VPT 321: Veterinary Neuropharmacology (2+1)

Pharmacological actions and Pathophysiological role

PHARMACOLOGICAL ACTIONS AND PATHOPHYSIOLOGICAL ROLES

Actions and pathophysiological roles

• The cyclic eicosanoids produce a variety of actions depending upon the particular prostaglandin, species on which tested, hormonal status and other factors.
• The same prostaglandin may have opposite effects under different circumstances.

Thromboxane A₂ (TxA₂)

• Released locally from activated platelets.
• Due to the short half life, it acts immediately at the site of release It is a potent vasoconstrictor (contracts vascular smooth muscle).
• It is also pro-aggregatory (it is released form platelets and promotes further aggregation of platelets).
• TxA₂ spontaneously degrades into TxB₂, which is an inactive metabolite.
• The action of TxA₂ suggests that it attempts to reduce blood flow to a site of damage by vasoconstriction and formation of a platelet plug.

Prostacyclin (PGI₂)

• Produced by the endothelium.
• It is a potent vasodilator (relaxes vascular smooth muscle).
• It spontaneously degrades into 6-keto-PGF₁, which is its inactive metabolite.
• It has anti-aggregatory effects on platelets.
• The other prostaglandins have very little effect on the vascular smooth muscle.
• Only TxA₂ and PGI₂ are the major vasoactive prostaglandins.
• The actions of the other prostaglandins affect smooth muscle in more local sites.
• All prostaglandins cause bronchial relaxation.
• The exception is PGD₂, which causes contraction of bronchial smooth muscle.
• PGE2 and PGF₂α cause contraction of the pregnant uterus. (In the non pregnant uterus, PGE₂ may cause relaxation).
• PGE₂ and PGF₂α cause the gastrointestinal to contract strongly.
• This can lead to side effects such as abdominal pains, constipation when giving these prostaglandins therapeutically.
• PGE₂ and PGI₂ can inhibit gastric acid secretion.
• More importantly, they can increase the flow of blood to the gastric lining (due to vasodilator effect).
•  Increased flow to the stomach enhances mucous secretion, which enhances the cytoprotection of the gastric cells against the acid environment.
• Under normal physiological conditions, prostaglandins are of minimal importance. However, under conditions where blood flow to the kidneys is compromised (Eg: When there is a reduced cardiac output in heart failure, or renal stenosis), prostaglandins become important in causing vasodilation of the arterioles, maintaining glomerular filtration rate and preventing ischaemia of renal tissue.
• PGE₂ plays a part in the induction of fever, since when it acts on the hypothalamus the body’s temperature set point is altered.
• PGE₂ and PGI₂ are involved in the generation of pain. They are not algesic (they do not cause pain directly) but are known as hyperalgesic.
• They increase the sensitivity of pain receptors to other chemicals (e.g. bradykinin), thus producing the sensation of pain.
• Prostaglandins (and leukotrienes) play an important part in all stages of the inflammatory reaction, from the initial vasodilatation, oedema and pain to the recruitment of other cells of the immune response.
• Under normal conditions, the actions of TxA₂ and PGI₂ balance each other out. When these are out of balance, then we see either a vasodilatation or vasoconstriction.

Leukotrienes

• Formed by the action of lipoxygenase. Leukotriene C₄ is the more powerful form of leukotrienes.
• Leukotriene D₄ and E₄ have the same effects, only to a smaller degree.

Role of leukotrienes

• LTC₄ - A vasoconstrictor. It acts very well in the coronary circulation.
• It can stimulate the release of prostaglandins which would cause vasodilatation (negative feedback effects) the spaces between the endothelial cells become wider, allowing for an exudate to form, resulting in oedema.
• LTB₄ - Does not affect smooth muscle in any way. Is chemotactic for leukocytes.
• Leukotrienes have been implicated in the involvement of asthma by being bronchoconstrictors.