximating the concentration in blood. In the CNS, the concentration rises quickly since the brain receives a large proportion of blood flow and ethanol readily crosses biologic membranesOver 90% of alcohol consumed is oxidized in the liverExcreted through the lungs and in the urine

Two Major Pathways of Alcohol Metabolism to Acetaldehyde:Alcohol Dehydrogenase Pathway:The primary pathway involves alcohol dehydrogenase (ADH), a cytosolic enzyme that catalyzes the conversion of alcohol to acetaldehyde. Enzyme found in liver, brain and stomachMicrosomal Ethanol Oxidizing system (MEOS)also known as the mixed function oxidase system uses NADPH as a cofactor in the metabolism of ethanolchronic alcohol consumption results in significant increases not only in ethanol metabolism but also in the clearance of other drugs eliminated by the MEOS system

Acetaldehyde Metabolism *The product of this reaction is acetate which can be further metabolized to CO2 and water.Oxidation is inhibited by disulfiram, a drug that has been used to deter drinking by alcohol dependent patients undergoing treatmentWhen ethanol is consumed in the presence of disulfiram, acetaldehyde accumulates and causes an unpleasant reaction of facial flushing, nausea, vomiting, dizziness, and headache.Other drugs like metronidazole, cefotetan, trimethoprimm inhibit aldehyde dehydrogenase and can cause a disulfiram like reaction if combined with ethanolSome people primarily of Asian descent, have a genetic deficiency in the activity of the mitochondrial form of

aldehyde dehydrogenase.

Blood Alcohol Concentration (BAC) and clinical effects in Blood Alcohol Concentration (BAC) and clinical effects in nontolerant individualsnontolerant individuals

BAC (mg/dl)BAC (mg/dl) Clinical EffectClinical Effect

50-10050-100 Sedation, subjective “high” Sedation, subjective “high” increased reaction timesincreased reaction times

100-200100-200 Impaired motor function, Impaired motor function, slurred speech, ataxiaslurred speech, ataxia

200-300200-300 Emesis, stuporEmesis, stupor

300-400300-400 ComaComa

>500>500 Respiratory depression, Respiratory depression, deathdeath

PHARMACODYNAMICS OF ACUTE ETHANOL CONSUMPTION:

Central Nervous System:

causes sedation, relief of anxiety and at higher concentrations slurred speech, ataxia, impaired judgement and disinhibited behavior- drunkennessCNS depressant, at high blood concentrations, it induces coma, respiratory depression and deathNo specific receptor but has been shown to participate in signaling pathways, including neurotransmitter receptors for amines, amino acids, and opioids; enzymes such as Na+/K+ ATPase, adenylyl cyclase, phosphoinositide specific phospholipase C and ion channels such as those for Ca+Acute ethanol exposure enhances the action of GABAAlso inhibits the ability of glutamate to open the cation channel associated with NMDA subtype of glutamate receptors, which is implicated in many aspects of cognitive function including learning and memory.

Heart:Heart:>significant depression of myocardial contractility >significant depression of myocardial contractility has been observed in individuals who acutely has been observed in individuals who acutely consume moderate amounts of alcohol at blood consume moderate amounts of alcohol at blood concentration above 100 mg/dL.concentration above 100 mg/dL.

Acetaldehyde is implicated as a cause of cardiac Acetaldehyde is implicated as a cause of cardiac dysfunction by altering myocardial stores of dysfunction by altering myocardial stores of catecholamines.catecholamines.

Smooth Muscle

Ethanol is a vasodilator probably as a result of both CNS effects (depression of the vasomotor center) and direct smooth muscle relaxation caused by acetaldehyde.Severe overdose may cause hypothermia

Also relaxes the uterus

CONSEQUENCES OF CHRONIC ALCOHOL CONSUMPTION

Liver and Gastrointestinal Tract:liver disease is the most common medical complication of alcohol abusealcoholic fatty liver, a reversible condition may progress to alcoholic hepatitis and finally to cirrhosis and liver failuremost common cause of chronic pancreatitis in Western worldalso alters pancreatic epithelial permeability and promotes the formation of protein plugs and calcium carbonate containing stonesmalnutrition and vitamin deficiencies due to malabsorption

Nervous System

Tolerance and physical dependenceAlcohol withdrawal – hyperexcitability in mild cases and seizures, toxic psychosis, and delirium tremens in severe onesPsychologic depencence – compulsive desire to experience the rewarding effects of alcohol and for current drinkers, a desire to avoid the negative consequences of withdrawalUp regulation of NMDA subtype of glutamate receptors and voltage sensitive Ca2+ channels may underlie the seizures that accompany the alcohol withdrawal syndrome.GABA neurotransmission –believes to play a central role in tolerance and withdrawal

Neurotoxicity

generalized symmetric peripheral nerve injury that begins with distal paresthesias of the hands and feetgait disturbances and ataxia due to degenerative changes in the CNSdementia and rarely demyelinating disease.- Wernicke-Korsakoff syndrome – paralysis of the external eye

muscles, ataxia and a confused state that can progress to coma and deathassociated with thiamin deficiency and rarely seen in the absence of alcoholismMost patients are left with a chronic disabling memory disorder known as Korsakoff’s psychosisalcohol may also impair visual acuity, with painless blurring that occurs over several weeks of heavy alcohol consumption

