Pharmacology of Anti-inflammatory Drugs

Pharmacology of Anti-inflammatory Drugs

Inflammation: (Latin, inflammare, to set on fire) is part of the complex biological response of vascular tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The invasion of tissues by these noxious agents triggers the release of cytokines (IL-1, IL-6 and TNF_α). Moreover membrane phospholipids are broken down to yield arachidonic acid (through the catalytic action of phopholipase A₂) and then it is converted to eicosanides (PGE₂, PGI₂, PGF₂α and TXA₂) and leukotriens by cyclo-oxygenase (COX) and lipo-oxygenase respectively. Prostaglandins, leukotriens, thromboxanes, cytokines and histamine are called inflammatory mediators that are responsible for the manifestation of cardinal signs of inflammation; dolor (pain), calor (heat), rubor (redness), tumor (swelling) and functiolesa (loss of function). Although inflammation is a protective attempt by the organism to remove the injurious stimuli and to initiate the healing process, widespread and chronic inflammation may become detrimental and interrupt normal body functioning (can also lead to abscessation and fibrosis if left untreated) thereby requiring optimal intervention through the use of anti-inflammatory drugs.

Origin and functions of some inflammatory mediators

Mediator(s)	Source	Main Actions
PGE2	Membrane phospholipids, mast cells	Inhibition of gastric acid secretion, broncho-constriction
PGI2		Vasodilation, inhibition of platelet aggregation
PGF2α		Improves uterine motility and renal perfusion
TXA2	Membrane phospholipids, platelets	Stimulation of platelet aggregation, vasoconstriction
Leukotriens	Membrane phospholipids, leukocytes	Increase vascular permeability, broncho-constriction
Histamine	Mast cells	Vasodilation and stimulation of nociceptors
Cytokines	Macrophages, lymphocytes	Cartilage degeneration, necrosis

Anti-inflammatory drugs: These are broadly divided into two groups; Corticosteroids and Non-steroidal anti-inflammatory drugs (NSAIDs).

1. Corticosteroids: Corticosteroids are a class of steroid hormones that are produced in the adrenal cortex to perform many significant physiological functions. Many synthetic steroids have been prepared that are used to achieve various therapeutic goals. Corticosteroids can strengthen the tolerance of organism to bacterial endotoxins, antagonize and relieve the reactions caused by bacterial endotoxins. However, they can’t neutralize bacterial endotoxins, and have no defensive effects on bacterial exotoxins. Large dose of Corticosteroids has the effect of antishock (by reducing peripheral vascular resistance, improving the blockage of microcirculation they incresase returned blood volume) and are widely used in various kinds of shock like toxic shock, septic shock, anaphylactic shock and hypovolumic shock.

Salient features of natural Corticosteroids (Adrenal steroids)

Portion	Functional zone	Secretion	Functions
Adrenal cortex	Zona Glomerulosa (outermost zone)	Mineralocorticoids (Aldosterone)	Regulate electrolyte and water levels, mainly by promoting sodium retention in the kidney
	Zona Fasiculata (middle zone)	Glucocorticoids (Cortisol)	Control carbohydrate, fat and protein metabolism and are anti-inflammatory by preventing leukotriene synthesis
	Zona Reticularis (inner zone)	Sex steroids (Androgens)	Affect the growth or function of reproductive organs, the development of secondary sex characteristics, and sexual behavioral of animals
Adrenal medulla	Chromaffin cells	Catecholamines (Epinephrine and Norepinephrine)	Catecholamines cause general physiological changes that prepare the body for physical activity (fight, flight or fright response). Some typical effects are increases in heart rate, blood pressure, blood glucose levels, and a general reaction of the sympathetic nervous system

Classification of Corticosteroids

Mode of action	Category	Biological half life	Examples	Anti-inflammatory potency
Inhibition of  leukotriene synthesis via blockage of lipo-oxygenase enzyme	Short acting corticosteroids	< 12 hours	Cortisone	0.7
			Hydrocortisone	1
	Intermediate acting corticosteroids	12-36 hours	Triamcinolone	3
			Prednisone	4
			Prednisolone	5
	Long acting corticosteroids	> 36 hours	Paramethasone	10
			Dexamethasone	25
			Betamethasone	25
			Flumethasone	30

Clinical uses: They are used in shock, allergic rhinitis, conjunctivitis, rheumatoid arthritis, bursitis, synovitis, tendinitis and otitis externa (inflammation of external ear). Corticosteroids can induce labor (inhibition of leukotriene synthesis favors the conversion of entire arachidonic acid reserves into prostaglandins, including PGF₂α that causes parturition by inducing uterine contraction) in cattle and has been used (as abortificient) to terminate pregnancy in bitches.

Adverse effects and contraindications: Corticosteroids should not be used in equines as they can cause laminitis or can worsen the already existing laminitis. These drugs suppress immune response and have many depressant effects on immunoreaction. They cause lymphocyte destruction, reduce the number of the lymphocyte by moving them outside the blood vessels, induce lymphocytic apoptosis and interrupt their division and proliferation. Therefore they should not be used in immuno-compromised patients. Animals receiving systemic corticosteroids may be more susceptible to bacterial or viral infections and the immune response to vaccination may be reduced when corticosteroids are given at the same time. Corticosteroids should be avoided during pregnancy and lactation unless the benefits outweigh the risks.

