Egészségügy | Farmakológia » László Drimba - Sedative-Hypnotic drugs, alcohols

Source: http://www.doksinet 1st seminar Sedative-Hypnotic drugs, Alcohols László Drimba M.D Department of Pharmacology and Pharmacotherapy University of Debrecen Source: http://www.doksinet Sedative-Hypnotic drugs
anxiolytic-hypnotic drugs
anxiety disorders:     
GAD (generalised anxiety disorder) panic disorder phobias PTSD (post-traumatic stress disorder) OCD (obsessive-compulsive disorder) hypnotic disorders  insomnia Source: http://www.doksinet
Classification:  benzodiazepines









buspirone (Buspar ®) „newer hypnotics”


 phenobarbital (Phenobarbital ®) pentobarbital (Nembutal ®) thiopental (Trapanal ®) secobarbital 5HT receptor agonists
 chlordiazepoxide (Librium®) diazepam (Valium ®, Seduxen ®) clonazepam (Rivotril ®) triazolam alprazolam (Xanax ®, Frontin ®) midazolam (Dormicum ®, Midazolam Torrex ®) flunitrazepam (Rohipnol ®) barbiturates
 Sedative-Hypnotic drugs zolpidem (Stilnox

®) zopiclon (Imovan ®) zaleplon melatonin receptor agonist
ramelteon Source: http://www.doksinet „Ideal” sedatohypnotics A CNS effects coma anaesthesia B hypnosis sedation increasing dose Source: http://www.doksinet Physiologic background GABA (γγ-aminobutyric acid) main NT in the CNS (inhibitory effect)
synthesis-destruction
GAD (glutamic acid decarboxylase)
GABA transaminase
GABAerg neurons, astrocytes Receptors
GABAA:  ligand gated Cl- channelCl-influxhyperpolarisation  pentamer structure – similar to nACh (α2β2γ1)
GABAB:  G-protein coupled, inhibits adenylyl cyclase  inhibiting VG Ca2+ ch, opening K+ channels  located pre-post synaptically
 Source: http://www.doksinet Benzodiazepines history: 1960’s – chlordiazepoxide tricyclic structure: 7 membered heterocyclic ring + aromatic ring + carboxamide group + halogen/nitro group 7 position sedato-hypnotic activity (another oxazole/triazole ring - alprazolam, triazolam)

alprazolam diazepam clonazepam Source: http://www.doksinet Benzodiazepines Classification
chemical structure  basic:
 triazole ring:
 alprazolam, cloxazolam potency (anxiolytic effect) • •
triazolam oxazole rings

diazepam, chlordiazepoxide, clonazepam, midazolam high potential (eff. dose < 10mg/day) low potential (eff. dose > 10mg/day) duration of action • • • • ultrashort: midazolam, triazolam short: lorazepam, oxazepam medium: alprazolam long: diazepam, clonazepam, flunitrazepam Source: http://www.doksinet Benzodiazepines mechanism of action: specific regulatory site on GABAA receptor GABAA R: Cl- channel, pentamer structure (2α1, 2β2, ɤ2) inhibitory function - hyperpolarisation in CNS binding site for GABA (ɤ-amino butyric acid), BZD, barbiturates BZD R = ω R ! BZD 1R - α1 BZD 2 R - α5 ↑ frequency of channel opening!!! allosteric modulator Source: http://www.doksinet Drugs acting on BZD receptor
BZD receptor

agonists:
BZD receptor antagonist: flumazenile (Annexate®) –   
benzodiazepines, „newer hypnotics” competitive antagonism short half life (t1/2: 0,7-1,3 hours)intoxication relapse antidotum! (NB.! complex therapy of intoxication) BZD receptor inverse agonist: β-CCB (β-carbolines)  experimental appl. Source: http://www.doksinet Benzodiazepines Pharmakokinetic features: absorption: 80-100%, oral application lipid solubility ↑ - penetrating, accumulating in CNS PPB: ↑ metabolised by CYP3A4 – CAVE! cross reaction H2R blockers (ulcus therapy) active metabolite: desmethyl-diazepam (diazepam,clonazepam, chlordiazepoxide) t1/2: 40-60 h prolonged effect! Source: http://www.doksinet Benzodiazepines Effects:

