VPT 321: Veterinary Neuropharmacology (2+1)

Event in the generation of action potential

Choline esters

Acetylcholine is a transmitter that is essential for the maintenance of body homeostasis. But, it is not used therapeutically as (1) acetylcholine acts simultaneously at various sites without any selectivity and (2) the duration of action is very brief.

Structure activity relationship:

1. Electrostatic bond exists between cationic group of acetylcholine and the anionic site of the receptor

2. Dipolar binding of ester of acetylcholine with the esterophilic site of the receptor

3. Hydrophobic bonds probably exist between the various methyl groups and adjacent proteins of the receptor surface.

Choline esters contain a quaternary nitrogen atom to which three methyl groups are attached. This is required for a direct potent action on cholinergic receptor. It carries a positive charge.

The cationic group electrostatically binds with a negatively charged site of the cholinergic receptor. The anionic site in the receptor is the main determinant of receptor events. Interaction of the cationic head of acetylcholine with this anionic site is the primary instigator of conformational changes that lead to alteration in membrane permeability.

Cholinesterase has a site similar to cholinergic receptor that combines with the ester component of acetylcholine. This is called esteratic site in cholinesterase and its combination with the carboxyl group of the ester results in hydrolysis of the ester. When acetylcholine combines with the esterophilic site of the receptor no such hydrolysis takes place. These esterophilic sites are arranged somewhat differently in the muscarinic and nicotinic receptors and therefore influence the specificity of the agonist and antagonist drugs.

Acetylcholine is the prototype cholinergic drug. In general the muscarinic effects are dominant in small doses and nicotinic effects are dominant in large doses.

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Catecholamines

Catecholamines are agents that contain OH group in both 3rd and 4th positions of the benzene ring. 3, 4, dihydroxybenzene is called catechol and hence the drugs that have this structure are called catecholamines. Epinephrine, norepinephrine and dopamine are known as endogenous catecholamines. Isoproterenol is also a catecholamine. Epinephrine (EPI), norepinephrine (NE) and isproterenol exhibit varying agonistic actions on the adrenoceptors.

EPI ≥ NE >> ISO → alpha adrenergic – contraction of smooth muscle

ISO > EPI > NE → beta adrenergic – relaxation of smooth muscle

Adrenoceptors

Pharmacological effects of adrenergic drugs are mediated by activation of adrenergic receptors. Two types of adrenergic receptors were proposed to explain the dissimilar effects of sympathomimetic agents in different tissues. They are α and β receptors. The α and β receptors are differentiated pharmacologically, initially based on the relative properties of catecholamines namely epinephrine, norepinephrine and isoproterenol.

CLASSIFICATION OF ADRENERGIC AGONIST

Synthetic autonomic ganglionic blockers

Bis quaternary compounds – Hexamethonium ,Pentamethonium

Non-bis quaternary compounds – Pempidine

• Autacoids are a group of diverse substances produced by a wide variety of cells in the body.
• The term autacoid is derived from Greek word meaning “Self remedy” (Autos – self, akos – remedy or healing substance).
• These substances have intense biological activity.
• They generally act locally (within inflammatory pockets) at the site of their synthesis and release.
• They are also known as local hormones.
• These substances differ from the other hormones in the following points.

         1. Hormones are produced by specific cells while autacoids, are produced by a wide variety of cells.

         2. Hormones are transported through circulation to act at distant target organ while autacoids act at the site of synthesis and release.

         3. Hormones generally act slowly while autacoids act fast.

• Histamine is a tissue amine derived from the word histos meaning “tissue”.
• Histamine is present in animal tissues and certain plants (stinging nettle).
• This autacoid is a mediator of hypersensitivity phenomenon and tissue injury reactions.
• It is stored in storage granules of mast cells (tissue phagocytes) and basophils.
• Tissues rich in histamine are skin, gastric and intestinal mucosa, lungs, liver and placenta.
• Non-mast cell histamine occurs in the brain, epidermis, gastric mucosa and growing region.
• The turnover of mast cell histamine is slow, while that of non-mast cell is fast.
• Histamine is also present in blood, most body secretions, venom and pathological fluids.

• The term antihistaminics generally mean the conventional antihistaminics that are antagonistic to the H₁ receptors. H₁ receptors are present in the bronchial, intestinal and vascular smooth muscles.
• The conventional antihistaminics block the actions of histamine competitively at the H₁ receptors.
• They are classified as H₁ and H₂ antagonists

ACE inhibitors

BASIC STRUCTURE OF BARBITURATE

BASIC OPIOID STRUCTURE OF MORPHINE

Antinociception: 
- Severe cancer pain is tolerated more when morphine is given; relieves all types of pain, but most effective against continuous dull aching pain
sharp, stabbing, shooting pain also relieved by morphine.
When morphine is given to a pain free individual :
- Morphine causes miosis (pinpoint pupils) due to kappa receptor effect
- Pinpoint pupils show still responsive to bright light
- Oculomotor nerve (Cranial Nerve 3) is stimulated by kappa receptor site
- If kappa receptor is blocked, mydriasis from sigma effect will result
- Atropine partially blocks effect indicating parasympathetic system involved
- High doses (overdose situation) of morphine cause excitatory and spinal reflexes
- High doses of many OPIOID agents cause convulsions  due to stimulation at sigma receptor

CNS- is the primary site of action of morphine.
Morphine causes sedation effect, with no loss of consciousness,analgesia, euphoria, mood change
mental cloudiness

Depending on the dose and its primary and continuous depression of respiration leads to : decrease rate, decrease volume and decrease tidal exchange.

CVS
Morphine produces vasodilatation
Morphine causes the release of histamine and
Suppression of central adrenergic tone and
Suppression of reflex vasoconstriction

GIT
Increase in tone and decrease in mobility leads to constipation
Decreased concentration of HCl secretion
Increased tone in stomach, small intestine, and large intestine delay of passage of food (gastric contents) so more reabsorption of water leading to constipation effect.

On smooth muscles
Biliary tract - marked increase in the pressure in the biliary tract
- Increase due to contraction of Sphincter of Oddi
urinary bladder
- Tone of detrusor muscle increased, feel urinary urgency
- Have urinary retention due to increased muscle tone where sphincter closed off

Bronchial muscle
Bronchoconstriction can result
Contraindicated in asthmatics, particularly before surgery

Uterus
contraction of uterus can prolong labor

Neuroendocrine effect
Inhibit the release of gonadotropin-releasing hormone (GnRH) and corticotropin-releasing factor (CRF)
Decreasing circulating concentrations of luteinizing hormone (LH), follicle-stimulating hormone (FSH), ACTH, and beta endorphin. TSH unaffected.

Uses and Toxicity

Interactions

• Results:            Date:             Dose:                Route:                            Time:

• Results:            Date:             Dose:                Route:                            Time: