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Pharmacology MBBS > Sedative hypnotics and opioids > Flashcards

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
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2
Q

Mechanism of sedation and hypnosis by GABA-A receptor

A
  1. 2 molecules of GABA bind
  2. α projection goes back
  3. Lumen opens
  4. Cl- moves through
  5. Neuro relaxation
  6. Sedation and hypnosis
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3
Q

3 types of drugs acting at BZD site

A

Between α and γ subunits

  1. Agonist: BZD
  2. Inverse agonist: β-carboline
  3. Antagonists: Flumazenil
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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
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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

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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
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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
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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
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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
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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
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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
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12
Q

Benzodiazepines used for abuse

A

Flunitrazepam-tasteless
• date rape
• drug abusers call it roofle, mixed with alcohol

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13
Q

Benzodiazepines used for insomnia

A

Preferred is triazolam

Temazepam

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14
Q

Benzodiazepines used for anxiety

A 
Diazepam
Lorazepam
Clonazepate
Oxazepam
Alprazolam-given night before surgery
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15
Q

Benzodiazepines used for treating alcohol dependence

A

Diazepam
Chlorazepate
Chlordiazepoxide

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16
Q

Alcohol withdrawal seizure treatment using benzodiazepines

A

DoC- lorazepam

Diazepam

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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

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18
Q

Intrathecal midazolam is used as

A

Analgesia for post operative pain

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19
Q

Benzodiazepine used as muscle relaxant

A

Diazepam

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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
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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
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22
Q

Classification of barbiturates

A 
1. Ultra short:
Thiopentone, methohexital
2. Short acting:
 Butobarbital, secobarbital, pentobarbital 
3. Long acting:
 Mephobarbital, phenobarbital
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23
Q

Ultra short acting barbiturates

A

Thiopentone
Methohexital
Uses:
IV induction of anaesthesia

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24
Q

Short acting barbiturates

A
  1. Butobarbital
  2. Secobarbital
  3. Pentobarbital
    Use: pre anaesthetic medication
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25
Q

Long acting barbiturates

A
  1. Mephobarbital
  2. Phenobarbital
    Use: anti epileptic
    Phenobarbital uses:
  3. DoC for seizures in neonates
  4. DoC for Criggler Najjar syndrome
  5. Status epilepticus
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26
Q

Side effects of barbiturates

A
  1. Paradoxical seizure
  2. Acute Intermittent Porphyria
  3. Hyperalgesia
  4. Ganglion blockade ➡️ hypotension
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27
Q

Treatment of barbiturate toxicity

A

Treatment - picrotoxin
For Phenobarbital, urine alkalisation of done
Treat hypovolemia - shock, hypotension

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28
Q

GABA-A receptor α subunit parts

A 
α1:
 Sedation
 Hypnosis
α2:
 Antiepileptic
 Muscle relaxation
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29
Q

Z-compounds

A 
Selective α1 agonists to produce hypnosis
Compared to BZD:
1. Lesser alteration of sleep
2. Reduced addiction
3. Reduced CNS suppression
DoC for insomnia
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30
Q

Examples of Z-compounds

A 
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
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31
Q

Melatonin receptors and their main functions

A

In hypothalamus, MT-I and MT-II

Sleep induction and circadian rhythm

32
Q

Examples of melatonin agonist

A
  1. Ramelteon
  2. Agomelatin: for major depression
  3. Tasimelton: for sleep awake disorders in blind
33
Q

Ramelteon

A

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
Q

Chloral hydrate

A

Metabolised to trichloroethanol, stimulating GABA-A
Used to treat paradoxical seizures for to BZD
Abused:
1. Mickey finn cocktail
2. Knock out drops

35
Q

Carisoprodol and meprobamate

A

Carisoprodol is a prodrug of meprobamate used as muscle relaxant
Meprobamate is used as an anxiolytic

36
Q

Seevorexant

A

Orexin receptor 1 and 2 antagonist
Uses: insomnia
S/E: depression, suicidal tendencies

37
Q

Endogenous opioids

A
  1. Endorphin: μ receptor
  2. Dynorphin: κ receptor
  3. Enkephalin: δ receptor
38
Q

