Aspirin mechanism of action
Acetylates ser530 and irreversibly inactivates COX
Aspirin is an acetylsalicyclate and by donating an acetyl group to COX, a salicyclate is formed (a reversible COX inhibitor, but low conc produced unlikely to have a therapeutic effect)
How does low dose aspirin inhibit platelet aggregation?
Platelets express COX1 and TX synthase (major source of TXA2 for platelet aggregation and vasodilatation)
Endothelial cells produce PGI2 (inhibits platelet aggregation)
Acetylated COX can be replaced in endothelial cells but not in platelets therefore TXA2 production is switched off for the platelet lifetime (10 days)
PPIs may also be co-prescribed to limit GI risk
Actions of aspirin on COX2
Aspirin is weakly selective on COX1 but also inhibits COX2
- Prevents production of PG and TX intermediates
- Production of 15R-HETE (isomer of 15S-HETE)
- 15R-HETE converted by 5-LO to produce aspirin triggered lipoxin (ATL)
- Similar functions to LXA4 e.g. reduced neutrophil chemotaxis/degranulation
Also antagonises CysLT1 receptors (anti-inflammatory)
Side effects of NSAIDs
- GI BLEEDING: PGs inhibit gastric acid secretion and increase the release of protective mucin
- RENAL INSUFFICIENCY & NEPHROPATHY: PGE2/PGI2 play a vasodilatory role in renal blood flow
- STROKE/MI: COX2 is constitutively expressed on endothelial/vascular smooth muscle cells. COX inhibition reduces PGI2 synthesis and therefore there is less inhibition of vasodilatation and platelet aggregation
- BRONCHOSPASM: mechanism unclear, appears to be COX-dependent
Side effects specific to aspirin
1) REYE’S SYNDROME
Almost exclusively in children. Hepatic encephalopathy, often occurs when taking aspirin for viral symptoms
2) SALICYCLISM
Result of an overdose, often seen in children or following suicide attempts.
-Krebs cycle inhibition and uncoupling of ox-phos, esp in skeletal muscle
-inc O2consumption, inc CO2 production
-chemoreceptor stimulation
-inc ventilation
-respiratory alkalosis (renal HCO3- secretion)
-direct inhibition of resp centres, CO2 accumulation and resp acidosis
-Fever, vomiting, dehydration, resp depression, coma and death
Treatment of salicyclism
- fluids and HCO3- administered to enhance aspirin elimination
- activated charcoal absorbs aspirin in the GI tract
- in severe cases haemodialysis
Paracetamol mechanism of action
poor anti-inflammatory but good anti-pyretic (fever) and analgesic properties
Inhibits both COX 1 and 2 with some COX2 selectivity
Reduces the active site in COX enzymes required for the conversion of PGG2 to PGH2
In canines paracetamol inhibits COX3. Likely non-functional in humans due to shift in reading frame producing a truncated form of COX3
What is another name for paracetamol and what is it derived from
Acetoaminophen derived from N-acetyl-para-aminophenol
Mechanism of paracetamol toxicity
Paracetamol is eliminated by conjugation, usually conjugated to glutathione
When hepatic conjugation enzymes are saturated oxidases act to metabolise paracetamol to N-acetyl- P -benoquinonimine (NAPQ1)
In OD there is insufficient glutathione and NAPQ1 can oxidise the thiol groups of cellular proteins leading to major hepato and renal toxicity
(NB NAPQ1 is also formed in therapeutic doses suggesting that there are other pathways for its formation)
Symptoms, treatment and risk factors of paracetamol toxicity
Symptoms often not observable until 24-48 hours post ingestion
- nausea, vomiting and liver failure induced death
- ACETYLCYSTEINE given to increase hepatic glutathione
- for a 65kg adult toxicity begins at 9.75g
- alcohol increases risk of toxicity due to upregulation of CYP2E1 which converts paracetamol to NAPQ1
- fasting also increases the risk as it reduces hepatic glutathione levels
Serotonin - actions on vasculature
Platelets contain 5-HT which is released during platelet activation and aggregation to induce further aggregation. Also causes vasoconstriction in damaged blood vessels
NB can cause both vasodilatation and constriction depending on receptor expression
Serotonin synthesis and uptake
5-HT = 5 hydroxytryptamine
synthesis from tryptophan through tryptophan hydroxylase (Tph) to form 5-hydroxytryptophan and L-aromatic acid decarboxylase (DDC) conversion to 5-hydroxytryptamine
rate limiting step = Tph step
- Tph1 predominantly in EC cells
- Tph2 predominantly in neurones
Platelets are not thought to synthesis their own 5-HT. Express a serotonin transporter (SERT) which enables platelets to become loaded with 5-HT when they pass through the intestinal circulation
Serotonin degradation
- oxidative deamination via monoamine oxidase
- oxidation to produce 5-hydroxyindoleacetic acid (5-HIAA) which is excreted in the urine
urine 5-HIAA levels are an index of systemic 5-HT synthesis
Serotonin receptors
- 5-HT 1A,B,D,F = Gi coupled GPCRs
- 5-HT 2A-C = Gq coupled
- 5-HT3 = ionotropic/ligand gated
- 5-HT4 = Gs coupled
- 5-HT5A Gi coupled
- 5-HT6 Gs coupled
- 5-HT7 Gs coupled
Emesis
Emesis = vomiting
response to chemicals in the intestine or blood or disturbances to the aural labyrinth
2 key components: vomiting centre and chemoreceptor trigger zone (CTZ) - both located in the medulla
Circulating chemicals can activated the CTZ which sends signals to the vomiting centre to produce emesis
Anti-emesis drug targeting 5-HT
ONDANSTERON
Visceral afferents to the CTZ and the CTZ itself possess 5-HT receptors. Inhibition of these receptors can prevent vomiting
Commonly used with anti-cancer drugs which induce vomiting by action on serotonin receptors
Anti-emesis drug targeting H1
CYCLIZINE = H1 receptor antagonist used for motion sickness and other forms of emesis
PROMETHAZINE = also H1R antagonist used for morning sickness
Anti-emesis drug targeting muscarinic receptors
SCOPOLAMINE
non-selective muscarinic receptor antagonist
action against M1R prevents emesis - used in motion sickness
Anti-emesis drug targeting dopamine receptors
D2 antagonists DOMPERIDONE & METOCLOPROMIDE
Act predominantly at CTZ but also at receptors in the GI tract
- metoclopramide can cause acute dystonia due to CNS effects
- replaced by domperidone. more peripherally selective therefore less dystonia
Receptors targeted by anti emetic drugs
5-HT
H1
Muscarinic
D2
3 hypotheses for the causes of migraine
- vascular hypothesis
- Brain hypothesis
- Inflammation hypothesis
Vascular hypothesis for migraine
Intracerebral vasoconstriction leads to aura and subsequent vasodilatation causes headache
However recent studies have shown that although blood flow changes happen in migraine, headache begins at vasoconstriction and not all substances causing changes in cerebral blood flow induce headache
Brain hypothesis for migraine
Cortical spreading depression (CSD) spreads across the brain (2-5mm/min)
- associated with aura
- CSD = near complete depolarisation which silences neuronal activity for minutes
- triggered by increased extracellular K+ (with neuronal activity)
- ionic imbalance and release of H+, glutamate, NO, 5-HT and arachidonic acid
Inflammation hypothesis for migraine
Activation of trigeminal nociceptors that innervate the meninges and extracranial blood vessels = initial event in migraine resulting in pain and neurogenic inflammation via CGRP release
(brain does not contain nociceptors)
