Pharma GIT

non pharma ulcer treatment

1. Avoid: ▪ Spicy Food ▪ Smoking & Alcohol (SPIRITO) ▪ Stress Sedatives (BZDs) ▪ Steroids & NSAIDs ▪ Stir-fried food, Strong Coffee & Tea

2. Small frequent Meals (esp. In DU).

3. Milk & Healthy Fat → Good for some pts

Acid secretion Inhibition:

a. Neutralizing HCl (Antacids)

b. Anti - secretory drugs (H2 blockers, PPIs & K+ competitive acid-blocker ‘’PCAB’’)

Mucous protection formation:

a. Sucralfate

b. Colloidal Bismuth

c. Carbenoxolone

d. PG analogue

• H – Pylori Infection Eradication

1. Antacids

• Symptomatic Relieve ONLY

• MOA: Alkaline → Neutralizes HCl

• Includes:

1. NaHCO3 (Fawar Fawakih) 2. CaCO3 (Rennie) 3. Al + Mg Salts (Maalox)

NaHCO3

Fast effect Systemically absorbed to blood

Salt & Water retension NaCl + CO2

SEs: 1. Bloating & Belching (CO2) 2. CI in HTN & HF 3. Metabolic Alkalosis

CaCO3

Slower Absorption 50% systemically Absorbed

SEs: 1. Bloating & Belching (CO2) 2. Stones & Milk Alkali Syndrome 3. HCl Rebound 4. M. Alkalosis

Al-Mg salts

Slow absorption Locally ( Not systemically absorbed)

SEs: 1. Al: CONSTIPATION 2. Mg: DIARRHEA So, both COMBINED

antacids general side effects

1. Bowel Disturbance:

2. Rebound Acid: Ca⁺ may Inc Gastrin → ↑ HCl

3. Excess Cation: Na⁺, Ca⁺, Al & Mg

4. Metabolic Alkalosis:

5. Chelations: prevent other drugs’ Absorption, (So give 30 minutes gap)

2.Anti - Secretory Drugs; enzepine m1 blockers

• Pirenzepine & Telenzepine. • Least Anti-secretory drug (only 10% of Basal HCl secretion) • SEs: Atropine SEs & ↓↓ GER

H2 Blockers idine anti secretory

Effective, 75% of HCl secretion of both types is decreased (Basal & Stimulated) o Well & Rapidly absorbed from GIT o Nocturnal time is the best time. o

Lafutidine → Dual mechanism → Mucosal defense

Clinical Uses: 1. Peptic Ulcer (GU & DU) & Stress Ulcer: IV before surgery 2. GERD 3. Zollinger Ellison Syndrome (Gastrinoma): Symptomatic relieve

H2 Blockers side effects

1. Diarrhea & Constipation.

2. Anti-androgen Effect:

3. D-D interaction: CytoP450 Except: Nizatidine

4. CNS Effect: headache, hallucination, agitation (esp. IV or high doses or extreme aged pts) 5. Reversible Hepatitis & Bone marrow Depression (VERY RARE)

PPI epreazole

• Pro-drugs → active metabolites are formed rapidly by HCl in the gastric cells & crypts (NOT in lumen), so the drug is coated to be protected.

• Omeprazole & NaHCO3 is a combination for faster absorption.

• Irreversibly Inhibit proton pump enzyme

• The Best group (Effective up to 95% of both basal & stimulated HCl)

• Orally & IV (esomeprazole or pantoprazole)

• 1 hour before meals or food (50% bioavailability) → Dexlansoprazole is an exception (taken without regard to food)

PPI clinical use

1. Ulcers: peptic, NSAIDs, Stress 2. GERD & Erosive esophagitis. 3. H – pylori eradication 4. Zollinger Ellison Syndrome

K+ Competitive Acid-Blocker (PCAB)

• Vonoprazan: FDA Approved in 2022

Helicobacter pylori eradication

Voquezna triple Rx = Vonoprazan + Amoxicillin + Clarithromycin

sucralfate

• Sulfated Sucrose with Al salt.

• Needs HCl to act

• MOA: 1. ↑↑ Mucous Layer & ↓↓ HCl penetration 2. ↓↓ back diffusion of H⁺ 3. ↓↓ Pepsin Secretion (pepsin may break the ulcer lesion) 4. ↑↑ PG synthesis from adjacent healthy cells • SEs: Al is absorbed (5%) leads to: Renal damage & Constipation

C.V I: Not effective when given with PPIs??

C.V II: SAFE in PREGNANCY

colloidal bismuth

Same as Sucralfate Except: 1. Cytotoxic to H-Pylori

2. Encephalopathy instead of Nephropathy

3. May cause blackness in teeth & stool (result of Bismuth Sulfide from Bacteria)

carbenoxolone

From liquorice

• Steroidal structure

• MOA: 1. Mucous production away from ulcer lesion 2. ↑ Blood flow → ↑ healing 3. ↑ PG endogenously

• SEs: Salt & water retention So, CI in Edema & HTN (Rx with DIURETICS EXCEPT??)

