Narcotic analgesics (tested), Sedatives & hypnotics (not-tested)

Question 1

(not tested) Physical symptoms of anxiety

Answer 1

(related to adrenergic activation)

Tachycardia
SOB
Nausea
Gastric acid hypersecretion
Trembling

Question 2

(not tested) Therapeutic rational of anxiety disorders

Answer 2

To correct the over-arousal of CNS

Sedative: Causes sedation, relaxation

Hypnotic (one level stronger than sedative): Induces drowsiness and sleep, may have amnestic effects

Anxiolytic: Reduces anxiety

Question 3

(not tested) What is the main class of drugs used as therapeutics for anxiety disorders?

Answer 3

Benzodiazepines

Can be used as anxiolytics/sedatives, hypnotics, pre-anesthetics, or for anti-convulsant effects.

Question 4

(not tested) Examples of benzodiazepines used as anxiolytics/sedatives

Answer 4

Diazepam, lorazepam

Question 5

(not tested) Examples of benzodiazepines used as hypnotics

Answer 5

Diazepam, triazolam, temazepam

Question 6

(not tested) Examples of benzodiazepines used as pre-anesthetics

Answer 6

Diazepam, midazolam

Question 7

(not tested) Examples of benzodiazepines used for anti-convulsant effects

Answer 7

Diazepam

Question 8

(not tested) Examples of non-benzodiazepines

Answer 8

Barbiturates (e.g. phenobarbital)

Buspirone

Zolpidem

Propanolol

Question 9

(not tested) What is the GABA and GABA receptor? How does it concern us?

Answer 9

GABA is the brain’s primary inhibitory neurotransmitter. When GABA binds to its receptors, it reduces the likelihood that a neuron will fire an action potential –> This inhibition is essential for maintaining balancing excitatory and inhibitory signals.

GABA A receptor is the primary target for most sedatives and hypnotics:
- Activation allows chloride to flow into the neuron, hyperpolarizing it and making it less likely to fire.

Question 10

(not tested) MOA of Benzodiazepines

Answer 10

Binds to benzodiazepine site, which in turn potentiates the binding of GABA to the GABA A receptor binding site

Once benzo bound to benzo site, it makes GABA open the chloride channel more easily –> Potentiates influx of chloride ions, leading to hyperpolarization, hence neurons will not be polarised and will not fire –> reduce activation of CNS

Note: Benzodiazepine does not directly bind to GABA binding site!

Question 11

(not tested) What are some short acting benzodiazepines?

Answer 11

Short acting: Short duration of action

Midazolam: Usually used for anxiety, induction of GA, procedural sedation

Triazolam: Used for insomnia

Question 12

(not tested) What are some long acting benzodiazepines?

Answer 12

Usually used for more chronic kind of conditions (e.g. alcohol withdrawal syndrome, status epilepticus, refractory seizure)

Chlordiazepoxide
Diazepam (status epilepticus)

Question 13

(not tested) What are some intermediate acting benzodiazepines?

Answer 13

Usually for anxiety, panic disorders

Lorazepam: Anxiety, insomnia, status epilepticus
Clonazepam: Seizures

Question 14

(not tested) Which benzodiazepine is used to treat status epilepticus

Answer 14

Long acting benzodiazepine.

Diazepam

Question 15

(not tested) Adverse effects of benzodiazepines

Answer 15

1. Acute toxicity leads to severe respiratory depression
   - especially used with alcohol
   - treatment is by FLUMAZENIL, a benzodiazepine antagonist
2. Side effects upon chronic use:
   - drowsiness, confusion, amnesia
   - impaired muscle co-ordination (impairs manual skills)
3. Tolerance and dependence
   - depends on frequency of use (tolerance develops faster for epilepsy than for use to induce sleep)
   - withdrawal effects, important to withdraw gradually
   - has abuse potential due to addiction

Question 16

(not tested) Withdrawal effect of benzodiazepines

Answer 16

• disturbed sleep
• rebound anxiety
• tremor
• convulsions

Question 17

(not tested) MOA of Zolpidem, a non-benzodiazepine

Answer 17

is a non-benzodiazepine

Also potentiates GABA A mediated Cl- currents at the same site as
benzodiazepines.

