Lecture 9: Pharmacology of pain 2: Non-opioids

Question 1

What are the different classifications of anti-inflammatory drugs?

Answer 1

• NSAIDs
• Steroid antiinflammatory drugs glucocorticoids e.g. dexamethasone
• 5-LOX inhibitors and leukotriene receptor antagonists

Question 2

What are the main things that NSAIDs do in the body?

Answer 2

• Analgesic (relieve pain)
• Antipyretic (prevent/reduce fever)
• Anti inflammatory

Question 3

What are some non selective COX inhibitors?

Answer 3

• Ibuprofen and naproxen (propionic acid derivative)
• Indomathacin (acetic acid derivative)
• Aspirin (Salicylate derivative)

Question 4

What are some examples of selective COX-2 inhibitors?

Answer 4

• Celecoxib
• Rofecoxib

Question 5

What is the synthesis of prostaglandins?

Answer 5

• Arachidonic acid is converted to prostaglandins using COX-1/2 then converted to different isomers
• Using prostacyclin synthase –> prostacyclin (inhibit platelet aggregation, vasodilation)
• Thromboxane synthase –> TxA2 (Vasoconstriction, platelet activation)
• PGE2 - vasodilation, fever
• PGD2 - smooth muscle contraction and inhibits platelet aggregation

Question 6

What are some of the common adverse effects of NSAIDs?

Answer 6

• Gastric bleeding (gastritis and peptic ulceration)
• Platelet Dysfunction
• Sodium water retention and edema (increase BP)
• Hypersensitivity (due to PG inhibition)
• Analgesic nephropathy (structural damage to the kidneys)

Question 7

What are each of the COX responsible for?

Answer 7

• COX-1 exists in tissue and at sites of inflammation, cytokines stim the induction of COX-2
• Inhibition of COX 2 is responsible for anti inflammatory effects
• Inhibition of COX-1 is responsible for GIT toxicity

Question 8

What do salicylates in aspirin do on the respiratory system?

Answer 8

• Low doses: uncoupling phosphorylation - increase CO2 and stimulates respiration
• Direct stimulation of respiratory centre -> Hyperventilation (rapid and deep breathing) -> resp alkalosis (body doesnt have enough CO2) -> renal compensation
• Depression on respiratory & cardio centres -> reduces BP and resp acidosis (lungs cant remove enough CO2 from the body so blood becomes acidic), compensation
• High doses cause partial uncoupling of oxidative phosphorylation with increased CO2 production -> hyperventilation

Question 9

What do salicylates do on the cardiovascular system?

Answer 9

1. Platelets: Inhibition of platelet COX-1 TxA2 increases bleeding time (inhibition of platelet aggregation)
2. Endothelial PGI2 can inhibit platelet aggregation
3. Aspirin covalently modifies and irreversibly inhibits platelet COX.
4. In stroke and MI - reduces mortality and recurrent events
5. Blood vessels - can antagonize catecholamine and angiotensin 2 vasoconstriction (NSAIDs can elevate BP)
   6: Atherosclerosis: Inhibition of COX-2 can destabilise atherosclerotic plaques

Question 10

What does salicylates do on the renal system?

Answer 10

• Generated PGs TXA2, PGF,PGI2,PGE2 can increase and decrease Na+ retention usually in response to changes in tubular Cl-
• NSAIDs promote Na+ retention -> incr BP. Can counteract effects of anti-hypertensives
• PGs have minimal impact on renal blood flow but become important in the compromised kidney

Question 10

What do salicylates do in the GI system?

Answer 10

• PGs generated by COX1 inhibit stomach acid secretion, stimulate mucus and HCO3- secretion, vasodilation and are cytoprotective for the gastric mucosa
• Therefore NSAIDs cause gastric distress, gastric bleeding, sudden acute hemorrhage

Question 11

What do salicylates do in gestation? (Time between conception and birth)

Answer 11

• PGs are involved in initiation and progression of labor and delivery. Therefore inhibition can prolong gestation

Question 12

What are the main differences between COX-2 inhibitors than non selective?

