Week 3 Pharmacology - Analgesics + NSAIDs

Question 1

What are the 3 main neurotransmitters involved in pain signalling?

Answer 1

Activation of nociceptors leads to release of 3 different kinds of neurotransmitters into synaptic cleft (at the dorsal horn of the spinal cord)

1. Glutamate
2. Substance P
3. Calcitonin Gene Related Peptide

Question 2

What receptors does glutamate interact with in dorsal horn? What electrolyte does each facilitate?

Answer 2

AMPA - Na+ entry
NMDA - Calcium entry

Question 3

What receptor does substance P interact with? What is the result of this interaction?

Answer 3

NK-1

Activation of PKC, which removes the Mg2+ which blocks the NMDA receptor, making it more available to bind glutamate and facilitate Ca2+ entry

Question 4

Where are mu opioid receptors located?

Answer 4

Densely located on pre and post synaptic neurons in the dorsal horn of spinal cord

Question 5

What are the effects of activation of mu receptors (comparing pre vs post synaptic effects)?

Answer 5

Pre-synaptic:
- Closure of voltage gated Ca2+ channels –> reduced fusion of NT vesicles with synaptic cleft and less neurotransmitter release (i.e. pain signal doesn’t make it to second order/dorsal horn neutron)

Post synaptic:
- Binding causes K+ efflux out of cell, hyper polarising and thereby inhibiting the post-synaptic neuron from transmitting the pain signal

Question 6

What type of receptors are opioid receptors?

Answer 6

G protein coupled receptors

Question 7

What are the functions of mu receptors?

Answer 7

Suprapsinal and spinal analgesia
Inhibition of respiration
Slowed GI transit
Euphoria
Sedation

Question 8

What are the functions of delta receptors?

Answer 8

Supra-spinal and spinal analgesia
Modulation of hormone and NT release

Question 9

What are the functions of kappaspinal analgesia; psychotomimetic effects; slow GI transit receptors?

Answer 9

spinal analgesia; psychotomimetic effects; slow GI transit

Question 10

What opioid drugs belong to the phenylpiperadines?

Answer 10

“Pip” is like “beep” –> short and sweet

Fentanyl (and similar synthetics) which have fast onset and offset , no active metabolites

Question 11

What opioid drugs belong to the phenanthrenes?

Answer 11

Morphine, oxycodone, codeine, buprenorphine –> have active metabolites

Question 12

What is the general pharmacokinetics of opioids?

Answer 12

A: very good absorption, high bioavailability - however undergo high first pass metabolism (some exceptions)

D: High Vd, leave vascular compartment and concentration in highly perfused tissues. Muscle is a significant reservoir due to sheer mass in body

M: Opioids converted to polar metabolites which are then readily excreted via kidneys –> some of these metabolites highly active but don’t readily cross BBB

Question 13

What are the 3 common endogenous opioid peptides?

Answer 13

Endorphins
Encephalins
Dynorphins

Question 14

What are the central effects of morphine?

Answer 14

Analgesia
Euphoria (via suppression of GABA inhibitory effect on dopamine)
Sedation
Respiratory depression to CO2 effect
Miosis
Nausea and vomiting

Question 15

What are the peripheral effects of morphine?

Answer 15

CVS = bradycardia, peripheral veno+arterial dilation
GIT = constipation, biliary colic
Renal = decreased renal plasma flow, increased sphincter tone (urinary retention)
Pruritis, urticaria

Question 16

How is arachidonic acid formed?

Answer 16

A stimulus (i.e. mechanical disruption) causes disturbance of cell membrane, which frees up membrane phospholipids.

These get acted upon by phospholipase A2 to be metabolised into arachidonic acid

Question 17

What are the steps involved in the synthesis of prostaglandins from arachidonic acid?

Answer 17

Arachidonic acid is acted on by cytosolic cyclooxygenase enzymes to be converted into prostaglandins, thromboxane and prostacyclin.

*N.B. Lipooxygenase converts AA into leukotrienes, this pathway can be unregulated by COX inhibors (i.e. why asthma can be triggered by NSAIDs)

Question 18

What are the general common characteristics of NSAIDs?

