SMART Vision Autacoids DR KHAZBAK

 Autacoids are heterogeneous substances, having complex physiologic and pathologic effects
through multiple receptor subtypes and they are often released locally.
 Autacoids include:  Physiological antagonism (adrenaline): adrenaline reverses all the effects of histamine by action on different receptors.
1- Amines: Histamine and 5-HT (serotonin)  Competitive antagonists:
2- Vasoactive peptides: a. H1 receptor blockers: (Antihistaminic).
a- Vasoconstrictors: Angiotensin II, Vasopressin, Endothelin & Neuropeptide Y. b. H2 receptors blockers: D gastric secretion e.g. cimetidine, ranitidine.
b- Vasodilators: Bradykinin, Natriuretic peptide, Substance P, Vasoactive intestinal To be discussed in treatment of peptic ulcer).
polypeptide (VIP) and calcitonin related gene peptide. c. H3 and H4 receptor blockers: are not yet available for clinical use.
3- Fatty acid derivatives: a-Eicosanoids: Prostaglandins and Leukotrienes.
b- Platelet activating factors (PAF).
Antihistaminics (H1 blockers) are classified into first & second generation

 Histamine is formed from the amino acid histidine by the action of histidine decarboxylase
1st generation 2nd generation
and is stored mainly in mast cells. Dimenhydrinate, Diphenhydramine, Clemastine, Chlorpheniramine, Fexofenadine, Loratadine, Cetirizine
 Non-mast-cell histamine is found in several tissues including the brain. Cyclizine, Meclizine, Carbinoxamine, Cyproheptadine, Promethazine &
 Histamine release can occur through 2 processes: Hydroxyzine
- ca+ 2 dependent mechanism: by fixation of lgE to the surface of mast cell, this causes ca+  They can cross BBB (more lipid soluble) so have strong sedative effect.  Cannot cross BBB (lipid soluble) & have NO sedation
2 influx and degranulation of mast cell. Many drugs can induce this type e.g. penicillin.  Block autonomic receptors  NO blocking for autonomic receptors Long
- ca+ 2 independent mechanism: either by displacement of histamine from storage granules  Duration short 4-6h  Duration 12-24 hours
by drugs e.g. morphine, vancomycin or by mast cell damage as in mechanical trauma. Effect related to H1 blocking: Other effects of 1ST generation anti-histaminics: 2nd: Other effects: Not present
 Histamine Receptors: Histamine acts on four types of histamine receptors: - Relief of itching, pain and allergic response.  Sedation: but excitation or even convulsion may occur in children
H1 H2 - Decrease capillary permeability and  Atropine like action: most of 1st generation can block muscarinic receptor lead to urine
Distributi  Blood vessels (endothelium)  Gastric partial cell mucosa inflammatory edema induced by histamine retention and blurred vision.
on  Non vascular smooth muscle  Heart - Decrease bronchoconstriction and  Antiemetic action: used in motion sickness.
 Skin: sensory nerve endings  Mast cell bronchial and lacrimal secretion  Alpha receptor blocking action: lead to postural hypotension in susceptible individuals.
 CNS  Blood vessels 5HTreceptor blocking action: (cyproheptadine) so used in carcinoid syndrome
[Link].  Gq receptors: I P3 & DAG.  -Gs receptors: increase cAMP Therapeutic uses:
 VD occurs by release of NO cGMP & IC ca+ 2 - Allergic conditions: use of H1 blockers is effective in allergic conditions where histamine is the 1ry mediator [Link] rhinitis&urticaria).
Actions 1. BL.V VD &  permeability (edema) 1. Increase gastric HCI, pepsin. N.B: in bronchial asthma which involve several mediators the use of H1 blockers is generally ineffective.
&BP. 2. Increase heart rate and cardiac - Motion sickness: The 1st H1 blockers (especially diphenhydramine and promethazine) are effective in # vomiting of motion sickness by
2. Non-vascular smooth muscles: contractility in heart blocking H1 & muscarinic receptor in vomiting center.
Bronchoconstriction and GIT spasm 3. Negative feedback on mast - Carcinoid syndrome: This syndrome caused by a serotonin secreting neoplasm of enterochromaffin in the GIT, when the tumor is not
3. Skin: Itching, urticaria and pain. 4. vasodilatation. operable, cyproheptadine with other 5-HT blockers can be used.
4. CNS: function related to appetite & satiety
• H3 receptors are predominantly presynaptic nerve ending and in CNS Adverse effects:
• H4 receptors are found mainly on inflammatory cells (leukocytes) and seem to play a role in -Sedation, so should be avoided in driving. - The 2nd generation of antihistamine are metabolized by the hepatic
regulation of inflammatory response But excitation may occur rarely in children. CYP450 enzymes,
- Clinical use of histamine: Histamine itself is not used clinically -Atropine like action: this may cause urine retention, dry - some of the early drugs in this group prolong the QT interval & cause
mouth & blurred vision. serious arrhythmia (torsade de pointes) specially when given with other
-Orthostatic hypotension due to blocking of alpha receptors. drugs that # CYP450 system e.g. ketoconazole and erythromycin.

Drug interactions:
1st generation antihistamines can potentiate the sedative effect Dangerous arrhythmia when given with other drugs that inhibit
of hypnotics. CYP450 system.
 SMART Vision Autacoids DR KHAZBAK

 Serotonin (5-HT) is formed from the amino acid tryptophan and stored mainly in the enterochromaffin tissue of the
GIT (90%) and platelet (10%).
 Serotonin act on 7 types of receptors. 1- Buspirone: 3- Dexfenfluramine: Appetite suppressant
 Effects of 5-HT: - It activates central 5-HT 1A receptors. but was withdrawn because of being
1- On the cardiovascular system: - It is used in the treatment of anxiety (nonbenzodiazepine associated with cardiac valve defects
 Powerful vasoconstriction effect (5-HT 2) (EXCEPT on blood vessels of skeletal muscle it will cause dilatation). anxiolytic). 4- ltopride & Cisapride: prokinetics
 Aggregation of blood platelets (5-HT 2). -Its therapeutic effect may take as long as 2 weeks to appear. used in the treatment of gastro-
 Reflex bradycardia by stimulating 5-HT 3 at coronary chemoreceptor nerve endings. 2- Sumatriptan, zolmitriptan esophageal reflux disease [GERD]
2- Gastrointestinal tract:  Selective agonists for 5-HT1D/1B mediate vasoconstriction. 5- Tegaserod:
- Contraction of GIT smooth muscle c> facilitates peristalsis (5HT 2).  Orally or subcutaneous in the treatment of acute migraine is a selective 5-HT4 agonist; it increases
- Stimulates acetylcholine release (5HT 4)  enhancing motility (prokinetic effect) attacks. GIT motility so it is used for the
3- Nervous System:  Side effects: tingling, dizziness, neck pain, chest pain treatment of irritable bowel syndrome
- Neurotransmitter and precursor of melatonin. (coronary vasospasm). with predominant constipation.
- Potent stimulant for pain & itch, nausea & vomiting.  Contraindicated in angina, hypertension, peripheral 6- Escitalopram, Fluoxetine, fluvoxamine:
- 5-HT is a powerful activator of 5HT3 receptors in chemo-sensitive endings located in the coronaries  marked vascular disease, pregnancy. selective serotonin reuptake inhibitors
hypotension & bradycardia, which can be blocked by atropine because this reflux is carried by the vagus nerve.  Short duration so requires multiple doses but only allowed (SSRls) (used in the treatment of psychic
2 doses/24h. depression and several other conditions)

 These alkaloids are produced by a fungus that infects grasses and grains. 1- Cyproheptadine:
 They act on alpha adrenoceptors, dopamine receptors and 5-HT receptors. - Actions: 5-HT 2 blockade. It has H1 and muscarinic receptor blocking actions.
 Ergot alkaloids have a powerful stimulant effect on the uterus. - Uses: Used in allergy, carcinoid tumor, prophylaxis of migraine.
 Clinical Uses: Toxicity & Contraindications of - Side effects: sedation, dry mouth
1. Migraine [Paroxysmal unilateral headache preceded by visual, sensory motor ergot alkaloids 2- Ketanserin:
or autonomic manifestations]. 1. Gastrointestinal disturbances: - competitive blocker at 5-HT2. Prevent bronchospasm and vasoconstriction of carcinoid tumor.
- Ergotamine tartrate is available for oral, sublingual, rectal suppository,& diarrhea, nausea, and vomiting. - Used for the treatment of carcinoid syndrome and hypertension associated with carcinoid tumors.
inhaler use. 2. Prolonged vasospasm usually 3- Ondansetron, Granisetron:
- It is effective when given during the prodrome of an attack; associated with overdosage of -They selectively block 5-HT3 receptors centrally (CTZ) and peripherally (GIT)
- it becomes progressively less effective if its use is delayed. ergotamine and ergonovine. - Used to prevent nausea & vomiting induced by cancer chemotherapy.
- It is often combined with caffeine to facilitate absorption of the ergot alkaloid.
2. Hyperprolactinemia This sign of vascular smooth
- Bromocriptine is effective in reducing the high levels of prolactin that result muscle stimulation may result in
from pituitary tumors and has even been associated with regression of the gangrene and may require
tumor in some cases. amputation.
- Cabergoline is similar but is more potent. Vasospasm caused by ergot is
- Bromocriptine has also been used to suppress physiologic lactation. refractory to most vasodilators, but
3. Postpartum Hemorrhage Although oxytocin is the preferred agent for infusion of large doses of
control of postpartum hemorrhage, however, Ergometrine (ergonovine) is nitroprusside or nitroglycerin has
usually effective within 1-5 minutes and is less toxic than other ergot been successful in some cases.
derivatives for this application.
3. Use of ergotamine for
- It is given at the time of delivery of the placenta or immediately afterward if
migraine is hazardous in
bleeding is significant.
pregnancy (abortion).
 SMART Vision Autacoids DR KHAZBAK

- Several peptides exert direct effects on vascular and smooth muscles they are classified into:
A) Vasoconstrictor peptides: Angiotensin II, vasopressin, endothelin, neuropeptide Y.
B) Vasodilator peptides: Bradykinin, natriuretic peptides, substance P, Vasoactive Intestinal Peptide (VIP), neurotensin.  Kinins are potent vasodilator peptides, formed from protein substrates called kininogens, by the effect of
kallikrein enzymes.
 Kinins act on at least 2 subtypes of receptors B1 and B2.
 They are rapidly metabolized by Kininase enzymes  Short duration of action (t1/2 <15s)
Angiotensins are polypeptide autacoids; they are
1- Angiotensin-I: inactive decapeptide (10 Aminoacids).
2- Angiotensin-II: Very Active octapeptide (8 Aminoacids).
3- Angiotensin-III: Less active heptapeptide (7 Aminoacids).

A) Angiotensinogen B) Renin
1-An 2-Globulin synthesized mainly in liver. 1- A protease enzyme synthesized & secreted by the JG cells of the kidney.
2- It is a substrate for renin enzyme. 2- Ren in Receptor Blockers: Enalkiren & Remikiren.
C) Angiotensin Converting Enzyme (ACE) -Mechanism of action of angiotensin II: It stimulates specific AT- actions of kinins: They stimulate specific B1&B2 receptors coupled to G-proteins, leading to:
1- ACE = Kininase-11 = dipeptidyl carboxy- receptors: 1- Powerful Arteriolar V.D. (10 times that produced by histamine).
peptidase. -Actions: They stimulate B2 receptors & Increase PG  decrease BP & Redness & Hotness.
2- Present in capillary endothelium, 1- Powerful V.C., 40 times more than that produced by noradrenaline. 2- Venous V.C.  increase venous pressure. 3-  Capillary permeability  Edema formation.
especially in the lungs. 2- It increases the release of noradrenaline and also stimulates sympathetic 4- Stimulation of sensory nerve endings Pain. 5- Important mediators of Inflammation & Anaphylaxis.
3- It converts the Inactive Angiotensin-1 to ganglia & the adrenal medulla  increase in sympathetic activity. 6- Spasmogenic on smooth muscle Bronchospasm & GIT colic.
the Very Active Angiotensin-11. 3- It increase the biosynthesis & the secretion of aldosterone. icatibant is a 2nd generation decapeptide which acts as a selective antagonist at bradykinin B2 receptors It
4- It metabolizes other autacoids e.g. 4- It decreases renin secretion & increases angiotensinogen. is given by SC injection for the symptomatic treatment of acute attacks of hereditary angioedema.
bradykinin & substance-P.
5- It has a mitogenic effect  hypertrophy & remodeling of the heart & the n.b:
5- ACE Inhibitors e.g. Captopril, Lisinopril &
blood vessels. • Aspirin  inhibit Kallikrein enzymes  decrease Synthesis of Kinins.
Enalapril have wide applications in • Kininase-II = Angiotensin Converting Enzyme (ACE).
cardiovascular system disorders.
6- On the C.N.S. it  ADH and ACTH (Dipsogenic effect=  in
• ACE. Inhibitors e.g. Captopril increase Kinins  VD
drinking).
7- It has a spasogenic effect on smooth muscles
8- Angiotensin-II is involved in the inflammatory response  Endothelins are vasoconstrictor peptides produced by the endothelium.
associated with several diseases including atherosclerosis  There are 3 isoforms.
 Endthelin-1 (ET-1) is the strongest vasoconstrictor currently studied.
D) Renin-Angiotensin-Aldosterone-Systemic Inhibitors (RAAS-1)  Endothelins act on at least 2 subtypes of receptors: ETA and ETB.
 Most of endothelins' effects are mediated through ETA receptors present in vascular smooth muscle &
1- Agents that decrease renin secretion: -Blockers & -aqonists. other tissues.
2- Renin-receptor blockers: Enalkiren.  -Its activation leads to potent VC, vascular smooth muscle proliferation, cardiac hypertrophy and  blood
3- ACE Inhibitors: such as Captopril, Lisinopril & Enalapril. pressure,  production of ET-1 has been implicated in a variety of CVS disease, including primary
4-AT1-Receptor blockers: such as Losartan, Valsartan, Candesartan & Telmisartan. pulmonary hypertension, heart failure and coronary artery disease
 Bosentan is an orally active non-selective ETA and ETB receptor blocker, while
 Ambrisentan is a selective ETA blocker.
Both drugs are approved for the treatment of pulmonary hypertension.
SMART Vision Autacoids DR KHAZBAK

• Eicosanoids are oxygenation products of polyunsaturated long-chain fatty acids. They are generated de-novo from phospholipids. Eicosanoids include: • [PG] / prostanoids, [TXA], leukotrienes & related compounds.
biosynthesis: effects of prostaglandins & thromboxanes:
The precursor of eicosanoids is arachidonic acid. (AA) I. On the cardiovascular system IV. On the kidneys
• The initial and rate limiting step in eicosanoids synthesis is liberation of arachidonic 1) TXA2 is synthesized in blood platelets. -PGE1,PGE2&PG'2 play important autoregulatory roles in renal function
acid from membrane phospholipids either in a one-step process or a two steps TXA2 is the most powerful endogenous stimulator of platelet aggregation V. On the CNS
process: and it also causes VC. - PGE2 produces a pyretic effect (increase in body temperature) via
The free arachidonic acid is metabolized by several pathways: 2) PGI2 is synthesized in smooth muscles & endothelial cells. stimulation of EP-3.
- By cyclooxygenases (COXs) which initiate the biosynthesis of PGs [prostanoids]. It produces VD and inhibits platelet aggregation and thrombus formation. - Pyrogens release IL.I from the inflammatory cells leading to increase
- By lipoxygenases (LOXs) which initiate the synthesis of leukotrienes, lipoxins & other N.B.: PGl2/TXA2 balance is critical in controlling vascular tone & platelet in the synthesis of PGE2.
compounds. function. VI. On the eye:
II. On the airways: -PGE & PGF derivatives lower IOP, probably through increasing the
• PGE2, PGE1 and PGD2 produce bronchodilatation. outflow of aqueous humor from the anterior chamber, via the
• TXA2 & PGF2a produce bronchoconstriction. uveoscleral pathway.
