Sedative hypnotics and opioids Flashcards
Structure of GABA-A receptor
Cl- on channel receptor Pentameric: 2α, 1 or 2 β and γ α subunits close the Cl- channel lumen 1. GABA binding site: junction of α and β 2. Benzodiazepine BZD site: b/w α and γ 3. Barbiturate site: in β subunit
Mechanism of sedation and hypnosis by GABA-A receptor
- 2 molecules of GABA bind
- α projection goes back
- Lumen opens
- Cl- moves through
- Neuro relaxation
- Sedation and hypnosis
3 types of drugs acting at BZD site
Between α and γ subunits
- Agonist: BZD
- Inverse agonist: β-carboline
- Antagonists: Flumazenil
GABA facilitators
1. Benzodiazepines: • GABA opens Cl- channel more frequently • Between α and γ subunits 2. Barbiturates: • GABA opens Cl- channel for more duration • Present at β subunit
Flumazenil
Antagonists of BZD site of GABA-A receptor
Used to treat BZD / Z-Compound toxicity
Route: IV
Duration of action: 30-60 min
Classification of benzodiazepines based on metabolism
1. Phase I: CYP3A4 Phase II: glucuronidation Eg., diazepam 2. Phase I: CYP3A4 Phase II: Faster glucuronidation 3. Only phase II: direct glucuronidation Eg., lorazepam
First type of benzodiazepines
Phase I: CYP3A4 Phase II: glucuronidation • Longest acting ➡️ minimum dependence and withdrawal symptoms • Maximum sedation Eg., D. Diazepam C. Clonazepam C. Chlordiazepoxide C. Clonazepate
Second type of benzodiazepines
Phase I: CYP3A4 Phase II: faster glucuronidation • Shortest acting ➡️ maximum dependence and withdrawal symptoms Eg., Triazolam, Midazolam - shortest acting
Third type of benzodiazepines
Only phase II: direct glucuronidation • Short acting • Safest in liver failure, no active metabolites Eg., O. Oxazepam T. Temazepam L. Lorazepam E. Estazolam
Uses of benzodiazepines as antiepileptics
• status epilepticus
• partial seizure
• febrile seizures
1. Status epilepticus: • lorazepam DoC • diazepam 2. Partial seizure - clorazepate 3. DoC for treatment and prophylaxis of febrile seizures: rectal diazepam Clobazam can also be used
Uses of clonazepam, clobazam and midazolam
Clonazepam: 1. JME 2. Absent seizure 3. Infantile spasm Clobazam: 1. Lennox Gastaut syndrome 2. Dravet syndrome 3. Febrile seizures Midazolam and clonazepam: Intranasally for crescendo seizure
Benzodiazepines used for abuse
Flunitrazepam-tasteless
• date rape
• drug abusers call it roofle, mixed with alcohol
Benzodiazepines used for insomnia
Preferred is triazolam
Temazepam
Benzodiazepines used for anxiety
Diazepam Lorazepam Clonazepate Oxazepam Alprazolam-given night before surgery
Benzodiazepines used for treating alcohol dependence
Diazepam
Chlorazepate
Chlordiazepoxide
Alcohol withdrawal seizure treatment using benzodiazepines
DoC- lorazepam
Diazepam
Benzodiazepines as anaesthetics
Lorazepam, diazepam and midazolam (preferred)
Uses:
1. Pre anaesthetic medication
2. Induction of anaesthesia
3. Maintenance
4. Prevent post operative nausea and vomiting
Intrathecal midazolam is used as
Analgesia for post operative pain
Benzodiazepine used as muscle relaxant
Diazepam
Side effects of benzodiazepines
1. CNS suppression: • Ataxia • Confusion • Anterograde amnesia 2. Paradoxical seizure 3. Diazepam- coronary vasodilation 4. Flurazepam- nightmares 5. Triazolam- behavioural abnormalities
Barbiturates
Mechanism: 1. GABA-A agonist-GABA facilitator 2. Decreases glutamate effect via AMPA inhibition 3. High doses- GABAmimetic action So highly unsafe
Classification of barbiturates
1. Ultra short: Thiopentone, methohexital 2. Short acting: Butobarbital, secobarbital, pentobarbital 3. Long acting: Mephobarbital, phenobarbital
Ultra short acting barbiturates
Thiopentone
Methohexital
Uses:
IV induction of anaesthesia
Short acting barbiturates
- Butobarbital
- Secobarbital
- Pentobarbital
Use: pre anaesthetic medication
Long acting barbiturates
- Mephobarbital
- Phenobarbital
Use: anti epileptic
Phenobarbital uses: - DoC for seizures in neonates
- DoC for Criggler Najjar syndrome
- Status epilepticus
Side effects of barbiturates
- Paradoxical seizure
- Acute Intermittent Porphyria
- Hyperalgesia
