PCOL SEROTONIN DRUGS

Buspirone (Buspar)

⏤ is a relatively specific 5HT1areceptor agonist.

⏤ Is useful for the management of anxiety disorders.

Dexfenfluramine

⏤ 5HT2c agonist

⏤ Used as appetite suppressant

⏤ Withdrawn: cardiac valve toxicity

Triptans

• Sumatriptan (Imitrex, Imigran)

• Naratriptan

• Zolmitriptan

• Rizatriptan

⏤ a 5HT 1B/1D-receptor agonist.

⏤ promotes the contraction of vessels in carotid circulation. This reduces the rebound vasodilation associated with migraine headaches.

⏤ used for the treatment of acute migraine.

⏤ A/E: Hypertension

Cisapride (Propulsid)

⏤ 5HT4 agonist

⏤ speeds gastric emptying and increases lower esophageal pressure.

⏤ Use: Treat nocturnal heartburn due to reflux, constipation, and anorexia nervosa. Not available in the Philippines. In USA, it is “compassionate use”

Tegaserod

⏤ 5HT4 partial agonist

⏤ used for irritable bowel syndrome with constipation.

Withdrawn due to cardiovascular toxicity.

Ergot alkaloids (Claviceps purpurea)

5HT1D agonist

ERGOTAMINE

Used for prevention and treatment of migraine.

ERGONOVINE

Used in the management of post-partum hemorrhage

Ergot

-Powerful hallucinogen

-behavioral effects are mediated by agonist effects at prejunctional or postjunctional 5-HT2 receptors in the central nervous system

-affect the following receptors:

● Adrenoceptors

● dopamine receptors

● 5-HT receptors

Ergot

Effect:

Vascular smooth muscle = Contraction

Uterus= contraction

Endocrine = suppress prolactin secretion from pituitary cells

Ergotism

accidental ingestion of ergot alkaloids in contaminated grain

Ergotamine, Caffeine, Methysergide

Ergots for migraine

Methysergide

Its therapeutic effect in migraine prophylaxis has been associated with its antagonism at the 5-HT2B receptor (PARTIAL AGONIST) It has a known side effect, retroperitoneal fibrosis, which is severe although uncommon

Ergonovine maleate

Ergot For Postpartum hemorrhage

Bromocriptine, Pergolide

Ergots for Hyperprolactinemia

Bromocriptine

an ergoline derivative

Trazodone (Desyrel)

Nefazodone (Serzone)

⏤ 5HT2 antagonists (peripheral)

⏤ Serotonin antagonist and reuptake inhibitor (SARI) (central)

⏤ Use: Antidepressant A/E: Priapism, Hepatotoxicty

Cyproheptadine (Periactin)

⏤ a potent H1-receptor antagonist of the phenothiazine class; it blocks both 5HT1- and 5HT2- receptors.

⏤ Use: diarrhea and intestinal spasms (serotonin-secreting carcinoid tumors and postgastrectomy dumping syndrome)

Ketanserin (Sufrexal)

⏤ 5HT2-receptor antagonist

⏤ it also antagonizes alphaadrenergic, H1-, and dopamine receptors.

⏤ Use: Antihypertensive (Europe), Antihypertensive and for vasospastic cond (USA)

Clozapine (Clozaril) Risperidone (Risperdal, Risdin)

⏤ 5HT2A- and 5HT2C

– receptor antagonist.

Use: Antipsychotic agents

Clozapine

5HT2A- and 5HT2C – receptor antagonist., also block D4 receptor

Risperidone

5HT2A- and 5HT2C – receptor antagonist., also block D2 receptor

SETRONS This includes

• Ondansetron (Zofran)

• Granisetron (Kytril)

• Palonosetron

• Alosetron

⏤ 5-HT3 antagonists

⏤ Clinical use: mgt. of chemotherapy induced nausea & vomiting

Scopolamine (Hyoscine)= Hyoscyamus niger or henbane

MOA: Antagonize receptor of acetylcholine receptor they reduce the excitability of labyrinth in muscarinic receptors and depress the conduction from the vestibular apparatus to the vomiting center USE: treat motion sickness and in preoperative operation A/E: Drowsiness, dry mouth, and blurred vision