Answer 12

• Anti inflammatory with less adverse GI events
• However potential toxicities: kidney and platelets - incr thrombotic events
• Associated with MI and stroke cause they dont inhibit platelet aggregation. Not given in CV disease

Question 13

Which prostaglandins are regulated by COX - 1 and which are by COX -2?

Answer 13

• PGE2 (GI protection), PGI2 (Platelet function, GI, Reg of blood flow), TXA2 (platelet function) - COX-1
• PGE2, PGI2 (inflammation, pain and fever) - COX-2

Question 14

What are the main comparable actions between COX-1 and COX 2?

Answer 14

• COX2 = more analgesic and anti inflammatory effect
• COX1 = antiplatelet aggregatory effect (preventing platelets from sticking together)
• COX1 = prolongation of labor and COX2 = infertility
• COX 2 = cardiotoxicity

Question 15

What is paracetamols mechanism of action for analgesia?

Answer 15

• Both centrally and peripherally
• Results from inhibition of PG synthesis. PGs cause little pain themselves but help cause pain from other mediators (histamine/bradykinin)

Question 16

What is the most serious side effect of paracetamol?

Answer 16

• High doses: severe hepatotoxicity (liver)

Question 17

What is paracetamols mechanism of action for anti pyretic effects?

Answer 17

• Fever -> releases endogenous pyrogens (interleukin 1) released from leukocytes acts directly on hypothalamus
• Associated with increase brain PGs
• Acts on hypothalamus - regulates body temperature.
• Inhibiting Prostaglandin Synthesis and Modulating the Hypothalamic Set Point (leading to vasodilation and increased heat loss through the skin)

Question 18

What type of med is carbamazepine and what does it treat?

Answer 18

• Anticonvulsant (prevent/control seizures in epilepsy)
• First anticonvulsant to treat trigeminal neuralgia (chronic facial pain) but not neuropathic pain
• It is a Na+ channel blocker

Question 19

What is Gabapentin and Pregabalin and differences?

Answer 19

• Gabapentin and Pregabalin are anticonvulsants that treats nerve related conditions and seizures
• They have different chemical structures
• Pregabablin is more potent and has a more linear absorption
• Pregabalin is approved for generalised anxiety disorders and fibromyalgia
• Gabapentin has a shorter half life - multiple daily doses

Question 20

How does Gabapentin and Pregabalin work in nerve related conditions?

Answer 20

• Calcium Channels: Gabapentin binds to alpha-2-delta subunit of voltage-gated calcium channels in the CNS. This reduces calcium into neurons, which decreases release of excitatory neurotransmitters (glutamate), which is involved in pain signaling and seizure activity.
• GABA Modulation: Although gabapentin/pregabalin is structurally similar to the neurotransmitter GABA, it does not directly bind to GABA receptors. However, its action may indirectly enhance GABAergic activity, contributing to its calming effects.

Question 21

What are Tricyclic antidepressants?

Answer 21

• treat depression, anxiety disorders, chronic pain, types of neuropathic pain, diabetic neuropathy
• e.g. amitryptyline (have 3 ring chemical structure)
• TCAs work by inhibiting the reuptake of neurotransmitters, primarily norepinephrine and serotonin, increasing their levels in the synaptic cleft and enhancing mood.
• Off target effect include inhibition of voltage gated Na+ channels and NMDA receptors

Question 22

What are NMDA receptors?

Answer 22

• Role in synaptic plasticity, memory formation, and learning. (ionotropic receptors)
• Activated by glutamate, which is the primary excitatory neurotransmitter in the CNS. NMDA receptors allow the flow of (Ca²⁺), (Na⁺), and (K⁺) ions, contributing to the excitatory signals in neurons.
• If you block they have analgesic and antidepressant effects