- Ganglion blockade ➡️ hypotension
Treatment of barbiturate toxicity
Treatment - picrotoxin
For Phenobarbital, urine alkalisation of done
Treat hypovolemia - shock, hypotension
GABA-A receptor α subunit parts
α1: Sedation Hypnosis α2: Antiepileptic Muscle relaxation
Z-compounds
Selective α1 agonists to produce hypnosis Compared to BZD: 1. Lesser alteration of sleep 2. Reduced addiction 3. Reduced CNS suppression DoC for insomnia
Examples of Z-compounds
1. Zaleplon: shortest acting • DoC for sleep induction and jet lag 2. Zolpidem: intermediate acting • short term Rx of insomnia 3. Eszopiclone: longest acting • DoC for sleep maintenance • long term Rx of insomnia
Melatonin receptors and their main functions
In hypothalamus, MT-I and MT-II
Sleep induction and circadian rhythm
Examples of melatonin agonist
- Ramelteon
- Agomelatin: for major depression
- Tasimelton: for sleep awake disorders in blind
Ramelteon
Melatonin agonist
• Oral route but with high first pass metabolism - 2% bioavailability
• t1/2 is 2 hours
• used for sleep induction and jet lag
• less effective than BZD/ Z-compounds but less dependence
Chloral hydrate
Metabolised to trichloroethanol, stimulating GABA-A
Used to treat paradoxical seizures for to BZD
Abused:
1. Mickey finn cocktail
2. Knock out drops
Carisoprodol and meprobamate
Carisoprodol is a prodrug of meprobamate used as muscle relaxant
Meprobamate is used as an anxiolytic
Seevorexant
Orexin receptor 1 and 2 antagonist
Uses: insomnia
S/E: depression, suicidal tendencies
Endogenous opioids
- Endorphin: μ receptor
- Dynorphin: κ receptor
- Enkephalin: δ receptor
Effects of μ opioid receptor
M. Miosis U. Urine retention S. Sedation C. Constipation A. Analgesia R. Respiratory depression I. Increased muscle rigidity N. Negative bile flow E. Euphoria
Effects of κ opioid receptor
C. Constipation
A. Analgesia
P. Psychminetic effect- dysphoria
Dynorphin is an endogenous stimulant
Effect of δ opioid receptor
- Analgesia
- Modulate release of hormones and neurotransmitters
Enkephalin is a stimulant
Classification of exogenous opioids based on source
1. Natural: • morphine, codeine • noscapine, thebaine, papaverine 2. Semisynthetic: • Heroin, apomorphine • Oxycodone, hydrocodone 3. Synthetic: non-opiate • Fentanyl, Alfentanyl • Sufentanyl, Remifentanil
Morphine derivatives
1. Heroin: Diacetyl morphine More potent than morphine 2. Apomorphine: D2 agonist Used in Parkinson’s disease
Common uses of derived opioids
Smooth muscle relaxant:
• Biliary colic
• GIT colic
• Urethral colic
Examples of derived opioids
- Heroin, apomorphine
- Derived from codeine: oxycodone, hydrocodone
- Buprenorphine, from thebaine
Synthetic opioids
They are not opiates More potent, so used in anaesthesia 1. Fentanyl: neuroleptic anaesthesia 2. Alfentanyl: TIVA 3. Sufentanyl: laryngoscopy intubation 4. Remifentanil: daycare surgeries
Fentanyl
100 times more potent than morphine
Uses:
1. In sequential opioid anaesthesia with rentazocine
2. Neuroleptic anaesthesia with dropiderol
S/E: rigid/wooden chest syndrome
Alfentanyl
20 times more potent than morphine
Uses:
In TIVA Total IV Anaesthesia with propofol
Sufentanyl
1000 times more potent than morphine ➡️ most potent opioid
Maximum plasma protein binding (minimum is for codeine)
Use: Block stress response in laryngoscopy intubation
Remifentanil
Synthetic opioid Metabolised by plasma esterase so shortest acting Fastest acting Given by continuous IV infusion Opioid of choice for daycare surgeries
Full agonist of opioid receptor
- Morphine
- Codeine
- Meperidine or pethidine
- Methadone
- Tramadol
- Loperamide
Morphine
Full agonist of opioid receptor
Metabolised into active compounds with duration of action of 1 day
Eliminated by kidney
t1/2 is 2 hrs
Uses of morphine
1. As analgesic: • labor pain • cancer pain • MI pain 2. To treat pulmonary edema: • reduces after load • reduces pre load 3. Anti tussive in bronchial cancer
Side effects of morphine
- Increases ICP, so CI in patients with head trauma
Increases histamine, so: - Bronchoconstriction, CI in bronchial asthma, COPD
