Analgesic Agents

Question 1

Does remifentanil undergo hepatic metabolism?

Answer 1

No. It is broken down by non-specific tissue and plasma esterases to remifentanil acid - essentially inactive

Question 2

What is the CSHL of remifentanil?

Answer 2

3 mins

Question 3

Why does remifentanil have a short duration?

Answer 3

Due to the high clearance and relatively small volume of distribution (steady state volume of distribution of 350 ml/kg)

Remifentanil has a short terminal elimination half-life of 3-10 minutes, consistent with its context sensitive half life of 3-6 minutes.

Therefore the duration of action of remifentanil is dependent on elimination rather than redistribution.

Question 4

How do the potency of fentanyl and remifentanil compare?

Answer 4

Similar potency

Question 5

Will remifentanil have a prolonged action in patients with pseudocholinesterase deficiency?

Answer 5

No

Question 6

What do the pharmacological effects of morphine include?

Answer 6

• constipation
• biliary spasm
• histamine release
• release of ADH
• cough suppression

Question 7

What is the potency of fentanyl compared to morphine?

Answer 7

Fentanyl is 100 times more potent

Question 8

Is fentanyl water or lipid soluble?

Answer 8

Highly lipid soluble

Question 9

What is the VoD of fentanyl?

Answer 9

Its lipid solubility gives fentanyl a large volume of distribution of 4 L/kg.

Question 10

Does fentanyl accumulate?

Answer 10

Because of its large volume of distribution, fentanyl accumulates with repeated doses and has a variable context-sensitive half-life.

Question 11

What is fentanyl metabolised to?

Answer 11

Fentanyl is N-demethylated to norfentanil and then hydroxylated for renal excretion. All metabolites are inactive.

Question 12

How does diclofenac have an antipyretic effect?

Answer 12

Prostaglandins regulate body temp within the hypothalamus.

Therefore inhibition of prostaglandin synthesis reduces body temperature

Question 13

What are NSAIDs avoided in pregnancy?

Answer 13

Use of NSAIDs in pregnancy can lead to premature closure of the ductus arteriosus and therefore Diclofenac is not used in pregnancy.

It is notable that low-dose aspirin is used in pregnancy and is now recommended in the primary prevention of pre-eclampsia in patients considered at high risk (eg Type I diabetes, previous pre-eclampsia).

Question 14

What is the effect of diclofenac on platelets?

Answer 14

COX produces Thromboxane A2 which causes platelet aggregation. It also produces PGI2 in vascular endothelium which inhibits platelets.

However the overall action of COX inhibition by diclofenac is to reduce platelet aggregation as its effect on Thromboxane A2 production is greater than its effect on PGI2 production.

Question 15

Which is the most to least lipid soluble out of pethidine, fentanyl and alfentanil?

Answer 15

(most) Fentanyl > alfentanil > pethidine (least)

Question 16

What % of alfentanil is protein bound?

Answer 16

Alfentanil is 85-92% protein bound, mainly to alpha-1 glycoprotein.

Question 17

Which is more potent, fentanyl or alfentanil?

Answer 17

Potency is a measure of drug activity expressed as the amount of drug required to give a certain clinical effect.

Alfentanil works quickly due to its pKa of 6.5, leaving it almost all unionized and therefore available to cross membranes and work at its effector site immediately. However, if time to effect is excluded, less fentanyl is required for the same clinical effect as alfentanil and therefore it is less potent than fentanyl

Question 18

How is alfentanil metabolised?

Answer 18

Alfentanil is metabolised by CYP3A3/4 which also metabolises midazolam (therefore if used together in large enough doses, they will prolong each others’ elimination half life).

The product of metabolism is noralfentanil which is inactive.

Question 19

Is tramadol a controlled drug?

Answer 19

Yes

Question 20

What is the affinity of tramadol for the mu opioid receptor?

Answer 20

It has weak affinity for the mu opoid receptor of 2.1 micromolar compared with 0.0003 micromolar for morphine

Question 21

How does tramadol work?

Answer 21

Whilst it is a mu agonist, it also acts as a serotonin and noradrenaline re-uptake inhibitor, NMDA antagonist and nicotinic/muscarinic Acetylcholine receptor antagonist.

Its main analgesic effect is due to the inhibition of NA and 5HT reuptake.

Question 22

What drug class must tramadol not be used with and why?

Answer 22

Tramadol’s serotonergic modulating activities mean that patients are more susceptible to serotonin crisis if used with MAOIs or SSRIs.

Question 23

What does the metabolism of morphine involve?

Answer 23

Morphine metabolism involves demethylation, oxidation and conjugation with glucuronide.

Some morphine is methylated to codeine.

70% of morphine forms Morphine 3-Glucuronide, a mu receptor antagonist. 30% becomes Morphine 6-Glucuronide which is 13 times more potent than morphine.

These metabolites are excreted by the kidneys and can accumulate in renal failure.

Question 24

Which receptor does clonidine act at?

Answer 24

Clonidine has a 200 fold higher affinity for the alpha-2 adrenoceptor than the alpha-1 adrenoceptor and is an agonist at the alpha-2 adrenoceptor

Question 25

What is the bioavailibility of oral clonidine?

Answer 25

It is very well absorbed orally with a bioavailability of 100% and an onset time of 30 minutes and reaching a peak plasma level around 60-90 minutes.

Question 26

How does clonidine lower the MAC of volatiles?

Answer 26

It acts on alpha-2 adrenoceptors in the lateral reticular formation to reduce the MAC of volatiles and central Sympathetic Nervous System (SNS) outflow.

It also acts in the spinal cord to increase endogenous opoid and increase descending pathway inhibition (gate theory of pain)

Question 27

What drugs can naloxone antagonise?

Answer 27

• bupranorphine
• dextropropoxyphene
• remifentanil

Question 28

What is paracetamol oxidised to?

Answer 28

NAPQI which is a potent cell toxin. 10% of paracetamol is oxidised to NAPQI which is usually safely conjugated with glutathione. If glutathione is depleted, as in paracetamol overdose, it bonds to exposed protein SH groups causing inactivation and cell necrosis in a centrilobular pattern.

Question 29

How does NAC work?

Answer 29

NAC replaces glutathione to allow safe metabolism of paracetamol.

Question 30

How does paracetamol affect prostaglandin synthesis?

Answer 30

Paracetamol reduces the COX enzyme to reduce prostaglandin synthesis.

Question 31

What effect does aspirin have on blood gases?

Answer 31

Aspirin (Salicylic acid) causes a metabolic acidosis and respiratory alkalosis in adults. It is an acid in itself and promotes hyperventilation by a direct effect.