Analgesics Flashcards
How is aspirin unique among the NSAIDs?
It irreversibly acetylates, and thus inactivates, cyclo-oxygenase
What happens to aspirin in the body?
It is rapidly deacetylated by esterases in the body, thereby producing salicylate
What effects does salicylate have?
Anti-inflammatory, antipyretic, and analgesic
What are the antipyretic and anti-inflammatory effects of salicylate due to?
Primarily due to blockade of prostaglandin synthesis at the thermoregulatory centres in the hypothalamus and at peripheral target sites.
How does aspirin achieve it’s anti-inflammatory action?
It diminishes the formation of prostaglandins, and thus modulates those aspects of inflammation in which prostaglandins act as mediators.
How does aspirin achieve its analgesic action?
PGE2 is thought to sensitise nerve endings to the action of bradykinin, histamine, and other chemical mediators released locally by the inflammatory process. Aspirin decreases PGE2 synthesis, and so represses the sensation of pain
How does aspirin achieve its antipyretic action?
Fever occurs when the set-point of the anterior hypothalamic thermoregulatory centre is elevated, which can be caused by PGE2 synthesis. Aspirin inhibits PGE2 synthesis, and so resets the thermostat to towards normal. This rapidly lowers the body temperature of febrile patients by increasing heat dissipation as a result of peripheral vasodilation and sweating.
In what conditions are the analgesic effects of aspirin utilised?
Gout, rheumatic fever, osteoarthritis, RA, headache, arthralgia, myalgia
What are the most common GI ADRs of aspirin?
Epigastric distress, nausea, and vomiting
How can dyspepsia caused by aspirin be minimised?
Should be taken with food and large volumes of fluid.
A PPI may be taken concurrently.
How long before surgery should aspirin be withheld?
At least a week
Why should aspirin be withheld for at least a week prior to surgery?
Because it can cause inhibition of platelet aggregation and a prolonged bleeding time
How has aspirin been related to Reye syndrome?
Aspirin given during viral infections have been associated with an increased incidence of Reye syndrome, especially in children
What is Reye syndrome?
An often fatal, fulminating hepatitis with cerebral oedema
What % of salicylate derived from aspirin is protein bound?
80-90%
What is the result of the high level of protein binding of aspirin?
It can be displaced from protein-binding sites by other drugs, thus increasing the concentration of free salicylate.
It can alternatively displace other highly protein bound drugs, such as warfarin, phenytoin, or valproic acid, resulting in higher free concentrations of the other agent.
In patients taking what drugs should aspirin use be avoided in?
Probenecid or sulfinpyrazone
Why should long-term aspirin use be avoided in patients taking probenecid or sulfinpyrazone?
Because these agents cause increased renal excretion of uric acid, whereas aspirin causes a reduced clearance of uric acid, so aspirin reduces their action
Why is concomitant use of ketorolac and aspirin contraindicated?
Because of increased risk of GI bleeding and platelet aggregation inhibition
Can aspirin be used during pregnancy and breastfeeding?
Should be avoided
What are the symptoms of mild aspirin toxicity?
Nausea, vomiting, marked hyperventilation, headache, mental confusion, dizziness, and tinnitus
What are the symptoms of severe aspirin toxicity?
The symptoms of mild, in addition to restlessness, delirium, hallucinations, convulsions, coma, respiratory and metabolic acidosis, and death from respiratory failure.
Who is particularly prone to aspirin toxicity?
Children
What is the mechanism of action of paracetamol?
Inhibits prostaglandin synthesis in the CNS
Why does paracetamol have weak anti-inflammatory properties?
Because it has less effect on cyclo-oxygenase in peripheral tissues
What are the therapeutic uses of paracetamol?
First choice in mild to moderate pain or fever.
Good alternative to aspirin for analgesia in those with gastric complaints, or prolongation in bleeding time is unacceptable.
Where is paracetamol absorbed?
Rapidly absorbed from GI tract
Does paracetamol undergo first pass metabolism?
Yes, extensively
What are the ADRs of paracetamol?
At normal therapeutic doses, it is virtually free of any significant adverse effects. Skin rash and minor allergic reactions occur infrequently.
What happens when large doses of paracetamol are given?
Available glutathione in the liver becomes depleted, and hepatic necrosis can result.
Who is at increased risk of paracetamol-induced hepatotoxicity?
Patients with hepatic disease, viral hepatitis, or history of alcoholism
What monitoring is recommended with paracetamol?
Periodic monitoring of liver enzyme tests for those on high-dose paracetamol
How to opiods exert their major effects?
By interacting with opioid receptors in the CNS and other organs. They cause hyperpolarisation of nerve cells, inhibition of nerve firing, and pre-synaptic inhibition of transmitter release.
What is the mechanism of action of morphine?
It acts at K receptors in laminae I and II or the dorsal horn of the spinal cord, decreasing the release of substance P, which modulates pain perception in the spinal cord.
It also inhibits the release of many excitatory transmitters from nerve terminals carrying painful stimuli
How does morphine relieve pain?
By raising the pain threshold at the spinal cord level, and altering the brains perception of pain - the patient still experiences pain, but it is not an unpleasant sensation
How does morphine cause respiratory depression?
By reduction of the sensitivity of respiratory centre neurones to carbon dioxide
What allows the safe use of morphine to treat pain, despite the risk of respiratory depression?
Tolerance to this effect develops quickly with repeated dosing, so use is safe if the dose is correctly titrated
How does morphine cause vomiting?
It stimulates the chemoreceptor trigger zone in the area postrema, causing vomiting
What is the advantage of administering morphine IV, IM, or SC?
Morphine undergoes extensive first pass metabolism, and GI absorption is slow and erratic. This means that IV, IM, or SC administration gives a much more reliable response.
How are plasma levels of morphine kept more consistent when administered orally?
An extended-release form is administered
Can morphine be used for analgesia during labour?
No
What happens in infants born to morphine-addicted mothers?
They show a physical dependance to morphine, and exhibit withdrawal symptoms if opioids are not administered.
What are the ADRs of morphine?
Severe respiratory depression Dysphoria Sedation Constipation Urinary retention Nausea Potential for addiction
Who is at particular risk of severe respiratory depression caused by morphine?
Those with emphysema or cor pulmonale
Who is at particular risk of urinary retention caused by morphine?
Those with benign prostatic hyperplasia
Who might experience extended or increased effects of morphine?
Patients with adrenal insufficiency or myxoedema
In whom should morphine be used cautiously?
Patients with bronchial asthma, liver failure, or impaired renal function
What does morphine withdrawal in physically dependant patients produce?
A series of autonomic, motor, and psychological responses that incapacitate the individuals and produce almost unbearable symptoms. However, these rarely cause death.
What are the DDIs of morphine?
Depressant actions of morphine are enhanced by phenothiazines, monoamine oxidase inhibitors, and tricyclic antidepressants.