Ill. On the GIT VII. On the reproductive system
• Most PGs & TXA2 activate GIT smooth muscles. A) The female reproductive system:
• PGE2 & PG'2 have cytoprotective effects in the GIT and these are: PGE2 & PGF2a have potent oxytocic actions.
1. Reduction of gastric HCL secretion. B) The male reproductive system
2. V.D. of gastric mucosal blood vessels, maintaining the functional • The major sources of PGs are the seminal vesicles, the prostate and
integrity of gastric tissues. the testis.
3. Stimulate release of viscous mucus which plays a defense role against • PGE1 enhances penile erection.
mucosal injury by gastric acidity.
therapeutic uses of prostanoids leukotrines
Products of cyclo-oxyqenase pathway; 1- Gynecological & obstetrical uses: -They are derived from arachidonic acid by the action lipooxygenase enzyme.
Cyclo-oxygenase (COX) exists in 3 forms: Dinoprostone: A synthetic preparation of PGE2 is administered - They are of 4 main types: LTB4, LTC4, LTD4 and LTE4.
1) COX-1 (physiological; constitutive): is involved in the synthesis of protective PGs as vaginal suppository for the induction of labor and abortion. - A mixture of L TC4, L TD4 and L TE4 is termed (the Slow Reacting Substance
(PGE2, PGb), responsible for protection of the stomach from HCI and regulation of 2- For the treatment of erectile dysfunction: Of Anaphylaxis = SRS-A) and is released during the inflammatory phase of
the renal blood flow. Alprostadil (PGE 1) is used for the treatment of erectile bronchial asthma.
2) COX-2 (pathological; inducible): induced in inflammatory cells by inflammatory dysfunction in men as a urethral insert; it produces VD of the Inhibitors of Eicosanoids
stimuli. It is responsible for the undesirable elevation in the production of vascular smooth muscle of the corpus cavernousm and improves 1- Glucocorticoids:
prostanoids that occurs in sites of disease or inflammation. erection. - They inhibit the activity of phospholipase A2 enzyme and consequently
3) COX-3 {central): is a variant of COX-2 & it is named also (COX-lb), found in the brain 3- Gastro-intestinal therapeutic uses: inhibit formation of arachidonic acid which is the precursor of PGs.
only and may be involved in the synthesis of PGs responsible for pain and fever. It Misoprostol: a synthetic analog of PGE 1 is used orally for the - So glucocorticoids inhibit synthesis of ALL the eicosanoids family.
is selectively inhibited by the analgesic/antipyretic drug named paracetamol. prevention of NSAID-induced peptic ulcer. 2- Non Steroidal Anti-Inflammatory Drugs (NSAIDs) :
4- Cardiovascular therapeutic uses: - All NSAIDs have analgesic/anti-inflammatory/antipyretic actions.
Prostanoid Receptors:
Alprostadil (PGE1): Used by IV infusion for maintaining the - They inhibit cyclooxygenase enzyme (COX inhibitors) either
• There are five main classes of prostanoid receptors, all of which are typical G-
patency of the ductus arteriosus prior to surgical correction of nonselectively, as the classical NSAIDs (e.g. aspirin) or selectively as the
protein-coupled receptors.
congenital heart disease in neonates. newer NSAIDs (e.g. celecoxib).
• They are termed DP, FP, IP, EP and TP receptors, respectively, depending on
Epoprostenol: A PGl2 preparation used by IV infusion for the 3- Dazoxiben : Is a selective inhibitor of thromboxane synthetase & it
whether their ligands are PGD2, PGF2, PGI2, PGE2 and TXA2.
treatment of pulmonary hypertension. inhibits platelets aggregation.
• Some have further subtypes; for example, the EP receptors are subdivided into four
5- Ophthalmic therapeutic uses: 4- Antileukotriene drugs = leukotrienes antagonists
subgroups (EP1 - EP2 - EP3 & EPs).
Latanoprost is used as eye drops for the treatment of open- Zafirlukast & Montelukast: they block leukotriene receptors.
angle glaucoma. Zileuton: inhibit 5-lipooxygenase enzyme   in LTs synthesis.
These drugs are used in the treatment of BA.