2.3 b Opioid Derivatives and Non Opiod Flashcards by Sean Hartigan

Diamorphine

What is it

How it is metabolised
to what

It is diacetylmorphine
(having two molecules of morphine).

It is a prodrug that is metabolised to
6 Monoacetylmorphine (6-MAM)

and then to morphine through ester hydrolysis.

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What drug is the effective

How potent is it

diacetylmrphine

Its analgesic action is then mediated by morphine.

Because it has two morphine molecules,
it is twice as potent.

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Diamorphine

Lipid solubility vs morphine (vs fentanyl)

It has higher lipid solubility than morphine

(but lower than fentanyl/ sufentanil).

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Diamorphine

Lip solubility affect its administration

1st pass metab

This makes it particularly well suited
for subcutaneous administration.

Orally, it has a high first-pass metabolism.

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Diamorphine

Intrathecal duration

How does the affect side effect

Given intrathecally, it has a

shorter duration of action than morphine
(6 vs 12 hours)
because of its higher lipid solubility.

This reduces the likelihood of
delayed respiratory depression
when compared with morphine.

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Diamorphine ?drug of abuse

As it causes high euphoria,
it is a drug of abuse
(street name is heroin).

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Methadone

Lipid solubility

1st pass

PO bioavailability

protein binding

It is a synthetic opioid agonist
used extensively in opioid deaddiction.

It is highly lipid-soluble,

has a low first-pass metabolism,

high oral bioavailability (80%),

high protein binding (90%)

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Methadone

How is it metabolised

Duration of action

How is this useful

and it undergoes rapid
N-demethylation to inactive metabolites.

It has a longer duration of action (30 hours),

hence prevents withdrawal reactions.

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What is its MOA

How is this useful

It is an NMDA antagonist,

and has been found useful
in many opioid resistant
chronic pain states.

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Codeine

Is it prodrug

Potency of Morphine?

Codeine

It is methylmorphine
(prodrug)

Has one-tenth the potency of morphine.

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Codeine

PO avail

other route?

Dose

What route is avoided + why (d/t)

Used orally (bioavailability 50%) 
or intramuscularly in doses:

30– 60 mg (adult) and
0.5–1.0 mg/kg (paediatric).

The intravenous route is avoided
because of hypotension
(histamine release).

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Codeine

Metabolism

Metabolism is by:

1 glucuronidation (20%) to codeine-glucuronide

2 N-demethylation (10%–20%) to norcodeine

3 O-demethylation (5%–15%) to morphine by CYP2D6: responsible for its analgesic action

4 excretion unchanged (15%).

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Codeine

Is there any genetic variations

How does this affect

Is there any drug that displays same

CYP2D6 exhibits genetic polymorphism,

hence poor metabolisers have poor analgesia.

Tramadol undergoes similar
O-demethylation to O-desmethyltramadol
(higher affinity than parent compound)
via CYP2D6.

Poor metabolisers show reduced
analgesic activity to tramadol as well.

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Positive side effect Codeine

Main adverse

Is there a compound drug twice as potent

It is a potent antitussive, with constipation being its main adverse effect.

Dihydrocodeine is twice as potent.

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Tramadol

Type of drug
acts on ?strength

It is a phenylpiperidine analogue of codeine.

It is an opioid-like drug having a
weak agonist effect on
MOP (μ) receptors.

Its effects are reversed by naloxone.

It is a norepinephrine and
serotonin reuptake inhibitor

producing analgesia by
enhancing descending inhibitory pathways

(which need NE and 5-HT for stimulation).

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Tramadol

Other hormone / Neurochemical effects

How does this produce analgesia

It is a
norepinephrine
serotonin reuptake inhibitor

producing analgesia by
enhancing descending
inhibitory pathways

(which need NE and 5-HT for stimulation)

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Tramadol what is the risk of MOA causes

+ caution with what drugs

For the same reason,

it potentiates 5-HT (serotonin) levels
when administered concurrently

with MAO inhibitors,

producing serotonin syndrome.

It may lower seizure threshold and so should be avoided in epileptics.

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Tramadol

PO bioavailability

How is it metabolised

via what enzyme

is there any issue with this type of breakdown

It has high oral bioavailability

(70%)

and undergoes

O-demethylation to O-desmethyltramadol

(higher affinity than parent compound)

via CYP2D6.

Poor metabolisers show reduced analgesic
activity to tramadol.

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Tramadol

Do opioids cause shivering

What is the most limiting S/E of Tramadol
what mechanism
how rx

Abuse potential high?

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Opioids are used to treat

post-operative shivering

(pethidine and tramadol in particular).

Nausea is the most limiting side effect
(due to 5-HT action on CTZ);
take ondansetron.

It has a low abuse potential and hence it is not a controlled drug

Pethidine

Type of drug

Lipid solubility
How does this affect where its commonly used

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Is an anticholinergic drug that was later
found to have analgesic actions.

Higher lipid solubility
hastens the onset,

but also offers higher transfer
to foetus when given during labour.

Pethidine

Potency V Morphine

What is it broken down to
% activity
How is this metabolite excreted

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One-tenth the potency of morphine.

Metabolised to norpethidine

(active metabolite with 50% activity)

which can accumulate in renal failure

Fentanyl

Potency v Morphine

Lipid solubility

How does this affect its intrathecal admin + S/E

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Hundred times the potency of morphine.

