Case Study

Question 1

What is the molecular targets of opioid analgesics + outline mechanism of action

Answer 1

Target mu-opioid receptors

Cause excitable cell hyperpolarisation via activation of GPCRs leading to decreased cAMP formation

Closure of Ca^{<strong>2</strong>+} channels + opening of K⁺ channels reduce neurotransmitter release

Question 2

Discuss common side effects of opioid medicines + explain pharmacological basis

Answer 2

Sedation

Respiratory depression

Pruritus

Nausea

Vomiting

Constipation

Urinary retention

Question 3

Considering excipients in different brands of oxycodone SR tablets, describe mechansims used to control release from these formulations

Answer 3

Hypromellose = Hydrophilic swelling matrices

Ethylcellulose = membrane controlled system - release mechanism

Ammoniomethacrylate + hydrogenated castor oil = hydrohphobic matrix

Question 4

What is multimodal analgesia + what are its principles?

Answer 4

Beneficial for post-management pain

Combinations of analgesics w/ different modes/site of action improve analgesia, reduce opioid requirements + reverse ADR of opioid

Question 5

What types of medicines are used for multimodal analgesia in the management of post-operative pain?

Answer 5

Local anaesthetic techniques

Paracetamol

nsNSAIDs

COXIBs

Steroids

Ketamine

Alpha-2-agonist

Alpha-2-delta ligands

Question 6

What is IV patient controlled analgesia?

Answer 6

Method of pain relief allowing patient to self-administer small doses of analgesic as required

Programmable infusion pumps that deliver opioid medications IV

Used for pain following trauma + cancer

Question 7

Drugs used for IV PCA

Answer 7

Morphine

Fentanyl

Oxycodone

Tramadol

Question 8

What are the dosing parameters in IV PCA to alter analgesia + what is their effect on plasma concentration?

Answer 8

Bolus dose - smallest amount capable of producing an appreciable analgesic effect. Provides minimal side effects. Optimal PCA Bolus dose for morphine = 1mg

Lockout interval - safety mechanism set to prevent further doses being delivered until the bolus dose has had time to achieve peak effect.

Background infusion - opioid will continue to be delivered regardless of patient’s sedation or respiratory level. Increases risk of respiratory depression

Question 9

Describe the pathophysiology of opioid-induced nausea + vomiting?

Answer 9

Nausea is mediated by neural pathways, whereas, vomiting is initiated + coordinated by the vomiting centre + chemoreceptor trigger zone (CTZ)

After stimulation of vomiting centre, efferent pathways involve salivary, respiratory + vasomotor centres + cranial nerves mediate vomiting.

Activation of several centres lead to nausea + vomiting.

D₂ receptors are located in the stomach, NTS, + CTZ. D₂ receptors in the stomach mediate inhibition of gastric motility that occurs during nausea + vomiting, + they participate in reflexes that relax upper part of stomach + delay gastric emptying. Emesis is promoted by slow gastric emptying.

Serotonin act @ (5-HT3)-receptor = important neurotransmitter in afferent pathways from the stomach + small intestine, CTZ, area postrema + NTS.

Question 10

What are the molecular targets for ondasetron + cyclizine?

Answer 10

Ondansetron = 5HT3 receptor antagonist

Cyclizine = piperazine-derivative antihistamine

Question 11

Why have ondansetron + cyclizine been prescribed in combination?

Answer 11

Combination of anti-emetics with different mechanisms have better outcomes than use of single agents

Question 12

Explain pharmacological effects of senna + docusate in managing opioid-induced constipation

Answer 12

Docusate - reduces surface tension of oil + water interface of the stool resulting in enhanced incorporation of water + fat allowing stool softening

Senna - sennosides A + B increase intestinal motility through release of active anthraquinones into the colon by colonic bacteria

Question 13

What are potential serious complication of epidural administration of analgesics?

Answer 13

Neurological Injury

Epidural Haematoma

Epidural abscess/infection

Question 14

Outline monitoring that is required whilst a patient is receiving epidural analgesia

Answer 14

HR + BP

Respiratory rate

Sedation score

Temperature

Pain score

Degree of motor + sensory block

Question 15

How is inadvertent IV administration of levobupivacaine treated?

Answer 15

Lipid emulsion 20%

Due to partitioning of local anaesthetic within emulsion

Question 16

Identify + describe features of bupivacaine that influence its action @ voltage-gated sodium channels

Answer 16

Amphiphilic molecule w/ hydrophobic aromatic ring, linking ester, weakly basic amine group

Incompletely protonated @ physiological extracellular pH

pH dependecy of membrane penetration, while protonation inside cell alters impact on VSNC function

They are weak bases

Question 17

Why is levobupivacaine preferred to racemic bupivacaine?

Answer 17

Levo = S-enantiomer

It has lower affinity @ myocardial + nervous vital centres in studies => fewer CVS + CNS side effects

Question 18

Recommendation for hypotension during epidural infusion

Answer 18

Cease/reduce epidural infusion rate

Fluid challenge

Vasopressors

Question 19

Describe pathways to paracetamol metabolism

Answer 19

Question 20

How does paracetamol cause hepatoxicity?

Answer 20

Large doses of paracetamol cause acute hepatic necrosis as a result of lack of glutathione + binding of the excess reactive metabolite to vital cell constituents

Question 21

Describe mechanism of action of NSAIDs + binding to their molecular target

Answer 21

Inhibit COX enzymes needed for conversion of arachidonic acid to cyclic endoperoxides

Inhibit prostaglandin + thromboxane production

Question 22

Common side effects of NSAIDs + explain pharmacological basis

Answer 22

GI Tract

• Irritation, erosion + ulceration
• Reduction of prostaglandins => lack of inhibition of gastric acid production, reduced mucus secretion + mucosal wall vasoconnstriction

Renal Impairment

• PGI2 + PGI3 are vital to renal vasculature smooth muscle tone + renal perfusion
• Analgesic nephropathy can occur
• Electrolyte imbalance

NSAID - Induced Asthma

• Increase leukotrienes + reduced PGE2-mediated bronchodilation

Altered platelet function

• Don’t inhibit platelet function

CVS

• Increase BP

Question 23

Strategies to prevent GI side effects of NSAIDs

Answer 23

H2 receptor antagonists

Misoprostol

PPI

Question 24

How do COXIBs differ from NSAIDs

Answer 24

COXIBs more selective to COX-2 enzyme than 1.

Inhibit prostaglandin synthesis

Question 25

How does mood influence pain?

Answer 25

Pain impacts mood + mood influences pain

Question 26

What are symptoms of a sprain?

Answer 26

Pain around affected joint Bruising Tenderness Swelling Inflammation

Question 27

Treatment for a sprain (injury)

Answer 27

RICE

Question 28

Signs + symptoms of dysmenorrhea

Answer 28

Pain @ lower abdomen Radiate to thighs + lower back Co-symptoms include: * N + V * Diarrhea * Constipation * Headache * Dizziness * Disorientation * Hypersensitivity to sound, light, smell, touch * Fainting * Fatigue

Question 29

How do prostaglandins contribute to symptoms of dysmenorrhea?

Answer 29

Prostaglandins regulate ovulation, endometrial physiology + menstruation etc COX enzymes have a role in pathology + angiogenesis, apoptosis + proliferation, tissue invasion + immunosuppression

Question 30

How are the absorption characteristics when ibuprofen is administered as different salt formulations?

Answer 30

Speed absorption Provide better analgesia Flux across lipophilic membrane is increased by formation of ion-pairs

Question 31

Where is the epidural space?

Answer 31

**Anatomic space that is the outermost part of the spinal cord.** It is space within canal **lying outside dura mater (arachnoid mater, cerebrospinal fluid + spinal cord)**. It contains a lymphatic spinal nerve roots, loose fatty tissue, small arteries + a network of large thin-walled blood vessels called **epidural venous plexus**

Question 32

Why did anaesthetist annotate the drug chart to ensure that enoxaparin was not administered on the day of surgery?

Answer 32

Enoxaparin = a LMW heparin Anticoagulant used to prevent venous thromboembolism

Question 33

Outline the benefits of using epidural analgesia over parenteral analgesic regimens

Answer 33

Provides better pain relief @ rest + movement after all types of surgery Decrease incidence of N+V + sedation * However, higher incidence of pruritis, urinary retention + motor block* * Improved pain relief led to increase PaO2 levels + decrease incidence of pulmonary infections + complications*

Question 34

What type of epidural drugs are prescribed?

Answer 34

Fentanyl = opiod Levobupivacaine = LAs

Question 35

Outline the monitoring that is required whilst a patient is receiving epidural analgesia

Question 36

How is inadvertent IV admin of levobupivacaine treated?

Answer 36

Lipid emulsion 20% Liquid emulsion helps to partition LAs within emulsion itself

Question 37

Identify and describe structural features of bupivacaine that influence its action at VGSC

Answer 37

Amphiphilic molecule witha hydrophobic aromatic ring, linking ester, weakly basic amine group, which is incompletely protonated @ physiological pH, pH dependency of membrane penetration while protonation inside cell alters VGSC function

Question 38

Calculate the proportion of bupivacaine + lidocaine ionised @ physiological pH (7.4)

Question 39

Explain the clinical onsequences of the difference in physicochemical properties of lidocaine + bupivacaine

Answer 39

Lidocaine has a faster onset of action than bupivacaine as it is more unionised @ physiological pH + will teach its target site more quickly than the drug which is less so

Question 40

Why is levobupivacaine preferred clinically to bupivacaine?

Answer 40

It has **lower affinity @ myocardial + CNS vital centres which leads to fewer CVS + CNS side effects** Levobupivacaine has **lower affinity + strength of inhibitory effect onto the inactivated state of cardiac Na+ channels** than racemic parent 1R-bupivacaine It has **longer duration of action**

Question 41

What would you recommend for hypotension during an epidural infusion?

Answer 41

Stop epidural or reduce infusion rate Fluid challenge Vasopressors

Question 42

Why would a patient on epidural suffer from hypotension?

Answer 42

1. Epidural - due to sympathetic blockage produces vasodilatation. Compensated for by an increase in cardiac output 2. Fluid loss - consequence of surgery 3. Ramipril = witheld around time of surgery

Question 43

Describe the pharmacokinetic + pharmacodynamic differences between tramadol + other opioids?

Answer 43

Tramadol is a weak mu-opioid receptor agonist Inhibits noradrenaline + serotonin reuptake + 5-HT release Less pronounced opioid side effects (e.g. constipation) but more pronounced side effects (e.g. nausea)