Pharmacology of antipyretic analgesics Flashcards
What are antipyretic analgesics:
Analgesic drugs that also reduce fever by reducing the body temperature
Aspirin, ibuprofen (Non-steroidal anti-inflammatory drugs)
- Analgesic
- Antipyretic
- Anti-inflammatory
Paracetamol
- Analgesic
- Antipyretic
How is temperature normally controlled?
- Normal body temperature is circadian
- -> 36.4°C in morning to 36.9 °C in the late afternoon
- Thermoregulation is produced by a network of neural connections:
- -> Hypothalamus, limbic system, brainstem, reticular formation, spinal cord and sympathetic ganglia
- The hypothalamus “sets” the mean body temperature
- Temperature-sensitive neurons integrate afferent messages from core body and periphery to modulate behaviour to maintain this “set” mean body temp
What happens if core temperature is too low?
Body has to increase heat conservation
- Vasoconstriction
- piloerection
Body increases heat production
- Shivering
- Exercise
What happens if If core temperature is too high?
Body has to increase heat loss:
- Vasodilation
- Sweating
Body has to decrease heat production
Pyresis versus Hyperthermia:
Pyresis
- Thermostat raised by hypothalamus
- Heat production and loss is in balance
- Feel cold
Hyperthermia
- Thermostat not altered
- Heat production > heat loss
- Feel hot
Pathogenesis of Fever:
Occurs due to release of cytokines released in response to tissue injury and infection:
- microbial surface components
- Gram-negative endotoxin (outer membrane lipopolysaccharide)
“Critical” endogenous mediators are:
- Interleukin 1b (IL-1b), tumour necrosis factor (TNF) & Interleukin 6 (IL-6)
- They work directly on the hypothalamus to effect a fever (pyretic) response
What is pyresis:
- IL-1b, TNF and IL6 causes increase in prostaglandin synthesis
- PGE2 raises “thermostat” in the thermoregulatory centre in the hypothalamus
- -> Through binding to E-prostanoid receptors (EP3 and EP4 receptors in hpyothalamus) sets of intrinsic firing onf neurons within hypothalamus which then cause the raise in body temp
- Core temperature is sensed as too low
- -> Feel cold
- Body feels cold so = Increased heat gain / conservation
Common mechanism of action:
1) Inflammatory stimulus
2) Membrane phospholipids – (phospholipase a2) –> arachidonic acid
3) lipoxygenases and cyclooxygenases (PGs)
PG’s produced idependent of what the inflammatory stimulus is, mostly due to some sort of infection .
Types of Cox enzymes:
COX-1
Constitutive
Present in many tissues
Functions to maintain physiological levels of prostaglandins
COX-2
Induced during inflammation/inflammatory stimulus
COX-3 – existence in humans is disputed
Constitutive
Splice variant of COX-1
Present in the spinal cord and brain
Cells producing COX-2:
- Macrophages, endothelial cells, synoviocytes, chondrocytes all have the capacity to rapidly produce COX-2 enzyme when required
- In the CNS (hypothalamus), microvascular endothelial cells are the most important in producing COX-2 during the fever response
How do drugs such as paracetamol word:
AIl drugs and paracetamol inhibit cox enzymes = no prostaglandins therefore stops action on thermostat and temp regulation
What drug inhibits which COX enzyme?
Aspirin, ibuprofen…
COX-1 & COX-2
Selective COX-2 inhibitors
COX-2 only
Paracetamol
COX-3? & COX-2 (weak)
Reversibility of drugs and cox enzymes:
Aspirin
Irreversible
Ibuprofen
Reversible, competitive
Parcetamol
Reversible, non-competitive
Inhibition of the COX active binding site of arachidonic acid (AA) by aspirin:
- Cox exisits as a dimer and active site is within this.
- Arachodonic acid cleaved, pg released and then the other pg’s produced however, when aspirin is used it will bind otthe diffenet components of the enzyme and block the AS and stops arachidonic acid from binding and being cleaved.
- It binds covalently which is why its irreversible.
Anti-pyretic action:
Aspirin, NSAIDs and paracetamol inhibit COX enzymes
- COX-2
- COX-3
Prostaglandin production decreased
Thermostat brought back to normal temp
Sweat and vasodilate to lose heat
Core temperature restored
Where do the anti-pyretics have their effect:
Aspirin and other NSAids tend to work peripherally rather than centrally
Paracetamol = central –> more effective therefore first line. Ibuprofen often given with paracetamol due to combined additional effects.
