Sedative hypnotics and opioids Flashcards
1
Q
Structure of GABA-A receptor
A
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
2
Q
Mechanism of sedation and hypnosis by GABA-A receptor
A
- 2 molecules of GABA bind
- α projection goes back
- Lumen opens
- Cl- moves through
- Neuro relaxation
- Sedation and hypnosis
3
Q
3 types of drugs acting at BZD site
A
Between α and γ subunits
- Agonist: BZD
- Inverse agonist: β-carboline
- Antagonists: Flumazenil
4
Q
GABA facilitators
A
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
5
Q
Flumazenil
A
Antagonists of BZD site of GABA-A receptor
Used to treat BZD / Z-Compound toxicity
Route: IV
Duration of action: 30-60 min
6
Q
Classification of benzodiazepines based on metabolism
A
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
7
Q
First type of benzodiazepines
A
Phase I: CYP3A4 Phase II: glucuronidation • Longest acting ➡️ minimum dependence and withdrawal symptoms • Maximum sedation Eg., D. Diazepam C. Clonazepam C. Chlordiazepoxide C. Clonazepate
8
Q
Second type of benzodiazepines
A
Phase I: CYP3A4 Phase II: faster glucuronidation • Shortest acting ➡️ maximum dependence and withdrawal symptoms Eg., Triazolam, Midazolam - shortest acting
9
Q
Third type of benzodiazepines
A
Only phase II: direct glucuronidation • Short acting • Safest in liver failure, no active metabolites Eg., O. Oxazepam T. Temazepam L. Lorazepam E. Estazolam
10
Q
Uses of benzodiazepines as antiepileptics
• status epilepticus
• partial seizure
• febrile seizures
A
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
11
Q
Uses of clonazepam, clobazam and midazolam
A
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
12
Q
Benzodiazepines used for abuse
A
Flunitrazepam-tasteless
• date rape
• drug abusers call it roofle, mixed with alcohol
13
Q
Benzodiazepines used for insomnia
A
Preferred is triazolam
Temazepam
14
Q
Benzodiazepines used for anxiety
A
Diazepam Lorazepam Clonazepate Oxazepam Alprazolam-given night before surgery
15
Q
Benzodiazepines used for treating alcohol dependence
A
Diazepam
Chlorazepate
Chlordiazepoxide
16
Q
Alcohol withdrawal seizure treatment using benzodiazepines
A
DoC- lorazepam
Diazepam
17
Q
Benzodiazepines as anaesthetics
A
Lorazepam, diazepam and midazolam (preferred)
Uses:
1. Pre anaesthetic medication
2. Induction of anaesthesia
3. Maintenance
4. Prevent post operative nausea and vomiting
18
Q
Intrathecal midazolam is used as
A
Analgesia for post operative pain
19
Q
Benzodiazepine used as muscle relaxant
A
Diazepam
20
Q
Side effects of benzodiazepines
A
1. CNS suppression: • Ataxia • Confusion • Anterograde amnesia 2. Paradoxical seizure 3. Diazepam- coronary vasodilation 4. Flurazepam- nightmares 5. Triazolam- behavioural abnormalities
21
Q
Barbiturates
A
Mechanism: 1. GABA-A agonist-GABA facilitator 2. Decreases glutamate effect via AMPA inhibition 3. High doses- GABAmimetic action So highly unsafe
22
Q
Classification of barbiturates
A
1. Ultra short: Thiopentone, methohexital 2. Short acting: Butobarbital, secobarbital, pentobarbital 3. Long acting: Mephobarbital, phenobarbital
23
Q
Ultra short acting barbiturates
A
Thiopentone
Methohexital
Uses:
IV induction of anaesthesia
24
Q
Short acting barbiturates
A
- Butobarbital
- Secobarbital
- Pentobarbital
Use: pre anaesthetic medication
25
Long acting barbiturates
1. Mephobarbital
2. Phenobarbital
Use: anti epileptic
Phenobarbital uses:
1. DoC for seizures in neonates
2. DoC for Criggler Najjar syndrome
3. Status epilepticus
26
Side effects of barbiturates
1. Paradoxical seizure
2. Acute Intermittent Porphyria
3. Hyperalgesia
4. Ganglion blockade ➡️ hypotension
27
Treatment of barbiturate toxicity
Treatment - picrotoxin
For Phenobarbital, urine alkalisation of done
Treat hypovolemia - shock, hypotension
28
GABA-A receptor α subunit parts
```
α1:
Sedation
Hypnosis
α2:
Antiepileptic
Muscle relaxation
```
29
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
```
30
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
```
31
Melatonin receptors and their main functions
In hypothalamus, MT-I and MT-II
| Sleep induction and circadian rhythm
32
Examples of melatonin agonist
1. Ramelteon
2. Agomelatin: for major depression
3. Tasimelton: for sleep awake disorders in blind
33
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