Misoprostol (PGE1

MOA: 1. ↓↓ HCl Secretion 2. ↑ ↑ Mucous secretion 3. VD

• SEs: Diarrhea & ABORTION

H pylori eradication

➢ P C A (PPIs + Clarithromycin + Amoxicillin) or

➢P C M (PPIs + Clarithromycin + Metronidazole)

➢ Voquezna triple Rx = Vonoprazan + Amoxicillin + Clarithromycin

• Quadruple Rx (COMMON): ➢PPIs + Bismuth + Metronidazole + Tetracycline

file 2

relax LES

β blockers, α blockers, Muscarinic Blockers, CCBs, Steroids, NSAIDs,

GERD drug therapy

2. Drug Therapy:

a. HCl: H2 blockers & PPIs (Before sleep & dinner).

b. Antacid: Specific for GERD GAVISCON

c. Prokinetics: drugs that Inc motility of Upper GIT → Inc Gastric evacuation:

1. D2 blockers: Metoclopramide + Domperidone

2. Erythromycin: Motilin Receptor Activation (Very rapid Tolerance, So IV once before endoscopy)

hepatotoxic drugs

Antibiotics Fluoroquinolones

Antiepileptics Carbamazapine

③ NSAID, Acetaminsphen

④ antihyperlipidemia > Statins

varices treatment

1. Fresh Blood transfusion

2. ↓↓ HCl to avoid Stress Ulcer: PPIs IV

3. Terlipressin (Glypressin): Vasopressin analogue VC but more selective to V1 in GIT.

4. Octreotide (Somatostatin SST): Indirect VC & Dec in mesenteric blood flow.

5. Endoscopic Sclerotherapy

6. TIPS = Transjagular-Intrahepatic Porto-systemic Shunt. SE: Inc Risk of Encephalopathy

7. Liver Transplantation

Treatment of Hepatic Encephalopathy

1. Diet: ↓↓ in Protein → ↓↓ in ammonia

2. Lactulose (Non Digestible): Acetic Acid + Lactic Acid → ↓↓ PH: Acidic Media: a. Kills Bacteria → ↓↓ in ammonia b. NH3 + H⁺ → NH4 c. Osmotic Laxative: ↑↑ Water secretion that washes the bacteria and its toxins.

3. Antibiotics: a) Neomycin (locally but...) b) Rifaximine (locally so less SEs)

4. Liver Transplantation:

Pancreatic Enzyme supplement

Used in: Pancreatitis, Cystic Fibrosis & Pancreatectomy.

• Pancrelipase: Lipase + Proteolytic Enzymes

• Coated tablets: NO need for PPIs.

• Non coated tablets: PPIs needed to avoid gastric inactivation.

• Swallowed not Chewed: to avoid Oropharyngeal Mucositis

SEs: 1. Diarrhea & Abdominal Pain 2. Renal stones (Hyperuraecemia)

Bile Acid Drugs

• Bile acid & their conjugates (Taurine & Glycine) are important for: 1. Inhibition of secretion & Excretion of Cholesterol. 2. Emulsification & absorption of lipid & Fat – soluble Vitamins.

• Ursodiol Clinical Uses: 1. Oral litholysis: ↓ cholesterol content of the bile → ↓ lithogenicity of gall & prevents gall stone formation. 2. To dissolve gall stones in pts who refuse cholecystectomy or not eligible for surgery

• It may cause Diarrhea

Gas & Flatulence Rx:

• Simethicone, a mixture of siloxane polymers stabilized with silicon dioxide, is an inert nontoxic, insoluble liquid.

• Attaches to the bubble surface with an antifoaming effect.

• Simethicone is available in chewable tablets, liquid-filled capsules, suspensions, and orally disintegrating strips, either by itself or in combination with other OTC medications, including antacids

lecture 3

Anti-Emetic Drugs

1. M1 blockers: Atropine & Hyoscine

2. H1 blockers: Diphenhydramine, Cyclizine,....

3. 5HT3 Blockers: Ondansetron, Granisetron,....

4. D2 Blockers: Metoclopramide & Domperidone

5. CB1 AGONIST: Nabilone & Dronabinol

6. NK1 Blockers: Aprepitant

7. OTHERS: Pyridoxine, BZD, Corticosteroids

Antihistamine Drugs (H₁ Blockers)

• Cyclizine, Promethazine, Diphenhydramine

• SEs: SEDATION & DRY MOUTH

➢C.V I: Promethazine is CI in children ˂2years. ➢C.V II: Cyclizine is CI in pregnancy & Breastfeeding.

5HT3 Antagonists

Ondansetron • Granisetron & Tropisetron

• Selective on 5HT3 peripherally (Intestine Vagal nerve) & Centrally

• Orally & IV

• Renal & Hepatic Excretion

• SEs: Well tolerated but: Headache, Dizzness & Constipation

D2 clinical uses

1. GERD & Bile Reflux

2. Diabetic Gastro-paresis

3. Before Endoscopy:

4. Before Emergency Surgery: aspiration

5. Anti-Emetic

metaclopramide se

dyskinesia, akathisia, dystonia

Domperidone

• Does not cross BBB

• D2 blocker Peripherally (Upper & Lower GIT)

• SEs: Prolonged QT Interval ??