2. Non-steroidal anti-inflammatory drugs (NSAIDs): NSAIDs by virtue of inhibiting cyclooxygenases, are effective in suppressing inflammation, alleviating pain, and lowering fever. Cyclooxygenases (COX) (localized in endoplasmic reticulum) are responsible for the formation of a group of local hormones comprising the prostaglandins, prostacyclin, and thromboxanes (from arachidonic acid). These enzymes possess an elongated pore into which the substrate arachidonic acid is inserted and converted to an active product. NSAIDs penetrate into this pore and thus prevent access for arachidonic acid, leading to reversible blockade of the enzyme. Two principal types of COX can be distinguished: COX-1 is constitutive, that is, always present and active; it contributes to the physiological function of organs. Inhibition inevitably produces unwanted effects, such as mucosal injury, renal damage, hemodynamic changes, and disturbances of uterine function. COX-2 is induced by inflammatory processes and produces prostaglandins that sensitize nociceptors, evoke fever, and promote inflammation by causing vasodilation and an increase in vascular permeability. However, in some organs, COX-2 is also expressed constitutively (kidney, vascular endothelium, uterus, and CNS).

Non-selective COX-inhibitors: These include Acetylsalicylic acid or Aspirin (Disprin), Paracetamol or Acetaminophen (Panadol), Ibuprofen (Brufen), Meclofenamic acid (Ponston), Diclofenac (Voren, Phlogen, Dyclo, Dicloron, Diclostar, Fenac), Metamizole (Dipyrone, Magnapyrol), Phenylbutazone (Butadin), Piroxicam (Feldene) and Naproxen (Neoprox).

Selective COX-inhibitors: Meloxicam and Celecoxib are included in this group.

Pharmacological actions of NSAIDs:

(a) Antipyretic effect: The hypothalamus that is responsible for thermo-regulation, is affected by exogenous pyrogens such as bacterial toxins and endogenous pyrogens (now considered to be IL -1). Pyrogens promote the synthesis and subsequent release of prostaglandin E (PGE). PGE can raise the set-point of body temperature, in order to increase heat production, dissipate heat production, and to raise the body temperature. NSAIDs being the inhibitors of prostaglandin synthesis are helpful to restore normal thermoregulatory control mechanism.

(b) Analgesic effect: Some inflammatory mediators like prostaglandins and bradykinins are also involved in pain sensation. Therefore the anti-prostaglandinic action of NSAIDs can provide good analgesia in many conditions such as neuralgia, myalgia, joint pain, muscle pain, and so on, but these agents are not effective for the suppression of acute pain and visceral pain.

(c) Anti-inflammatory effect: Prostaglandins are key mediators in inflammatory reaction, a large number of them exist in inflammation organizations. NSAIDs have the ability to subside inflammation by inhibiting the synthesis of prostaglandins.

Clinical uses: NSAIDs are generally indicated for the symptomatic relief of the many conditions like rheumatoid arthritis (auto-immune-mediated inflammatory disorder that may affect many tissues and organs, but principally attacks synovial joints), osteoarthritis, laminitis, dysmenorrhoea (menstrual pain), metastatic bone pain, headache and migraine, postoperative pain, pyrexia (fever), renal colic, myalgia and mild-to-moderate pain due to inflammation and tissue injury. Aspirin is used (for its inhibitory effect on platelet aggregation) in dissiminated intravascular coagulation (DIC), thrombo-embolic disorders and heartworm (Dirrofilaria immitis) infection in dogs.

Adverse effects: The following side effects are linked with improper administration of NSAIDs.

1. Some prostaglandins (like PGE) possess beneficial role in terms of suppression of gastric acid secretion and regulation of renal microperfusion. Thus prostaglandin inhibitors (NSAIDs) can cause (or aggravate) gastric hyperacidity and renal disturbances.

2. Inhibition of TXA₂ synthesis by NSAIDs results in profused bleeding and delayed clotting time (via inhibiting platelet aggregation). This property can be benefited to resolve intravascular thrombi (that can cause embolism and ischemia) in some cardiac disorders like myocardial infarction.

3. NSAIDs that are acidic in nature (like Aspirin and Paracetamol) undergo hepatic metabolism through glucoronide conjugation. Species that are inherently deficient in glucoronide conjugatory mechanism (such as glucoronyl transferase deficiency) are susceptible to serious toxicosis (the half life of these drugs is abnormally prolonged due to lack of sufficient biotransformation). Acetylcysteine (precursor of Glutathione and potent antioxidant) should be used to suppress free radical induced cellular damage that occurs during this idiosyncratic condition.

4. Large doses of Aspirin may cause hyperglycemia (by uncoupling phosphorylation during glycolysis) followed by glycosuria (release of glucose in urine) and deplete liver and muscle glycogen.

5. In humans the use of Aspirin has been implicated in the causation of salicylism (a syndrome that is characterized by dizziness, vertigo and reversible visual and auditory impairment) and Reye’s syndrome (occurs in infants suffering from viral infection and it is manifested by hepatic damage and encephalopathy).

6. Metamizole is known to cause agranulocytosis (decresed synthesis of agranuloctes; lymphocytes and monocytes).

Contraindications: NSAIDs are contraindicated in persons suffering from gastrointestinal ulceration, bleeding disorders and human infants (having viral infection). Aspirin therapy should be stopped one week before surgery (to avoid excessive bleeding), and it should be used cautiously in species with improper metabolizing potential (cats and fish).

Interactions: Aspirin enhances the action and toxicity of oral anticoagulants and Heparin by increasing risk of bleeding.  The urinary excretion of acidic NSAIDs is increased and decreased by the concomitant administration of urinary alkalizers (like sodium bi carbonate) and urinary acidifiers (like ammonium chloride) respectively.