Applied pharmacology Flashcards
What is the meaning of analgesic?
Objective of treatment in all types of pain, irrespective of origin, is to achieve symptom control and improve the patient’s quality of life.
Basic meaning of analgesic?
Drug that relieves or reduces pain.
What is the name of the one mechanism that explains most NSAID actions?
The arachidonic acid cascade.
What is the arachidonic acid cascade?
Starts with arachidonic acid (AA)=> COX that converts AA to intermediates=> intermediates converted to prostanoids
What are some examples of prostanoids?
Prostaglandins (activation of nociceptive nerve endings) and thromboxane (involved in blood clotting).
How do NSAIDs impact the AA pathway?
NSAIDs block COX (block the AA binding site) so the rest of the pathway can’t occur.
What is AA?
Part of cell membrane, produced by enzyme.
Where is COX 1 found?
Most tissues/ cells, mainly endoplasmic reticulum.
What is the function of COX 1?
-Gastric protection
-blood flow
-platelet aggregation
-involved in producing prostaglandins
Where is COX 2 found?
Mast cells, fibroblasts, macrophages, endothelial cells (nuclear membrane).
What is the function of COX 2?
Inflammation, pain and fever.
Where is COX 3 found?
Mainly in CNS (animal models).
What is the function of COX 3?
Poorly understood, may not be active in humans.
What are some examples of NSAID molecules?
-aspirin
-ketoprofen
-fenoprofen
-celecoxib
Which NSAID is most COX 1 selective?
Ketoprofen (most prevalent effects are gastric protection and blood flow).
Which NSAID is most COX 2 selective?
Celecoxib (more prevalent effects are inflammation, pain and fever).
What are the 4 main therapeutic effects of an NSAID?
-anti-inflammatory
-analgesic
-antipyretic (help control body fever and temp)
-platelet aggregation
What kind of binding does aspirin have?
Irreversible binding (will have to wait for more COX to be produced).
What kind of binding do all other NSAIDS have?
reversible.
What happens to cascade if you take aspirin?
Blocks the binding of COX and therefore, inflammation is reduced, improved pain response and control fever.
What are examples of inflammatory mediators?
H+, bradykinin, serotonin, K+ and prostaglandins.
Which substances are powerful vasodilators?
Histamine and Substance P.
How do NSAIDs cause anti- inflammatory effects?
COX 2 prostaglandins are inhibited (vasodilators). Promotes release of other vasodilators (substance P and histamine).
If reduce prostaglandins, reduce production of substance P (reduce vasodilation).
Reduced vasodilation leads to reduced oedema, swelling, redness and neurogenic inflammation.
How do NSAIDs cause analgesic effects?
Prostaglandins are inhibited and therefore, there is a reduced sensitisation of free nerve endings- help guard against peripheral sensitisation. If there is less sensitivity in pathway, fewer pain signals transmitted to brain.
How do NSAIDs cause anti-pyretic effects?
Pyrogens are released in body and they stimulate PGE2 in hypothalamus. This inhibits temp sensitive neurons. NSAIDs reduce PGE2 production by binding to COX 2 (body temp won’t increase as much).
How is a fever produced?
Prostaglandins are produced in the hypothalamus and the trick the body into thinking too cold, so raises body temp.
How do NSAIDs cause platelet aggregation?
COX 1 inhibition reduces thromboxane production (lower ability for platelets to activate and blood clotting= blood thinner).
Since aspirin irreversible, platelets never recover ability to aggregate and new ones are required to be produced.
What are the 4 main types of side effects of NSAIDs?
-gastrointestinal
-respiratory
-renal
-liver
What are the gastrointestinal effects?
Prostaglandins promote production of alkaline mucus which protects stomach wall. Reduced prostaglandins cause inflamed stomach wall (aspirin induced gastritis and ulceration).
What are the effects of COX 2 selective NSAIDs?
-fewer gastric complications
-reduced effects on platelet aggregation
-reduced analgesia
-increased thrombic and CV risks
What is leukotriene?
Bronchoconstrictors.
What are the resp effects of NSAIDs?
AA can either convert to COX or lipoxygenase. Lipoxygenase then produces leukotriene. Since NSAIDs block binding of COX, means it will shift the balance to produce much more leukotrienes that are bronchoconstrictors.
What are the renal effects of NSAIDs?
Prostaglandins promote vasodilation and therefore glomerular filtration. Less prostaglandins and so reduced renal filtration (accumulate damaging metabolites that normally would’ve been secreted in the urine).
What are other side effects of NSAIDs?
-retention of bile (destroy and damage cells)
-mitochondrial damage (lower production of ATP)
-inhibition of prostaglandin E2 (controls cell death- therefore, lower cytoprotective effect and liver cells will just die)
-reactive metabolites
-endoplasmic reticulum stress (not able to produce proteins properly).
What is paracetamol?
-pain relief
-non-opioid
Why doesn’t paracetamol have an anti-inflammatory effect?
They have poor peripheral COX 1/2 inhibition.
Which COX does paracetamol target?
COX 2
What is the usual dose for paracetamol daily?
Up to 1g 3-4 times a day (not exceeding 4g).
What is produced when paracetamol is metabolised in the liver?
NAPQI (really toxic, potent oxidiser, can damage DNA).
What is NAPQI conjugated to?
Glutathione (detoxifies NAPQI)- this is inactive and excretable in the body.
Why is it important not to exceed 4g daily dose?
There is a limited supply of glutathione to detoxify metabolites.
What is the meaning of an opioid?
A compound resembling opium in its physiological effects.
What is the function of dynorphins?
Inhibit/ stimulate nociceptive pathways.
What are the natural opioids?
Morphine and codeine.
What are some examples of semisynthetic opioids?
Buprenorphine and oxycodone.
What are some examples of synthetic opioids?
Fentanyl, methadone.
Which opioids are associated with analgesia and euphoria?
µ (supraspinal, peripheral).
Which opioids are associated with dissatisfaction?
K (kappa)- spinal.
What is the process of G- protein coupled receptors?
opium binds to receptor- cascade of intracellular signalling molecules (spread through cell and lead tp other effects) eg ion channels, genes.
What is the mechanism for analgesia in opioids?
When the opioid receptors are activated, activate the intracellular cascade (less Ca2+). Therefore, this causes lower glutamate release and means there is a decreased sensitivity and transfer of nociceptive info to brain.
Mechanism for peripheral analgesia?
µ- opioid receptors located on free nerve endings and when activated, reduces nociceptor sensitivity.
What are the central analgesic mechanisms?
-spinal (inhibition of nociception)
-supraspinal effects (limbic system activity decreased and so decreased importance of nociceptive signal)
-nociceptin receptors (activate descending inhibition- lower nociceptive signals to body)
What is the function of the limbic system?
Understand how important something is.
What are the functions of mild opioids?
Work by weakly activating opioid receptors, lower efficacy at the receptor.
What is the efficacy of strong opioids?
Good, high potency and strong agonists of opioid receptors.
What are the side effects of opioids?
-constipation (downregulation of enteric NS)
-depression of cough reflex
-resp depression
-nausea and vomiting
-tolerance effects
-euphoria
-physical dependance
What are the long term issues of opioids?
-immune supression
-decreased sex hormone production
-opiate induce hyperalgesia
-surrounding cells also have opiate receptors- prolonged exposure and so produce pro-inflammatory (higher sensitivity).
How do local anaesthetics work?
Block voltage gated sodium channels. Inject local anaesthetic- cause state of nerve block (channel inactivation).