Effects of μ opioid receptor

A 
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
Q

Effects of κ opioid receptor

A

C. Constipation
A. Analgesia
P. Psychminetic effect- dysphoria
Dynorphin is an endogenous stimulant

40
Q

Effect of δ opioid receptor

A
  1. Analgesia
  2. Modulate release of hormones and neurotransmitters
    Enkephalin is a stimulant
41
Q

Classification of exogenous opioids based on source

A 
1. Natural:
• morphine, codeine
• noscapine, thebaine, papaverine 
2. Semisynthetic:
• Heroin, apomorphine 
• Oxycodone, hydrocodone
3. Synthetic: non-opiate
• Fentanyl, Alfentanyl
• Sufentanyl, Remifentanil
42
Q

Morphine derivatives

A 
1. Heroin:
 Diacetyl morphine
 More potent than morphine
2. Apomorphine:
 D2 agonist
 Used in Parkinson’s disease
43
Q

Common uses of derived opioids

A

Smooth muscle relaxant:
• Biliary colic
• GIT colic
• Urethral colic

44
Q

Examples of derived opioids

A
  1. Heroin, apomorphine
  2. Derived from codeine: oxycodone, hydrocodone
  3. Buprenorphine, from thebaine
45
Q

Synthetic opioids

A 
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
Q

Fentanyl

A

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
Q

Alfentanyl

A

20 times more potent than morphine
Uses:
In TIVA Total IV Anaesthesia with propofol

48
Q

Sufentanyl

A

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
Q

Remifentanil

A 
Synthetic opioid
Metabolised by plasma esterase so shortest acting
Fastest acting
Given by continuous IV infusion
Opioid of choice for daycare surgeries
50
Q

Full agonist of opioid receptor

A
  1. Morphine
  2. Codeine
  3. Meperidine or pethidine
  4. Methadone
  5. Tramadol
  6. Loperamide
51
Q

Morphine

A

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
Q

Uses of morphine

A 
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
Q

Side effects of morphine

A
  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
Q

Codeine

A 
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
Q

Meperidine or pethidine

Metabolism

A

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
Q

Uses of meperidine or pethidine

A 
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
Q

Anticholinergic side effects of meperidine or pethidine

A

Mydriasis

Tachycardia

58
Q

Methadone

pharmacokinetics

A

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
Q

Uses and side effects of methadone

A 
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
Q

Tramadol and tapentadol

A

Derived from codeine
Inhibits reuptake of NE and serotonin ➡️ TCA or SNRI like effect
Use: analgesic- mild and moderate pain

61
Q

Opioids used for non-secretory diarrhoea

A

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
Q

Mixed agonist antagonists opioids examples

A 
Do. Dezocine
Not. Nalbuphine
 Nalorphine
Party. Pentazocine
Boys. Butorphanol
 Buprenorphine
63
Q

Receptor action of mixed agonist antagonist

A 
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
Q

Uses of mixed agonist antagonist

A
  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
Q

Is pentazocine used as analgesic in MI

A

No

It increases BP and heart rate

66
Q

Buprenorphine

A

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
Q

Central opioid antagonists

A 
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
Q

Uses of IV administered central opioid antagonists

A

Naloxone and nalmefene
Used in opioid toxicity
DoC naloxone
Reverses all effects except sedation

69
Q

Uses of naltrexone

A
  1. Alcohol dependence
  2. Opioid dependence to prevent relapse
  3. Obesity along with bupropion
  4. Along with morphine to prevent abuse
70
Q

Side effects of naloxone

A

Increases release of catecholamines:

  1. Hypertension
  2. Arrhythmia
  3. Pulmonary edema
71
Q

Peripheral opioid antagonists

A
  1. Alvimopen: post-op ileus
  2. Methyl naltrexone
  3. Naloxegol
  4. Naldemedine
    The last 3 are used for treatment of opioid induced constipation
72
Q

Opioid effects showing no tolerance

A
  1. Miosis
  2. Constipation
  3. Convulsion
73
Q

Withdrawal symptoms are proportional to

A
  1. Potency

2. Dose

74
Q

Withdrawal symptoms of opioids

A 
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
Q

Deaddiction of opioids

A
  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

Pharmacology MBBS (19 decks)

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