Analgesic action of NSAIDs
Nsaids – have most of their effect at NC. NSAIDS prevent the pg sensitizing the NC’s. PG usually make the NC more responsive to the stimulus of the other mediators.
Analgesic effect of paracetamol:
Prostaglandins facilitate pain signal at the level of the spinal cord and brain
- COX-3?
- COX-2 – different neuronal environment (low peroxidases present)
PGE2 receptor (EP3/EP4) present on most of the serotonergic, noradrenergic, and adrenergic cell groups suggests that PGE2 modulates many physiologic processes
PGE2 may modulate nociceptive and autonomic processes by affecting the descending serotonergic pathway
Paracetamol: more aspects to analgesic effect:
- AM404 metabolite is similar in structure to anandamide (endogenous cannabinoid)
- Acts as a cannabinoid (CB1) receptor agonist
- Produces analgesic effect at the level of the spinal cord and brain
- Also activates TRPV1 channels (continually activated, highly expressed in NC’s)
- -> Analgesic effect through desensitisation of the channels after initial activation
- Paracetamol is also a free radical (molecules with free electrons usually associated with inflammation that can bind to cells and cause damage) scavenger
- Reactive oxygen free radicals are produced by neutrophils and macrophages in response to inflammation or trauma
- Paracetamol “mops” up these free radicals preventing them from causing further tissue damage
Minor analgesic effect
Combination with opioids:
Different mechanisms of analgesia
- > Additive or synergistic
- > Lower doses can be used
Reduces incidence of side effects
Use what when?
Paracetamol
- Safe for use in children
- Very effective antipyretic
- Central effect – better for headache?
Aspirin
- Effective antipyretic (not used with children)
- Effective for inflammatory pain
NSAIDs
- Best for inflammatory pain
- Mainly peripheral effect
- Effective antipyretic
Physiological and pathophysiological roles of COX enzymes:
COX-1 physiological roles
- Gastrointestinal protection
- Platelet aggregation
- Blood flow regulation
COX-1 pathophysiological roles
- (Inflammation)
- Chronic Pain
- Increased blood pressure
COX-2 physiological roles
- Renal function
- CNS function
- Tissue repair and healing
- Reproduction
- Uterine contraction
- Blood vessel dilation
- Pancreas
- Inhibition of platelet - aggregation
COX-2 pathophysiological roles
- Inflammation
- Fever
- Blood vessel permeability
- Chronic pain
Drug Safety of aspirin and NSAIDs:
Toxic at high doses
Accidental death & suicide
GI problems:
- Excess acid production
- Ulceration
- Bleeding
Bronchoconstriction
Drug safety of paracetamolL
- Toxic at high doses
- Accidental death & suicide
- Safer alternative at therapeutic doses
- Risk of liver damage with high (over) doses
Aspirin & NSAIDs normal dose: side effects:
- GI:
- Direct damage
- -> Acidic drug
- -> Increased HCl output because of PGE1 loss
Bronchoconstriction
- Diversion of AA to leukotrienes
Bleeding
- Decrease in thromboxane A2 induces change in platelet behaviour
- Decrease in PGI2 (prostacyclin prevents platelets from aggregating) too
Aspirin & NSAIDs: side effects (high dose):
- CNS stimulation
- Hyperventilation
- Decreased pCO2
- Respiratory alkalosis
- Disturbance of cellular metabolism
- Increased lactic acid & ketoacid production
- -> Leads to metabolic acidosis
- -> Imbalance in acid / base balance
Treatment of Overdose: aspirin–>
- Treatment depends on time of ingestion. Gastric lavage?
- Monitor plasma electrolytes
HCO3
- Makes urine alkaline
- Increases ionisation of aspirin
- Increases excretion
Treatment of Overdose:
Paracetamol–>
- Minor metabolite of paracetamol, the free radical NAPQI is toxic to liver (and kidney)
- Becomes major metabolite in overdose
- -> Free radical excess – cell damage
Gastric lavage + methionine / N-acetylcysteine
- Scavenge free radical
- Prevent cellular damage