Scopolamine (Hyoscine)= Hyoscyamus niger or henbane

USE: treat motion sickness and in preoperative operation

A/E: Drowsiness, dry mouth, and blurred vision

Antihistamines like

Diphenhydramine

• Meclizine

• Cyclizine

• Dimenhydrinate

• Promethazine

MOA: act by inhibiting cholinergic pathways of the vestibular apparatus by receptor crossover

USES: motion sickness, true vertigo and nausea in pregnancy

A/E: sedation and dry mouth

Dopamine Antagonists

Metoclopramide (Plasil) Domperidone (Motilium)

Dopamine receptor (D2) blockade ⏤ blocks the dopamine receptors in the CTZ

USE: ⏤ Used to treat nausea due to chemotherapy and narcotic induced vomiting ⏤ Motion sickness

⏤ Sedation

⏤ Diarrhea

⏤ extrapyramidal effects

⏤ elevated prolactin secretion

cisplatin and doxorubicin

Dopamine Antagonists Used to treat nausea due to chemotherapy

Metoclopramide

Dopamine Antagonists used to treat narcotic induced vomiting

Domperidone

Dopamine Antagonists used to treat Motion sickness

SETRONS This includes

• Ondansetron (Zofran)

• Granisetron (Kytril)

• Palonosetron

• Alosetron

MOA: 5HT3 Antagonists

Ondansetron (Zofran)

more effective than metoclopramide against nausea induced by high dose cisplatin. (Adv: No extrapyramidal effect)

Granisetron (Kytril)

⏤ has a greater affinity for 5-HT3 receptors than ondansetron

⏤ longer acting and more potent than ondansetron or metoclopramide

⏤ most common adverse effect is headache

Cannabinoids (Synthetic THC Analog)

⏤ Dronabinol (Marinol)

⏤ Nabilone (synthetic derivative)

MOA: may act by inhibiting the vomiting center

USE: chemotherapy induced nausea administered either as an oral preparation or smoked as a cigarette (if other drug is ineffective only)

A/E: sedation, psychoactive effects, dry mouth and orthostatic hypotension

Tetrahydrocannabinol

psychoactive component of Marijuana

Glucocorticoids

Dexamethasone and Betamethasone Methylprednisolone (Solu-medrol)

Use: can be effective as a treatment for vomiting caused by highly emetic agents. high doses are given as an intravenous bolus or orally for delayed nausea often combined with other anti-emetics

A/E: may cause adrenal suppression and metabolic disturbances

Benzodiazepene

Lorazepam (Ativan)

Diazepam (Valium

MOA: GABA Agonist Uses:

⏤ Acts as anxiolytic agents to reduce anticipatory emesis

A/E: anterograde amnesia which lasts for 4-6 hours

Diazepam (Valium)

is useful as a treatment for vertigo and it controls symptoms of Meniere’s disease

Aprepitant

MOA: Neurokinin receptor antagonist Central blocker of area postrema It also inhibits substance P

USE: ⏤ combination with 5HT3 blocker and corticosteroids for acute and delayed N & V associated with chemotherapeutic agents Enzyme inhibitor (CYP3A4)

IPECAC

mixture of alkaloids including emetine and cephaeline derived from the ipecacuanha plant.

MOA: induces vomiting by stimulating the CTZ and by causing GIT irritation and afferent input to the vomiting center

administered orally fast acting, causing vomiting in 85% of the patients within 20 minutes useful in removing unabsorbed toxins from the stomach

APOMORPHINE

The only opioid derivative not classified as narcotic analgesic.

MOA: ⏤ Dopamine agonist

⏤ directly stimulates the CTZ

APOMORPHINE

Administered parenterally (SQ)

More toxic than ipecac- it causes CNS and respiratory depression., therefore it is not widely used.

Magnesium sulfate

Bitter salt; Epsom salt

The laxative action probably results from two factors:

(1) SO4 ion-Not absorbed from the GI tract and, thus, draws water into the lumen of the bowel to make an isotonic solution and

(2) Magnesium ion-Release of cholecystokinin-pancreozymin, which causes an accumulation of fluid and electrolytes within the small intestine

Magnesium sulfate

Bitter salt; Epsom salt

Oral-dissolve in iced water or orange juice to mask nauseous taste

IV-(125/500mg/ml) not as laxative, used to manage pre-eclampsia

Sodium biphosphate (NaH2PO4. H2O)

⏤ One of the most palatable of the saline laxatives

⏤ Its major use, however, is for diagnostic procedures such as proctoscopy, colonoscopy, or barium enema