anxiolytic:
calming effects anaesthetic:





premedication: ET intubation, etc. amnestic:
anterograd and retograd amnesia sedative:
depressant on psychomotor and cognitive functions hypnoid:
↓ latency of sleep onset
↑

duration of NREM (4 stages)
↓ duration of REM anticonvulsant:
anti seizure therapy (see below) muscle relaxant Source: http://www.doksinet Benzodiazepines Adverse effects:

tolerancedependenceabuse respiratory depression, coma (ethanol!) withdrawal syndrome


psycological physical cardiovascular depression
(impaired cardiac/metabolic/respiratory function) Source: http://www.doksinet Benzodiazepines Therapeutical use/Clinical indication:
relief of anxiety (GAD, Phobias, OCD)
insomnia
sedation and amnesia before and during medical and surgical procedures (Anaesthesia, Preoperative phases)
main component of balanced anaesthesia (i.v)
treatment of epilepsy and seizures (GTCS)
control of ethanol or other sedative-hypnotic withdrawal states Source: http://www.doksinet Barbiturates history: - 1960’s barbituric acid classification: (based on duration of action)
ultrashort: thiopental (Trapanal)
short: cyclobarbital
medium:

secobarbital
long: phenobarbital (Phenobarbital) Source: http://www.doksinet Barbiturates mechanism of action: specific regulatory site on GABAA receptor binding site for barbiturates ↑ duration of channel opening!!! allosteric modulator Source: http://www.doksinet Barbiturates Effects:


similar to sedative-hypnotic drugs’ effects but! extremly depressant on CNS cardiovascular/respiratory depression hepatic enzyme induction (phenobarbital)  OAC, coumarin, phenytoin, digitalis (serum cc.↓) Source: http://www.doksinet Barbiturates Therapeutical use:
obselete in sedato-hypnotic, anxiolytic appl.
anti-seizure therapy: infants, childrenphenobarbital


sedation and amnesia before and during medical and surgical procedures thiopental main component of balanced anaesthesia (i.v) thiopental therapy of neonatal jaundice phenobarbital Source: http://www.doksinet Barbiturates Adverse effects:

tolerancedependenceabuse respiratory

depression, coma (ethanol!) withdrawal syndrome  
psycological physical more marked than, BDZs Source: http://www.doksinet „Newer hypnotic drugs”
zolpidem, zopiclon, zaleplon  selective ω1  ω1 receptor: cortex, hippocampus  novel  no receptor agonist (bind selectively to α1 subunit) hypnotic effects – no CNS depression anxiolytic, sedative, muscle-relaxant effects  can be antagonized by flumazenil Source: http://www.doksinet 5 HT receptor agonists
Buspirone  partial agonism on 5HT1A receptor  sedative, hypnotic, euphoric effects  no anticonvulsant, muscle relaxant properties  no withdrawal symptoms, no abuse  no prompt effect (appr. 1 week)  active metabolit: α2R agonism, BP↓  other drugs: gepirone, ipsapirone Source: http://www.doksinet Melatonin receptor agonists
Ramelteon:    agonism on MT1, MT2 receptors (suprachiasm. nucl) no direct effects on GABAerg neurons hypnotic drug
 oral administration
 

rapid absorption, excessive first-pass metabolism no anxiolytic, sedative, muscle-relaxant effects adverse effects:

 treatment of insomnia dizzines, fatigue endicrine changes: testosterone↓ prolactin↑ no withdrawal symptoms, no abuse Source: http://www.doksinet Other drugs producing sedatohypnotic-anxiolytic effects  cloralhydrate  promethazin,  TCA cyclizin (1st gen. antihistamines) (imipramine)  Alcohols Source: http://www.doksinet Alcohols
history:
main types:    8000 years analgetic/ effects water destillation/purification destillation-spirits „most commonly abused drug” ethyl-alcohol methyl-alcohol ethylen-glycol Source: http://www.doksinet Ethanol
Pharmacokinetic aspects  water-soluble  rapid absorption  rapid distribution, CNS („well perfused”)  metabolized in the liver