Answer 18

• Weak organic acid
• High bioavailability - not influenced by food
• Metabolised by phase I and then II reactions, or phase II alone
• **Low volume of distribution –> highly protein bound to albumin in plasma

Question 19

What is the dominant function of COX-1?

Answer 19

Function of COX-1 is to promote production of thromboxane A2 (promoting coagulation) and gastroprotection via PGE2 (increased HCO3-, gastric perfusion, mucus production )

Question 20

Why do COX-2 selective inhibitors carry a risk of increased cardiovascular/CVA risk?

Answer 20

Increased production of thromboxane because of AA being shunted to COX-1 –> increased disposition towards coagulation

(However decreased GI bleeding risks for much the same reason, as you are not inhibiting the housekeeping COX-1 functions of gastric mucosal protection)

Question 21

How do NSAIDs cause renal impairment?

Answer 21

Prostaglandins are used in the kidney to help dilate the afferent arteriole to increased glomerular blood flow - which is impaired by the use of NSAIDs

Question 22

What are the general adverse effects associated with NSAIDs?

Answer 22

CVS: fluid retention, HTN, MI, CCF
GI: dyspepsia, vomiting, gastritis, GI bleed
Haem: cytopaenias, aplastic anaemia
Renal: AKI/interstitial nephritis, proteinuria
Resp: asthma

Question 23

What are the PK of aspirin?

Answer 23

A: rapid absorption
D: 90% protein bound, Vd 0.2L
M: blood/tissue esterase’s –> salicylate and salicylic acid, then conjugated in liver
E: Renal excretion, enhanced by alkalisation of urine

Question 24

What are examples of non selective NSAIDs?

Answer 24

Ibuprofen
Diclofenac
Indomethacin
Naproxen

Question 25

What are examples of COX-2 selective NSAIDs?

Answer 25

Meloxicam
Celecoxib

Question 26

How long does aspirin inhibit platelet function for?

Answer 26

8-10 days

Question 27

What is the half life of ibuprofen vs diclofenac vs indomethacin?

Answer 27

Ibuprofen = 2 hrs
Diclofenac = 1.1 hrs
Indomethacin = 4-5 hrs

Question 28

What is the cause of gout?

Answer 28

Deposition of monosodium urate crystals in synovial space

Question 29

What is uric acid a byproduct of?

Answer 29

Purine metabolism

Question 30

What is the pathophysiology of the inflammatory response in gout?

Answer 30

Synoviocytes are activated by urate crystals, which release prostaglandins and lysosomal enzymes –> chemotaxis for PMNC and amplification of inflammatory response –> macrophage migration and phagocytosis of crystals, with more inflammatory mediator response

Question 31

What are the PK of colchicine?

Answer 31

A: readily, peak plasma in 2 hrs
D: t/12 9 hrs
E: urinary excretion

Question 32

What is the MoA of colchicine?

Answer 32

Inhibition of formation of chemical mediators along with inhibiting migration of leukocytesW

Question 33

What are the PK of allopurinol?

Answer 33

A: good, 80% bioavailability
D: T/12 1-2 hrs
M: metabolised by xanthine oxidase into metabolite which continues to act and inhibit xanthine oxidase following this

Question 34

What are the steps of purine metabolism to get to uric acid?

Answer 34

Purine ribonucleotides converted to xanthine or hypoxanthine and oxidised to uric acid

Question 35

What is the MoA of allopurinol?

Answer 35

Inhibits conversion of xanthine/hypoxanthine to uric acid, lowering urate level and plasma urate burden

Question 36

What are adverse effects of allopurinol?

Answer 36

Precipitate gout flare, GI upset, interstitial nephritis, hepatic toxicity

Question 37

What is the role of probenacid in gout treatment?

Answer 37

Uricosuric drug, decreased body pool of urate by increasing elimination renal. Can increase risk of uric acid renal stones. Prevents reabsorption of uric acid in proximal tubule, leading to reabsorption of tophaceous deposits