Cardiovascular System:

dilated cardiomyopathy with ventricular hypertrophy and fibrosisinterference of ethanol with the beneficial effects of B blockers and ACE inhibitorsheavy drinking, associated with both atrial and ventricular arrhythmiashypertension (more than three drinks per day)A number of observational studies concluded that moderate alcohol consumption actually prevents CHD and even reduces mortality – ethanol’s ability to raise serum levels of HDL cholesterol, the ability to inhibit some of the inflammatory processes that underlie atheroscelrosis and the presence in alcoholic beverages (red wine) of antioxidants and other substances that may protect against atherosclerosis.

Blood

indirectly affects hematopoiesis through metabolic and nutritional effects ,directly inhibits the proliferation of all cellulalr elements in bone marrowmost common is mild anemia resulting from alcohol related folic acid deficiency.Iron Deficiency Anemia may result from gastrointestinal bleedingEndocrine System and Electrolyte balancegynecomastia and testicular atrophyascites, edema and effusions – decreased protein synthesis and portal hypertensionalterations of whole body potassium induced by vomiting and diarrheasevere secondary aldosteronism hypoglycemia – impaired hepatic gluconeogenesisketosis caused by excessive lipolytic factors

Fetal Alcohol syndrome

chronic maternal alcohol abuse during pregnancyintrauterine growth retardationmicrocephalypoor coordinationunderdevelopment of midfacial region ( appearing as a flattened faceminor joint anomaliesthe fetal liver has little or no alcohol dehydrogenase activity, so the fetus must rely upon maternal and placental enzymes for elimination of alcoholImmune Systeminhibited in the lungs, enhanced in the liver and pancreassuppression of the function of alveolar macrophages, inhibition of chemotaxis of granulocytes, and reduced number and function of T cellsIncreased Risk of Cancerrisk for cancer of the mouth, pharynx, larynx, esophagus and liver

small increase in the risk of breast Ca in women.Alcohol Drug Interactions:chronic ethanol consumption and acetaminophen-induced hepatotoxicityinhibits metabolism of Phenothiazines, tricyclic antidepressants and sedative hypnotic drugspotentiates the effects of vasodilatora and oral hypoglycemic agentsenhances the antiplatelet action of aspirin

MANAGEMENT OF ACUTE ALCOHOL INTOXICATION:most important goals in the treatment are to prevent severe respiratory depression and aspiration of vomitustreatment of hypoglycemia and ketosis by administration of glucoseThiamine – Wernicke-Korsakoff SyndromeSevere vomiting – large amounts of potassium

MANAGEMENT OF ALCOHOL WITHDRAWAL SYNDROMEThe major objective of drug therapy is prevention of seizures, delirium and arrhythmias

Potassium, magnesium and phosphate balance should be restored as rapidly as is consistent with renal functionThiamine therapy initiated

Substituting a long acting sedative hypnotic drug for alcohol and then gradually reducing (“tapering”) the dose of the long acting drug (benzodiazepines preferred)

PHARMACOTHERAPY OF ALCOHOLISM

Disulfiram – tetraethylthiuraman inhibitor of aldehyde dehydrogenase is the drug most commonly usedrapidly and completely absorbed from the GITinhibits the metabolism of phenytoin, oral anticoagulants and isoniazid

management should be initiated only when the patient has been free of alcohol for at least 24 hoursusual oral dose is 250 mg daily taken at bedtime

Naltrexone

orally available opioid receptor antagonist that blocks the effects of exogenous and endogenous opioids50 mgs taken once a day Should be used with caution in alcoholic patients with evidence of mild abnormalities in serum aninotransferase activity

Combination with disulfiram should be avoided (hepatotoxins)

Topiramate drug used for partial and generalized tonic clonic seizures may be effective in reducing craving in chronic alcoholics

OTHER ALCOHOLS:METHANOL (methyl alcohol, wood alcohol)a constituent of many commercial solventsin the home, found in the form of “canned heat” or in windshield washing productscan be absorbed through the skin or from the respiratory or GIT and is then distributed in body water.

Primary mechanism of elimination of methanol in humans is by oxidation to formaldehyde, formic acid and CO2.Methanol poisoning – visual disturbance described as “like being in a snowstorm.”

ETHYLENE GLYCOLused as heat exchangers in antifreeze formulations and as industrial solventsrelatively harmless and eliminated by the kidney, it is metabolized to toxic aldehydes and oxalate.

Three stages of ethylene glycol overdoseWithin the first few hours after ingestion – transient excitation followed by CNS depression4-12 hours – severe metabolic acidosis Finally – delayed renal insufficiency follows deposition of oxalate in renal tubules * Fomepizole * - an alcohol dehydrogenase inhibitor used for the treatment of ethylene glycol poisoning and methanol poisoning

THANK YOU VERY MUCHTHANK YOU VERY MUCH

ANDAND

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