OBJECTIVES

By the end of the lecture, you should: Know the different autacoids regarding their synthesis, storage, release and pharmacological effects.

Be oriented with the drugs acting on the different autacoid receptors regarding their pharmacological properties, therapeutic uses and adverse effects.

Autacoids
They are a group of endogenous chemical substances which differ in their structure and pharmacological actions. They are locally-acting hormones which act on the site of release, however, they may enter the systemic circulation and act on a distant site.

Classification: - Decarboxylated amino acids: histamine and serotonin (5-HT). - Polypeptides: angiotensins, kinins. - Lipid derived: eicosanoids, platelet-activating factor (PAF).

1. Histamine
Synthesis and storage: Histamine is synthesized locally in the tissues from amino acid L-Histidine by histidine decarboxylase enzyme. Histamine present in diet is not added to tissue histamine due to rapid degradation by GI enzymes.

Histamine is stored in the tissue mast cells (especially in skin, lungs, intestine, liver) and in the basophils.

Physiological function of histamine: It acts as an allergic mediator, neurotransmitter and stimulates gastric secretory function.

L-Histidine

Histamine

Histamine receptors: (G-protein-coupled receptors) H1receptors: Stimulate PLC and increase IP3 and intracellular Ca2+. They are present in:

-Vascular endothelium of arterioles and capillaries causing vasodilatation by NO release, increase capillary permeability causing edema and decrease blood pressure.

-Extravascular smooth muscles (bronchi, GIT, uterus, urinary bladder) causing contraction.

- Sensory nerve endings causing itching and pain sensation.

H2-receptors: Linked to Gs protein and stimulate adenyl cyclase increasing cAMP. They are present in:

Vascular smooth muscles of arterioles and capillaries causing vasodilatation by increasing cAMP with calcium efflux and decrease blood pressure. The effect of histamine on blood vessels is mediated mainly through H1receptors and to a lesser extent H2-receptors.

Gastric mucosa increasing volume of gastric juice, secretion of gastric acid, pepsin and intrinsic factor.

Heart increasing heart rate and force of contraction.

 Intradermal

injection of histamine results in triple response (Lewis

response) which is local redness (capillary dilatation), spreading flare (arteriolar dilatation) and local edema with wheal formation (increased capillary permeability).

Histamine is not used clinically because it has non-specific action.

H1-receptor antagonists (H1-antihistaminics)

They are competitive antagonists with histamine at H1-receptors. Classification: First-generation (sedating) antihistaminics: Diphenhydramine, dimenhydrinate, promethazine. They cause: - Marked sedation. - Marked anticholinergic (atropine-like) action. - Antimotion sickness and antiemetic actions (due to block of muscarinic receptors in the vomiting center). Chlorpheniramine causes slight sedation. Second-generation (non-sedating) antihistaminics: Fexofenadine and loratadine. They have no sedative, anticholinergic, antiemetic effects.

Therapeutic uses: Allergic disorders as urticaria, eczema, allergic rhinitis, allergic conjunctivitis, drug and food allergy, anaphylactic shock (adjuvant to epinephrine). However, allergic bronchial asthma is not treated with H1-antihistaminics because there are other more important mediators involved in allergic bronchial asthma as leukotrienes and PAF.

Antiemetic and prophylaxis against motion sickness especially diphenhydramine and dimenhydrinate in long journeys.

Adverse effects: CNS: sedation, drowsiness (first-generation antihistaminics) which may be desirable in some clinical conditions. However, second-generation antihistaminics are preferred when alertness is required as in car drivers and machine operators.

Anticholinergic action: occur with first-generation antihistaminics (xerostomia, blurred vision, tachycardia, constipation, urine retention).

H2-receptor antagonists They include cimetidine, ranitidine (Zantac), famotidine.

They are competitive antagonists with histamine at H2-recptors in the gastric mucosa. This results in reduced volume of gastric juice, reduced gastric acid and pepsin secretion, intrinsic factor.

Therapeutic uses:
Peptic ulcer: H2-recptor antagonists are used for short-term treatment and long-term prophylaxis to prevent recurrence (relapse).

Reflux esophagitis (gastro-esophageal reflux).

Zollinger-Ellison syndrome (gastrinoma in pancreas or duodenum), H2-recptor antagonists are used in large dose.

Pre-ansethetic medication to prevent aspiration pneumonia.

Acute upper GI bleeding as bleeding esophageal varices.

Cimetidine is rarely used now due to its adverse effects which are: CNS: it crosses blood-brain barrier causing headache, dizziness, confusion especially in elderly patients.

Microsomal enzyme inhibitor which reduces metabolism of other drugs.

Antiandrogenic effect which leads to endocrinal disturbances (gynecomastia and impotence in males and galactorrhea and loss of libido in females).

Ranitidine has the following advantages over cimetidine: More potent, so can be used in smaller dose. Has longer duration of action. Does not cross blood-brain barrier, so has no CNS adverse effects. Does not affect hepatic microsomal enzymes (minimal drug interactions). No or minimal antiandrogenic effect (no endocrinal disturbances).

Famotidine is similar to ranitidine but more potent and used in a smaller dose.

Serotonin (5-HT)
Synthesis and storage: Tryptophan in diet is converted by tryptophan hydroxylase (rate-limiting enzyme) to 5-hydroxytryptophan which is converted by amino acid decarboxylase to 5-hydroxytryptamine (5-HT).

About 90% of 5-HT is stored in enterochromaffin cells of GIT. These cells contain tryptophan hydroxylase and can synthesize 5-HT. The remaining 10% are stored mainly in platelets and very small amount in CNS.

The platelets do not contain tryptophan hydroxylase and can not synthesize 5-HT but obtain it by active uptake of 5-HT released from enterochromaffin cells into the blood.

Fate of 5-HT: The majority of secreted 5-HT undergoes active reuptake into the serotoninergic neurons.

The

remaining part of

5-HT is

metabolized

by MAO

to

5-hydroxyindoleacetic acid (5-HIAA) which is excreted in urine (normal amount is 1-10 mg/day which is markedly increased in carcinoid syndrome).

Physiological functions of 5-HT: It acts as a neurotransmitter in the CNS (decreased brain serotonin results in anxiety, psychic depression and obsessive-compulsive disorder).

It acts as a precursor for melatonin in the pineal gland.

It regulates GI motility.

It causes vasoconstriction and platelet aggregation in vessel injury (hemostasis).

Serotonin (5-HT)-receptors: 5-HT1-receptors: Different subtypes from 5-HT1A-E present mainly in the CNS mediating central actions of 5-HT. They are linked to Gi protein that inhibit adenyl cyclase and decreases cAMP.

5-HT2-receptors: Mediate peripheral actions of 5-HT. They stimulate G protein which activates PLC and form IP3 and increases intracellular Ca2+ .They are present in: Blood vessels causing vasoconstriction in most vessels (mainly veins). Extravascular smooth muscles causing contraction. Increased platelet aggregation. Positive chronotropic and inotropic effects.

5-HT3-receptors: Ligand-gated ion channel receptors which increases intracellular Ca2+ concentration. They are present in GIT and medulla oblongata causing emesis.

5-HT4-receptors: They open Ca2+ channels causing Ca2+ influx. They are present mainly in GIT increasing tone and motility.

Drugs acting on 5-HT receptors: 5-HT receptor agonists: Buspirone (Buspar) is 5-HT1A agonist used in treatment of anxiety.

Sumatriptan is an agonist on the presynsaptic 5-HT1D decreasing 5-HT release. It is used in treatment of acute attacks of migraine. Its oral bioavailability is low, so it is given by SC injection. It has short duration of action, so frequent administration is necessary.

Metoclopramide (Primperan) is 5-HT4 agonist used as prokinetic drug (stimulate tone and motility of GIT) in treatment of delayed gastric emptying and reflux esophagitis (increase tone of lower esophageal sphincter). It is also used as antiemetic agent.

5-HT receptor antagonists: Ondansetron is 5-HT3 antagonist used as antiemetic drugs for vomiting of cancer chemotherapy and postoperative vomiting.

Cyproheptadine is 5-HT antagonist, H1-receptor antagonist. It is used as antiallergic drug (treatment of urticaria), prophylaxis of migraine and treatment of carcinoid syndrome.

Methysergide is 5-HT antagonist used in prophylaxis of migraine and treatment of carcinoid syndrome.

Ketanserin is 5-HT antagonist and

1-receptor

blocker (causing vasodilatation)

used in treatment of hypertension and peripheral vascular diseases.

3. Angiotensins
Synthesis and fate: Angiotensinogen (polypeptide composed of 14 amino acids produced by the liver) is converted by renin (secreted from renal juxtaglomerular cells) to the inactive angiotensin I (decapeptide).

Angiotensin I is converted to the active angiotensin II (octapeptide) by angiotensin converting enzyme (ACE).

Angiotensin II is converted by aminopeptidase into angiotensin III (heptapeptide which is much less active than angiotensin II). It is metabolized by angiotensinases into inactive fragments.

Angiotensin II-receptors: AT1-receptors are responsible for all known actions of angiotensin II. AT2-receptors have no known function.

AT1-receptors are coupled to G protein which activates PLC producing IP3 and increases intracellular Ca2+. They produce the following actions:

Powerful vasoconstriction of arterioles and veins (40 times more potent than norepinephrine) with marked hypertension.

Stimulation of synthesis and release of aldosterone from adrenal cortex. Aldosterone acts on renal distal convoluted and collecting tubules leading salt and water retention and increased K+ excretion.

Inhibitors of renin-angiotensin system: Inhibitors of renin release: -adrenergic receptor blockers.

Angiotensin-converting enzyme (ACE) inhibitors: captopril, enalapril.

Angiotensin II-receptor antagonists: losartan.

Aldosterone receptor antagonist: spironolactone (K+-sparing diuretic).

4. Kinins
Synthesis and fate: Two types: plasma bradykinin (nonapeptide) and tissue kallidin (decapeptide). They are synthesized from the precursors, kininoges by kallikrein enzymes. Kinins are rapidly are metabolized by kininase enzyme (ACE) into inactive metabolites.

Physiological functions of kinins: They are important mediators in inflammation, allergy and pain.

Aprotinin inhibits kallikrein and plasmin enzymes and used to reduce bleeding after surgery.

5. Atrial natriuretic peptide (ANP) ANP is released from the wall of right atrium in response to hypertension. It acts on specific receptors causing vasodilatation and diuretic effect, thus reducing blood pressure.

6. Endothelins Endothelins are peptides released from vascular endothelium and act on specific receptors in the vascular smooth muscles causing vasoconstriction.

Bosentan is an endothelin-receptor antagonist causing vasodilatation. It is used in treatment of pulmonary hypertension.

7. Eicosanoids
They are a group of unsaturated fatty acids composed of 20 carbon atoms and contain double bonds.

Biosynthesis of eicosanoids: They are synthesized from cell membrane phospholipids. The first step is separation of arachidonic acid from cell membrane phospholipids by the action of phospholipase A2 which is stimulated during inflammation, allergy and cell injury.

Arachidonic acid is metabolized by one of two pathways to give different eicosanoids which are:

I. Cyclooxygenase (COX) pathway which gives: - PGs (PGE2, PGD2, PGF2 ) by prostaglandin synthetase. - TXA2 in platelets by thromboxane synthetase. - Prostacycline (PGI2) in vascular endothelium by prostacycline synthetase. There are two types of COX enzyme, COX-1 (constitutive enzyme) which is responsible for synthesis of PGs for physiological functions (cytoprotective effect of gastric mucosa, maintain renal function, platelet aggregation) and COX-2 (inducible enzyme) produces PGs which act as mediators in inflammation, pain, fever.

II. 5-Lipooxygenase pathway to form leukotrienes (LTB4 , LTC4 , LTD4 , LTE4).

Therapeutic uses of prostaglandins: PGF2 (Dinoprost) and PGE2 (Dinoprostone) are used as vaginal suppositories for therapeutic abortion (abortifacients) in early pregnancy and for induction of labor. Misoprostol (synthetic analoge of PGE1) provides cytoprotective effect on gastric mucosa and is used in treatment of peptic ulcer and to prevent gastric ulceration during treatment with NSAIDs. PGF2 derivative (Latanoprost) decreases IOP by reducing aqueous humor synthesis and is used as eye drops for glaucoma. Pharmacological actions of leukotrienes: They produce powerful bronchospasm and are important mediators in allergic bronchial asthma. Leukotrienes are not used clinically.

Inhibitors of eicosanoid synthesis: 1. Glucocorticoids inhibit phospholipase A2 and prevent synthesis of all eicosanoids. They are used as anti-inflammatory, antiallergic and immunosuppressive agents. 2. Nonsteroidal anti-inflammatory drugs (NSAIDs): - Aspirin and indomethacin inhibit cyclooxygenase (COX) enzyme and reduce synthesis of PGs. They are nonselective (inhibit both COX-1 and COX-2). Inhibition of COX-1 results in adverse effects as gastric ulcer, renal impairment and bleeding tendency. - Selective COX-2 inhibitors are meloxicam (selectivity for COX-2:COX-1 is 10: 1), and roficoxib and celecoxib (selectivity for COX-2:COX-1 is 350: 1) have minimal gastric ulceration, renal impairment and bleeding tendency. 3. Zileuton is a selective 5-lipooxygenase inhibitor that reduces leukotriene synthesis and used for treatment of bronchial asthma. 4. Zafirlukast is a LT-receptor antagonist used for treatment of bronchial asthma.

8. Platelet activating factor (PAF)

It is synthesized by the action of phospholipase A2 on cell membrane phospholipids through a different pathway than cyclooxygenase and lipooxygenase pathways.

It is a powerful inflammatory and allergic mediator (especially in allergic bronchial asthma).

It produces bronchospasm, vasodilatation, increased capillary permeability, edema, increased platelet aggregation.