– Has good hypnotic effect, primarily used to treat INSOMNIA.
– Not effective as anxiolytics, not useful to treat anxiety disorder

Question 18

(not tested) MOA of Buspirone, a non-benzodiazepine

Answer 18

is a non-benzodiazepine

• exact MOA is unclear, but involves SEROTONIN AND DOPAMINE receptor system (not just GABA receptor system is involved in anxiety)
• is a serotonin 5-HT1A receptor partial agonist, also binds dopamine receptors

– Indicated for GAD but anxiolytic effects takes 1-2 weeks.

– Lacks anticonvulsant and muscle relaxant properties. (as it does not work on GABA A receptors)

Question 19

(not tested) MOA of Barbiturates, a IMPORTANT non-benzodiazepine

Answer 19

Also potentiate GABA A mediated Cl- currents, but at a site distinct from benzodiazepines (barbiturate site)

• Not commonly used currently,
  due to its tendency to develop tolerance and dependence (even more than benzodiazepines)
• HIGH ABUSE POTENTIAL
• Severe withdrawal symptoms
• Flumazenil not effective for treating barbiturate overdose (as barb does not bind to benzodiazepine site)
• At very high does, they can directly open Cl channels as well as block Na+ channels. e.g. phenobarbital

Question 20

(not tested) What are some long-acting barbiturates?

Answer 20

effect lasts for 1-2 days

usually used as anticonvulsants/antiepileptics
(but NEVER first-line, usually as a last resort)

e.g. phenobarbital

Question 21

(not tested) What are some short acting barbiturates?

Answer 21

effect lasts for 3-8hrs

usually used as sedative and hypnotics

e.g. pentobarbital and amobarbital

Question 22

(not tested) What are some ultrashort acting barbiturates?

Answer 22

effect lasts for 20 mins

Used for IV induction of anaesthesia

e.g. thiopental

Question 23

(not tested) MOA of Propanolol, a non-benzodiazepine

Answer 23

MOA: Beta-adrenergic receptor antagonist, is a beta-blocker

Used for treating performance anxiety and social phobias

Reduces physical symptoms associated with adrenergic activation (e.g muscle tremor, tachycardia)

Contraindicated in patients with asthma and heart conditions

Question 24

How do opioid analgesia work?

Answer 24

Plays on endogenous mechanism to:

1. Inhibit propagation of pain signals
2. Alter emotional perception of pain
3. Elevate the pain threshold

Question 25

Sites of opioid receptors regulating pain includes:

Answer 25

Peripheral nociceptive terminals (peripheral analgesia) The spine (spinal analgesia) The brain (supraspinal analgesia)

Question 26

Three major opioid receptor types

Answer 26

µ (Mu) δ (Delta) κ (Kappa) All 3 types belong to the G-protein coupled receptors

Question 27

Examples of functional effects of analgesia

Answer 27

Analgesia - Supraspinal Analgesia - Spinal Analgesia - Peripheral Respiratory depression Pupil constriction (Miosis) Reduced GI motility Euphoria Dysphoria Sedation Physical dependence

Question 28

Which receptor mediates which effect?

Answer 28

Majority of functional effects are mediated by µ (Mu) receptors. One exception: κ (Kappa) receptor mediates dysphoria (a state of unease or generalized dissatisfaction with life)

Question 29

Good to bad (fatal) effects of analgesia ranking

Answer 29

Peripheral Analgesia (good) Spinal Analgesia Cough suppression Supraspinal Analgesia Sedation Reduced gut motility Euphoria Pupil constriction Constipation Dysphoria Severe sedation Respiratory depression (fatal)

Question 30

How does age affect the dosing of opioids?

Answer 30

Elderly patients usually require a lower dose to achieve effective pain relief than younger patients.

Question 31

Which requires a higher opioid dose? Neuropathic or nociceptive pain?

Answer 31

Neuropathic pain usually requires higher opioid doses than nociceptive pain. Neuropathic pain: pain signals that arise from spinal-thalamic tract (nerves) Nociceptive pain: arise from tissue damage

Question 32

What doses are required for continuous maintenance of pain relief?

Answer 32

Lower doses are usually required for continuous maintenance of pain relief than administration in response to recurrence of pain.

Question 33

Dosing to effect process for opioids

Answer 33

- should be started at a low dose and carefully titrated until an adequate level of analgesia is obtained, or until persistent and unacceptable side effects - Failure of at least partial analgesia with incremental dosing in the opioid-naive patient may indicate that the pain syndrome is unresponsive to opioid therapy - For some patients with chronic pain, opioids do not exert an appreciable analgesic effect until a threshold dose has been achieved.