⏤ It also is used in the form of the oral solution as an antihypercalcemic

⏤ Used also incystitis (combined with Methenamine)

Rectal solution-also known as Fleet Enema

Oral solution-Fleet Phospho-Soda

Sodium biphosphate (NaH2PO4. H2O)

rectal and oral solution

Sodium sulfate

Glauber’s salt

⏤ Used also as laxative to evacuate bowel prior to surgery

⏤ Used also electrolyte replenisher and is used inisosmotic solutions so that administration does not disturb normal electrolyte balance and does not lead to absorption or excretion of water and ions

Mannitol

Osmotic laxative in oral doses larger than 20 g

Mannitol I.V. (mannitol injection)

is a diuretic used to increase urine production, and to treat or prevent medical conditions that are caused by an increase in body fluids/water (e.g., cerebral edema, glaucoma, kidney failure)

- 5 %( 5mg/100ml), 10 %( 10mg/100ml), 15 %( 15 mg/100ml), 20 % ( 20mg/100ml), 25 %( 12.5mg/50ml)

Mannitol injection doses

Lactulose

Cholac®, Lilac®

⏤ cannot be hydrolyzed by digestive enzymes

⏤ Fermentation of lactulose by colon bacteria to lactic acid leads to acidification of bowel contents and a reduced number of bacteria.

⏤ Depends on its breakdown by colonic bacteria to carbon dioxide, lactic acid, and small amounts of acetic and formic acids, which acidify the contents of the colon.

⏤ The acidic environment converts ammonia to ammonium ion (NH4+), which cannot be absorbed

Lactulose

Cholac®, Lilac®

used in liver failure to forestall hepatic coma by preventing bacterial production of ammonia and its subsequent absorption (absorbable NH3 + -nonabsorbable NH4+).

Adverse Effect: Flatus & cramps- gas generated in the stomach or bowels. due to fermentation in the gut producing CO2

Lactulose

Cholac®, Lilac®

Drug Interaction:

▪ Neomycin- eliminate colonic bacteria reducing the fermentation of lactulose to lactic acid thus decreasing the acidification of colon

Contraindication:

▪ Used with caution to patients with diabetes (it contains monosaccharide 1 molecule of galactose and 1 molecule of fructose

Bisacodyl (Dulcolax)

converted by gut bacteria into the active colon-irritant principle.

Given by the enteral route, _____ is subject to hydrolysis of acetyl residues, absorption, conjugation in liver to glucuronic acid (or also to sulfate), and biliary secretion into the duodenum.

Oral administration: 6–8 hours by discharge of soft formed stool.

Suppository: ___ effect (one hour)

Phenolphthalein

t tends to act longer than other laxatives because it enters the enterohepatic circulation and is re-excreted in bile into the intestine

In susceptible individuals, phenolphthalein may cause allergic reactions, including SJS and lupus erythematosus. It also may cause a Bartter’s-like syndrome

The drug has been discontinued.

Diphenylmethanes

Chronic intake:

• Disrupts the water and electrolyte balance of the body and can thus cause symptoms of illness (e. g., cardiac arrhythmias secondary to hypokalemia).

• May also result in cathartic colon (melanosis coli)

Melanosis coli

is a condition usually associated with chronic laxative use in which dark pigment is deposited in the lamina propria (one of the lining layers) of the large intestine (colon). The pigment deposition results in a characteristic dark brown to black discoloration of the lining of the large intestine.

Cascara sagrada

From dried bark of Rhamnus purshiana

Nature’s Remedy; Sacred Bark; Chittem; Dogwood;Bearberry; Bitter Bark

• Widely used cathartic.

• It is used for relief of transient constipation.

• It has very little action on the small intestine but promotes peristalsis in the large intestine

Sennosides

Example: Calcium sennosides (Senokot)

A natural complex of anthraquinone glycosides found in senna, isolated from Cassia angustifolia as calcium salts, contains 55% to 65% of the calcium salts.

Castor Oil

❑ obtained from the seed of Ricinus communis Linné (Fam Euphorbiaceae)

❑ Brand: Emulsoil; Neoloid; Purge

❑ Small bowel irritant laxative

Castor Oil

MOA: Hydrolyzed to ricinoleic acid (upper GIT)which stimulates water secretion in the intestine while decreasing glucose absorption