 ADH (ethanolacetaldehyde), reduced activity, risk for alcoholism MEOS (when ADH is saturated) ALDH (acetaldehyde acetate), polimorph

represent., blocked by disulfiram (Antaethyl®) – therapy of alcoholism excreted by kidney, lungs Source: http://www.doksinet Ethanol (acute consumption)
mechanism of action  CNS:



 Heart
 cardiodepressive effect Respiratory system
 inhibiting glutamate R (NMDA channel) enhancing the act. of GABA on GABAAR blocking VG sodium/calcium channels activating VG potassium channels depression Smooth muscle
vasodilation BAC (mg/dl) symptoms 50-100 sedation, „subjective high”, slower reactions 100-200 impaired motorium, slurred speech, ataxia 200-300 emesis, stupor 300-400 coma >500 respiratory depression, death Source: http://www.doksinet Ethanol (chronic consumption)
Liver and GIT  fatty liver, alcohol induced hepatitis, cirrhosis  enzyme induction (early phases)  chronic pancreatitis  malabsorption syndrome
CNS   neurotoxicity (Wernicke-Korsakoff syndrome) tolerance – dependence – alcohol withdrawal syndrome



Cardiovascular system    
cardiomyopathy heart failure arrhythmia CHD Blood/Immune system  
delirium tremens anaemia infections Fetal alcohole syndrome    intrauterine growth retardation microcephaly abnormalities in development of midfacial region Source: http://www.doksinet Ethanol Management of acute alcohol intoxication      prevent respiratory depression prevent aspiration (vomitus) glucose i.v thiamine i.v (Vitamin B1) prevent electrolyte disturbances: antiemetic drugs (metoclopramide, Vitamin B6) Source: http://www.doksinet Ethanol Management of alcohol withdrawal syndrome  sedation, anxiolysis, anti-seizure therapy
 antipsychotic
 glycerol, mannisol, Oradexon® neuroprotection

 haloperidol, carbamazepine, mepobramate ICP↓
 diazepam, clonazepam, chlordiazepoxide thiamine (Vitamin B1) glucose electrolyte, saline suppl. Source: http://www.doksinet Ethanol Treatment of alcoholism  disulfiram (Antaethyl® )


blocking ALDH acetaldehyde↑, „hangover”  sweating, facial flushing, nausea, vomiting, hypotension, confusion  acamprosate

 NMDA antagonist, GABAAR activator effects based on receptor occupancy – partial agonism naltrexone Source: http://www.doksinet Methanol




industrial application, detergents accidental/suicide intoxication absorbed from skin, GIT metabolized by ADH, ALDH (methanolformaldehydeformate) Symptoms  visual disturbances (snow storm)(retina destruction)  nausea, vomitus, seizures (metabolic acidosos)  respiratory distress, coma Source: http://www.doksinet Intoxication of methanol
Therapy  decontamination  ethanol (p.o, iv) – saturating ADH  fomepizole – inhibitor of ADH  alkalinization (Na2HCO3)  haemodialysis  support of respiration  anti seizure therapy Source: http://www.doksinet Ethylene glycol
windshield washing, anti-freeze formulations accidental/suicide intoxication rapid absorption from GIT

metabolized by ADH
Symptoms


 headache  nausea, vomitus, seizures (metabolic acidosos)  acute renal failure  respiratory distress, coma Source: http://www.doksinet Intoxication of ethylene glycol
Therapy  decontamination  ethanol (p.o, iv) – saturating ADH  fomepizole – inhibitor of ADH  alkalinization (Na2HCO3)  haemodialysis  support of respiration  anti seizure therapy