34
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
35
Carisoprodol and meprobamate
Carisoprodol is a prodrug of meprobamate used as muscle relaxant
Meprobamate is used as an anxiolytic
36
Seevorexant
Orexin receptor 1 and 2 antagonist
Uses: insomnia
S/E: depression, suicidal tendencies
37
Endogenous opioids
1. Endorphin: μ receptor
2. Dynorphin: κ receptor
3. Enkephalin: δ receptor
38
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
```
39
Effects of κ opioid receptor
C. Constipation
A. Analgesia
P. Psychminetic effect- dysphoria
Dynorphin is an endogenous stimulant
40
Effect of δ opioid receptor
1. Analgesia
2. Modulate release of hormones and neurotransmitters
Enkephalin is a stimulant
41
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
```
42
Morphine derivatives
```
1. Heroin:
Diacetyl morphine
More potent than morphine
2. Apomorphine:
D2 agonist
Used in Parkinson’s disease
```
43
Common uses of derived opioids
Smooth muscle relaxant:
• Biliary colic
• GIT colic
• Urethral colic
44
Examples of derived opioids
1. Heroin, apomorphine
2. Derived from codeine: oxycodone, hydrocodone
3. Buprenorphine, from thebaine
45
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
```
46
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
47
Alfentanyl
20 times more potent than morphine
Uses:
In TIVA Total IV Anaesthesia with propofol
48
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
49
Remifentanil
```
Synthetic opioid
Metabolised by plasma esterase so shortest acting
Fastest acting
Given by continuous IV infusion
Opioid of choice for daycare surgeries
```
50
Full agonist of opioid receptor
1. Morphine
2. Codeine
3. Meperidine or pethidine
4. Methadone
5. Tramadol
6. Loperamide
51
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
52
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
```
53
Side effects of morphine
1. Increases ICP, so CI in patients with head trauma
Increases histamine, so:
2. Bronchoconstriction, CI in bronchial asthma, COPD
3. Vasodilation - hypotension
4. Pruritis
54
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
```
55
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
56
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
```
57
Anticholinergic side effects of meperidine or pethidine
Mydriasis
| Tachycardia
58
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
59
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
```
60
Tramadol and tapentadol
Derived from codeine
Inhibits reuptake of NE and serotonin ➡️ TCA or SNRI like effect
Use: analgesic- mild and moderate pain
61
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
62
Mixed agonist antagonists opioids examples
```
Do. Dezocine
Not. Nalbuphine
Nalorphine
Party. Pentazocine
Boys. Butorphanol
Buprenorphine
```
63
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
```
64
Uses of mixed agonist antagonist
1. Nalbuphine: analgesic for MI
2. Nalorphine: opioid toxicity
3. Pentazocine: analgesic and pre-anaesthetic medication
4. Butorphanol:
Analgesic for post op and migraine (intranasal route)
65
Is pentazocine used as analgesic in MI
No
| It increases BP and heart rate
66
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)
67
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
```
68
Uses of IV administered central opioid antagonists
Naloxone and nalmefene
Used in opioid toxicity
DoC naloxone
Reverses all effects except sedation
69
Uses of naltrexone
1. Alcohol dependence
2. Opioid dependence to prevent relapse
3. Obesity along with bupropion
4. Along with morphine to prevent abuse
70
Side effects of naloxone
Increases release of catecholamines:
1. Hypertension
2. Arrhythmia
3. Pulmonary edema
71
Peripheral opioid antagonists
1. Alvimopen: post-op ileus
2. Methyl naltrexone
3. Naloxegol
4. Naldemedine
The last 3 are used for treatment of opioid induced constipation
72
Opioid effects showing no tolerance
1. Miosis
2. Constipation
3. Convulsion
73
Withdrawal symptoms are proportional to
1. Potency
| 2. Dose
74
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
```
75
Deaddiction of opioids
1. To reduce withdrawal symptoms, start opioids which don’t cause withdrawal symptoms:
• methadone
• buprenorphine
2. When only mild withdrawal symptoms, β-blockers and clonidine
3. To prevent relapse, naltrexone
