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