Question 34

What opioid agonists are used for analgesia purposes?

Answer 34

codeine, morphine, pethidine

Question 35

What opioid agonists are used for anaesthetic adjuvant (give together with another analgesic drug) purposes?

Answer 35

fentanyl

Question 36

What opioid agonists are used for cough suppressant/antitussive purposes?

Answer 36

codeine

Question 37

What opioid agonists are used for anti-diarrhoeal purposes?

Answer 37

diphenoxylate note: this leads to opioid induced constipation

Question 38

What are some examples of strong opioid agonsists?

Answer 38

1. Morphine 2. Fentanyl 3. Methadone 4. Pethidine (merperidine)

Question 39

MOA and uses of Morphine

Answer 39

Strong µ (mu) agonist (weaker δ and κ agonist). High maximum analgesic efficacy. High liability for addiction/ abuse.

Question 40

MOA and uses of Methadone and Fentanyl

Answer 40

Strong µ agonists (no significant δ and κ affinity). High maximum analgesic efficacy. High liability for addiction/ abuse. Note: Methadone is long-acting, Fentanyl is short-acting (anaesthetic adjuvant).

Question 41

MOA and uses of Pethidine (meperidine)

Answer 41

Strong µ (mu) agonist (probably weaker δ and κ agonist). SHORTER duration of action than morphine (useful as an epidural during labour as drug less likely to remain in neonate). hallucinogenic and convulsant effects at high dose Results in restlessness rather than sedation Antimuscarinic effects (e.g. dry mouth, blurring of vision but no miosis and less spasm of smooth muscle)

Question 42

Examples of moderate opioid agonists

Answer 42

Codeine/dihydrocodeine Tramadol

Question 43

MOA of codeine

Answer 43

- Weak µ and δ agonist (probably not a κ agonist). - Low maximum analgesic efficacy. - Moderate liability for addiction/abuse. - When taken, is a low efficacy drug, but can be converted into a higher efficacy drug (morphine) - 10 % of population show reduced analgesic effect due to lack of demethylating enzyme (into morphine)

Question 44

MOA of tramadol

Answer 44

- Weak µ (mu) agonist - Weak inhibitor of 5-HT and noradrenaline re-uptake note: Ondansetron (anti-emetic) blocks analgesic effect

Question 45

Where does respiratory depression occur in the brain?

Answer 45

Nucelus tractus solitarius Nucleus ambiguus leads to: - reduced responses to CO2 and H+ - suppressed voluntary breathing Note: Opioids should be avoided in infants!

Question 46

What is the most important adverse effect of the use of opioids?

Answer 46

Respiratory depression

Question 47

Respiratory depression should not occur at normal therapeutic doses but can be lethal in:

Answer 47

- overdose - respiratory disease - hepatic dysfunction - combination with other CNS depressants

Question 48

Other common adverse effects arising from the use of opioids

Answer 48

1. N&V 2. Drowsiness (do not oeprate machinery/drive!) 3. Constipation due to reduced GI motility (esp with chronic use) 4. Miosis (pinpoint pupils) due to actions in the oculomotor nucleus. Is a diagnostic feature of opioid overdose. 5. Urinary retention due to increased bladder sphincter tone 6. Postural hypotension and bradycardia 7. Immunosuppressant effect with long-term use 8. Morphine can also trigger histamine release from mast cells: - urticaria and itching - bronchoconstriction - hypotension due to vasodilatation - to be used WITH CAUTION IN ASTHMATICS

Question 49

What is drug tolerance?

Answer 49

drug becomes less effective after prolonged use. dose escalation required

Question 50

What is drug addiction?

Answer 50

psychological craving. compulsive use. loss of control over use.

Question 51

What is physical dependence?

Answer 51

physiological dependence such that stopping the drug leads to physical withdrawal symptoms.

Question 52

Signs of opioid withdrawal

Answer 52

- anxiety - irritability - chills - hot flushes - joint pain - lacrimation (tears), - rhinorrhea (runny nose), - nausea, vomiting - abdominal cramps - diarrohea

Question 52

How to treat opioid overdose?

Answer 52

Opioid antagonists ---> Naloxone/Naltrexone/Nalmefene Naloxone is short-acting (usually IV) Naltrexone is long-acting (oral administration) Nalmefene is long-acting (IV) new, most commonly used (replaced naloxone and naltrexone combo) Note: Use with extreme caution in patients with opiate dependency as they can precipitate potentially fatal withdrawal syndrome.