1. AUTOCOIDS

2. Prostaglandins, histamine and serotonin belong to this group.
Act as local hormones
Mainly produced from diff. tissues

3. PROSTAGLANDINS Derived from unsaturated fatty acids
Cause the arteries to dilate 
Influence blood clotting
Stimulate pain nerve endings  
Reduce stomach acid secretion
Abortifacient

4. Prostaglandin receptors:
Most affect other cells by interacting with plasma membrane G-protein coupled receptors.
Depending on the cell type, the activated G-protein may stimulate or inhibit formation of cAMP, or may activate a phosphatidyl inositol signal pathway leading to intracellular Ca++ release.

5. PROSTAGLANDINS
CARBOPROST
DINOPROST
DINOPROSTONE
MISOPROSTOL

6. USES
GIT
PGEs and PGI2 inhibit gastric acid secretion, stimulated by feeding, histamine or gastrin
Maintainance of the gastric mucosa - stimulation of mucus secretion
misoprostol (substituted PGE1) used for NSAID-induced gastric ulcer;
administered intra-vaginally with mifepristone(oral) for non-surgical abortion

7. Uterus
Certain Prostaglandins cause uterine contraction in pregnancy
clinically used as abortifacients or to induce labor
Dinaprostone (PGE2) and
Carboprost (15-methyl-PGF2a)
Misoprostol + Mifepristone

8. Histamine
Histamine is a chemical messenger that mediates a wide range of cellular responses, including allergic and inflammatory reactions, gastric acid secretion and neurotransmission in parts of the brain
Histamine has no clinical applications, but agents that interfere with the action of histamine(antihistamines) have important therapeutic applications

9. Location: occurs in all tissues but found in high amounts in the lung, skin and GIT.
Found in high conc in mast cells or basophils by type-1 hypersensitivity reactions
Histamine also occurs as a component of venoms and in secretions from insect stings
Synthesis: is an amine formed by decarboxylation of histidine

10. H1 receptors stimulate phosphoinositide turnover and Ca++ influx
Location: smooth muscle, endothelium and CNS tissue
H2 receptors stimulate adenylate cyclase resulting in increase cAMP
Location: parietal cells of the stomach, vascular smooth muscle

11. H₁ ACTIVATION ↑ capillary dilation (via NO) → ↓BP
↑ capillary permeability → ↑edema
↑ bronchiolar smooth muscle contraction
↑ activation of peripheral nociceptive receptors → ↑ pain and pruritus
↓AV nodal conduction
Responsible for allergic rhinitis and motion sickness

12. H₂ ACTIVATION (GS) ↑ gastric acid secretion → ↑ GI ulcers
↑ SA nodal rate, positive inotropism and automaticity

13. H1- BLOCKERS 1ST generation
First-generation agents tend to be relatively more sedating and more likely than second-generation drugs to block autonomic receptors -- for example blockade of cholinergic, α-adrenergic and serotonin receptor

14. Chlorpheniramine
Dexchlorpheniramine
Clemastine
Dimenhydrinate
Diphenhydramine
Doxylamine
Methdilazine
Promethazine
Cyclizine
Hydroxyzine
Azatadine
First generation

15. Second-generation agents   are relatively less sedating compared to the earlier first-generation agents and exhibit less CNS penetration, which accounts for reduced sedation.

16. 2nd Generation Terfenadine Astemazole Loratidine (Claritin) Cetirizine
Fexofenadine (Allegra)

17. USES Allergic conditions
Motion sickness – Dimenhydrinate, Diphenhydramine, Cyclizine, Meclizine.
Preoperative sedation
Nausea and vomiting with pregnancy
Acute EPS
Parkinson disease
Insomnia & cold– Diphenhydramine
Meclizine – long duration of action

18. Astemazole – long duration of action
Terfenadine & Astemazole – CI with Macrolides, antifungals, which can cause severe ventricular arrhythmias

19. SE Drowsiness Fatigue Tremors Vertigo Blurred vision
Dry mouth with some
Overdoses – hallucinations, excitement, ataxia.

20. H 2 - BLOCKERS
H2 receptor antagonists inhibit histamine-induced stomach acid secretion
Mainly used in the treatment of the peptic ulcers.
Cimetidine
Ranitidine
Famotidine
Nizatidine

21. serotonins Pharmacologic actions
serotonin has profound effects on gastrointestinal, cardiovascular, respiratory, and central and peripheral nervous system function

22. Serotonin receptor subtype pharmacology and therapeutic agents
5-HT1 Receptors Agonist binding to these receptors results in the inhibition of adenylate cyclase via the inhibitory GTP-binding protein (Gi).
for 5-HT1A Effects in generalized anxiety
Buspirone - partial-agonist for 5-HT1A receptor, the first specific non-benzodiazepine anxiolytic

23. 5-HT1D Receptor
Sumatriptan - used in acute treatment of migraine headaches a highly selective agonist of the 5-HT1D subtype receptor
Sumatriptan blocks the neuropetide-mediated inflammatory response after trigeminal stimulation and may block trigeminal neurotransmission.
vasoconstriction of intracranial arteries

24. Ergotamine and dihydroergotamine have high affinity 5-HT1 receptors
They are used for the treatment of migraine.
Methysergide a semi-synthetic ergot alkaloid is a 5-HT2 antagonist with greater potency than ergotamine and dihydroergotamine that is used for migraine prophylaxis.

25. 5-HT2 receptors have a role in depression and anxiety
Risperidone, a new antispychotic blocks 5-HT2 receptors

26. 5-HT3 receptors are located peripherally on vagal nerve terminals and centrally at the Chemoreceptor Trigger zone (CTZ).
Antagonists of these receptors are potent inhibitors of chemotherapy and radiation -induced emesis.
Ondansetron and Granisetron are currently available in the U.S. as an anti-emetics.

27. 5-HT4 receptors
These receptors are positively coupled to adenylate cyclase, opposite of 5-HT1 receptors
Cisapride is a specific 5-HT4 receptor agonist, similar to metoclopramide but with much weaker dopaminergic action.
It also enhances release of Ach from nerve terminals in the myenteric plexus.
It is a prokinetic agent that enhances and promote motility in the GI tract.
It relieves Gastroesophageal reflux disease by increasing lower esophageal sphincter pressure.

28. 5-HT Reuptake Inhibitors
Many drugs useful as antidepressant block the reuptake of serotonin.
These include many tricyclic agents (eg. amitryptilline, nortryptilline, imipramine) which may also inhibit catecholamine reuptake.
Newer agents which selectively block the reuptake of serotonins include fluoxetine, sertraline, fluvoxamine, paroxetine, venlafaxine, and citalopram.

29. MIGRAINE Family history is there May be there life long
A symptom complex occurring periodically and characterized by pain (pulsating & throbbing) in the head (usually unilateral), vertigo, nausea and vomiting, photophobia, and scintillating appearances of light.

30. Sumatriptan
Ergotamine
Dihydroergotamine
NSAID’s
Beta blockers
Methysergide

31. Sumatriptan
Serotonin agonist acts at 5 –HT 1d receptors – found in peripheral nerves that innervate the cerebral vessels – vasoconstriction
Oral or SC
Rapidly and effectively aborts the severity of the migraine headaches.
SE: dizziness, flushing nausea, hypertension.
CI – heart diseases

32. Ergotamine Serotonin agonist of 5HT1-D – vasoconstrictor
Caffeine potentiates the actions
So mostly used in combined form.
Oral, Sublingually, Rectally, Nasally
Most effective – early phase of an attack
CI – preg, vascular diseases
SE: Diarrhea , nausea & vomiting

33. Dihydroergotamine (IV administration mainly) may be appropriate for intractable migraine.

34. NSAID’s May be sufficient for mild /moderate migraine Aspirin
Acetaminophen
Naproxen
Aspirin combination (Aspirin + Caffeine + butalbital)
If severe pain may need – opioids

35. Prophylaxis Methysergide (Sansert) Effective in about 60% of patients
Toxicity:
Retroperitoneal fibroplasia
Subendocardial fibrosis
The side effects are the basis of recommending a 3-4 week drug holiday every six months.

36. Beta - Blockers
Propranolol (Inderal) -- Prophylaxis- Most common for continuous prophylaxis
Nadolol and Timolol can also be used.
all beta2-blockers: contraindicated in asthmatics
Best established drug for migraine attack prevention.

37. Other drugs for prophylaxis
Calcium channel blocker such as verapamil can be used also as prophylaxis.
Antidepressant such as amitriptyline.