- Vasodilation - hypotension
- Pruritis
Codeine
90% inactivated by glucuronidation 10% metabolised by CYP2D6 to morphine Uses: 1. As anti-tussive like noscapine 2. As analgesic: monotherapy or with NSAIDs like oxycodone and hydrocodone
Meperidine or pethidine
Metabolism
Metabolised in liver and excreted by kidney
1. 99% is hydrolysed to meperidinic acid to be excreted
2. 1 % is dealkylated to normepiridine which is then hydrolysed to normepiridinic acid to be excreted
• Normepiridine is neurotoxic
• Both hydrolysis steps are inhibited by MAO inhibitors causing serotonin syndrome
Pethidine is CI in liver and kidney failure
Uses of meperidine or pethidine
1. Analgesia: • post operative • migraine • labor 2. DoC in treatment of child: • post operative • amphotericin B-infusion reaction • monoclonal antibody-infusion reaction Maximum duration of usage- 48 hours
Anticholinergic side effects of meperidine or pethidine
Mydriasis
Tachycardia
Methadone
pharmacokinetics
It takes 30 min to be absorbed from GIT to blood stream
It takes 10-20 min to be absorbed to CNS ➡️ analgesia
Sequestered in tissues, so slowly released
No withdrawal syndrome
Uses and side effects of methadone
Uses: 1. Decrease withdrawal syndrome in opioid dependence 2. In chronic pain 3. Anti tussive in bronchial cancer S/E: 1. QT prolongation 2. Anticholinergic
Tramadol and tapentadol
Derived from codeine
Inhibits reuptake of NE and serotonin ➡️ TCA or SNRI like effect
Use: analgesic- mild and moderate pain
Opioids used for non-secretory diarrhoea
DoC: Loperamide- do not cross BBB ➡️ no dependence
Diphenoxylate and difenoxin cross BBB so they are formulated with atropine to prevent dependence
Inflammatory bowel disease , iminotecan (anti cancer drug) are examples of non-secretory diarrhoea
Mixed agonist antagonists opioids examples
Do. Dezocine Not. Nalbuphine Nalorphine Party. Pentazocine Boys. Butorphanol Buprenorphine
Receptor action of mixed agonist antagonist
Full agonist of κ Antagonist of μ, so less S/E Exceptions: 1. Pentazocine: Partial agonist of μ 2. Buprenorphine: Antagonist of κ Partial agonist of μ
Uses of mixed agonist antagonist
- Nalbuphine: analgesic for MI
- Nalorphine: opioid toxicity
- Pentazocine: analgesic and pre-anaesthetic medication
- Butorphanol:
Analgesic for post op and migraine (intranasal route)
Is pentazocine used as analgesic in MI
No
It increases BP and heart rate
Buprenorphine
Mixed agonist and antagonist opioid
• Antagonist of κ
• Partial agonist of μ
50 times more potent than morphine
1. High affinity for μ ➡️ dissociates slowly ➡️ no withdrawal symptoms ➡️ sublingually in opioid dependence
2. IM as analgesic for mild and moderate pain only (Ceiling effect)
Central opioid antagonists
1. Noloxone: • shortest t1/2 • less potent • IV administration 2. Nalmefene: • intermediate t1/2 • more potent • IV administration 3. Naltrexone: • long t1/2 • most potent • orally administered
Uses of IV administered central opioid antagonists
Naloxone and nalmefene
Used in opioid toxicity
DoC naloxone
Reverses all effects except sedation
Uses of naltrexone
- Alcohol dependence
- Opioid dependence to prevent relapse
- Obesity along with bupropion
- Along with morphine to prevent abuse
Side effects of naloxone
Increases release of catecholamines:
- Hypertension
- Arrhythmia
- Pulmonary edema
Peripheral opioid antagonists
- Alvimopen: post-op ileus
- Methyl naltrexone
- Naloxegol
- Naldemedine
The last 3 are used for treatment of opioid induced constipation
Opioid effects showing no tolerance
- Miosis
- Constipation
- Convulsion
Withdrawal symptoms are proportional to
- Potency
2. Dose
Withdrawal symptoms of opioids
M. Mydriasis I. Increased yawning 🥱 T. Hyperthermia H. Hyperventilation D. Diarrhoea R. Rhinorrhea A. Anxiety M. Myalgia L. Lacrimation Opposite of μ receptor effects
Deaddiction of opioids
- To reduce withdrawal symptoms, start opioids which don’t cause withdrawal symptoms:
• methadone
• buprenorphine - When only mild withdrawal symptoms, β-blockers and clonidine
- To prevent relapse, naltrexone