Highly lipid-soluble,
hence dissipates to systemic circulation quickly
when given intrathecally.

This reduces rostral spread potential,
reducing the consequent respiratory depression.

Fentanyl
Why used Paeds

Whats metabolised to
% activity

Study These Flashcards

Useful in paediatrics due to its shorter action than morphine.

Metabolised to inactive norfentanyl.

Alfentanil:

Potency V Morphine

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Ten times the potency of morphine.

Alfentanil: Compare it to fentanyl - Lipid solubility - pKa (fraction unionised drug) - speed onset

Lower lipid solubility than fentanyl, Lower pKa 6.5 vs 8.4 at pH 7.4 This results in higher fraction of unionised drug 89% vs 9% with fentanyl resulting in faster onset.

Remifentanil: How administered Intrathecal use? Why

Used as an infusion only. Not used intrathecally (as commercial preparation has glycine).

Remifentanil: Metabolism Context sensitive t1/2 does it accumulate?

Metabolised by ester hydrolysis, having a context-sensitive half-life of 4 minutes. Hence does not accumulate despite prolonged infusions.

Remifentanil Problem with use for analgesia intra op

However, analgesia does not continue post-operatively, and a morphine bolus is required at the end of surgery for postoperative analgesia.

Naloxone: What is it at which receptor What type of compound

It is an opioid receptor antagonist at all three receptors. It is an N-allyl derivative of oxymorphone.

Naloxone: What is its use? What is its onset and duration Issues with reversal what patient group is very susceptible

It is used for opioid overdose rather than dependence (naltrexone is used for opioid and alcohol dependence). It is short-acting hence is best given as a bolus followed by an infusion. Opioid reversal can produce withdrawal symptoms, including seizures and pulmonary edema, especially in a neonate.

Paracetamol: Uses Where does it affect PG

It is a weak analgesic, antipyretic very weak anti-inflammatory. It inhibits CNS prostaglandin synthesis.

Dose Paracetamol is it more or less effective v morphine when combined with weak opioid

Oral/intravenous dose is 20 mg/kg (adult) and 15 mg/kg (paediatric) . Combined with a weaker opioid (tramadol or codeine), its efficacy may exceed morphine because of synergism.

What's propacetamol

Propacetamol is the prodrug form of paracetamol (intravenous formulation). The intravenous formulation is more effective than the oral.

How is Paracetamol metabolised To what How is this broken down

Metabolised in liver to N-acetyl-p-benzoquinone imine (NAPQI), which is very toxic. It is rapidly detoxified by glutathione, + N-acetylcysteine (precursor of glutathione).

What does this lead to in paracetamol OD How is this Rx

hence paracetamol overdose results in glutathione depletion and consequent hepatotoxicity. This can be treated with methionine (promotes glutathione synthesis)

NSAIDs: How do they work Role of X involved in analgesia

act by reversible cyclooxygenase (COX) inhibition. 2 isoenzymes COX-2: inducible. Expressed at the site of injury in response to inflammation.

NSAIDs Role of COX 1

Two isoenzymes are found: ``` COX-1: constitutively expressed in kidneys (prostaglandin production for maintenance of renal blood flow) ``` and gastric mucosa (protection against acidity).

NSAIDs Protein binding Vd

They have high protein binding and low volume of distribution.

Adverse effects: x7

1 gastric ulceration (via inhibition of protective prostaglandins) 2 renal damage – via vasoconstriction due to inhibition of prostaglandin synthesis 3 asthma exacerbation – in susceptible individuals (15%) due to unopposed leukotriene synthesis 4 perioperative bleeding – inhibit platelet aggregation 5 affect bone healing (equivocal evidence) 6 hepatotoxicity – transient elevation of transaminases (15%). 7 Drug interactions: displacement reaction with warfarin (leading to its toxicity).

Selective COX 2 Inhibitors Do they reduce side effects? Do they have an serious S/E

1 Same risk of gastrointestinal ulcers. 2 Same risk of renal side effects. 3 Since they may inhibit vascular prostacyclin synthesis, they may promote platelet aggregation, ``` leading to a higher incidence of myocardial infarction and stroke (compared with non-selective COX inhibitors). ```

Selective COX 2 Inhibitors 5 examples and are they in use?

Rofecoxib: withdrawn because of higher incidence of myocardial infarction. Celecoxib: contraindicated in sulphonamide allergy. Valdecoxib: withdrawn due to serious dermatological effects. Parecoxib: parenteral preparation. Lumaricoxib: liver toxicity.

How does one deal with a true opioid allergy and analgesia

In the event of a true allergy (severe hypotension, skin rash, respiratory difficulty and mucosal oedema), it is advisable to either ``` 1 avoid opioids (use non-opioids) or ``` 2 use opioids of a different chemical class with close monitoring.

Morphine derivatives

``` Morphine derivatives Morphine Hydro/oxycodone Hydro/oxymorphine Butarphanol Nalbuphine Pentazocine ```

Phenylpiperidines

Phenylpiperidines ``` Fentanyl Sufentanil Remifentanil Alfentanil Pethidine ```

Diphenylheptanes

Diphenylheptanes Methadone Propoxyphene

2.3 b Opioid Derivatives and Non Opiod Flashcards

(45 cards)