CB1

• Cannabinoid Agonists

• Active Chemical in Marijuana

• 1 st pass Metabolism

• Renal & Hepatic Excretion over days & weeks.

• SEs: Euphoria, Sedation, Hallucination, Drug Abuse, orthostatic hypotension, ↑ Appetite

NK1 Blockers

• Aprepitant (Oral)

• Fosaprepitant (IV) → Aprepitant by Liver

• Highly Selective NK1.

• Centrally in Area postrema

• Used in combination with Ondansetron & Dexamethasone.

• SEs: Fatigue & Dizzness

• D-D Interaction: ↓↓ Metabolism of some cancer chemotherapy drugs (Vincristine, ....)

BZD

• In stress – related Vomiting

• Also in Severe - Refractory vomiting

• In combination with Ondansetron & Cortisone

• Lorazepam & Diazepam

Glucocorticoids

• Dexamethasone & Prednisolone

• Unknown Mechanism

• In combination with other drugs.

• MAINLY in Cancer Induced Vomiting

used for motion sickness

promethazine, scopolamine, meclizine

Hyperemesis Gravidarum

• 4-20 weeks gestation

• 3 Theories: 1. Hormonal: ↑ hCG, Estrogen & Progesterone 2. Glutamate vs GABA: ↑ excitatory 3. Psychological Factor

• Rx: 1. Pyridoxine (B6) 2. H1 Blockers (avoid Cyclizine) 3. Ondansetron 4. Cortigen (Vitamin B6 & Cortisone)

Post-operative Vomiting

• Most common in children & women • Etiology: 1. Anesthesia & its drugs: Emetogenic 2. Tissue Injury • Rx: 1. Ondansetron 2. Metoclopramide

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Management of Acute Diarrhea

1. Correction of fluid & Electrolytes disturbance

2. Nonspecific Drugs:

3. Specific Rx → Causative Rx

4. Diarrhea + Vomiting → Antiemetic drug

5. Diarrhea + colon Spasm → Spasmolytic drug

Management of Chronic Diarrhea

1. Correction of fluid & Electrolytes disturbance

2. Specific Rx → Causative Rx

Correction of fluid & Electrolytes disturbance

• Mild → Oral ORS (Na⁺, K⁺, Mg, Glucose)

• Severe & Dehydration: IV → After PH, Na⁺& K⁺ Investigations → IV saline: Glucose Na⁺ (Iso, hypo, hypertonic) Ringer Lactated

adsorbents

Diosmectite, kaolin, pectin

absorb water and thicken stool

diosmectite absorbs bacteria also

Bismuth Salicylates

1. Covers the exposed inflamed intestine

2. Anti – inflammatory & Anti – microbial effect

• Used in: Traveler’s or GE diarrhea.

• SEs: Black Stool & Rey’s Syndrome (Rare)

Anti – cholinergic Drugs:

• M3 blockers: anti-diarrheal + Antispasmodic

• Meth-scopolamine & Hyoscyamine

Nonspecific Drugs; 2.4. Octreotide

• Somatostatin is a peptide that is released in GIT & pancreas from different cells & nerves. • Octreotide is a longer acting analogue of SST.

• Physiological effects: ➢ Inhibits secretion of several exocrine & endocrine hormones including: gastrin, motilin, VIP, glucagon, growth hormone (GH), insulin, 5-HT. ➢ Decreases intestinal fluid & pancreatic secretion. ➢ Slows GIT motility & inhibits gall bladder contraction.

octreotide

• Clinical uses ➢Secretory diarrhoea that induced by carcinoid tumours or VIPomas. ➢In Acromegaly

• Side effects ➢Impaired pancreatic secretion leads to steatorrhea (fat soluble vitamin deficiency). ➢May cause GIT upsets ➢Gallstones formation ➢Hyperglycaemia & less frequently hypoglycaemia

Nonspecific Drugs; 2.5. Opioids Agonists

• Loperamide & Diphenoxylate (Meperidine)

• Loperamide does not cross BBB whereas Diphenaxylate very few amount crosses BBB

diphenoxylate usually combined with atropine

Specific Drug used non-specifically; Bile Acid Sequestrants (Resins)

• Cholestyramine & Colesevelam

• In bile acid Malabsorption: resection of distal ileum or Crohn’s Disease

• In LDL treatment

• SEs: Bloating, Flatulence & Constipation

• C.V: D – D Interaction with Cholestyramine but not with Colesevelam.

Probiotics

• The GIT contains many Normal microflora necessary for health GIT.

• Alterations in the balance or composition of the microflora (leaving C. Difficile alone) by broad spectrum antibiotics may cause diarrhea.

• Probiotic have shown some usefulness in acute diarrheal conditions, especially antibioticassociated diarrhea.

• Lactobacillus GG is an example of microflora

IBD Treatment: 1. Aminosalicylates (5 ASA)

• Locally not Systemically (absorbed in intestine)

So: a. AZO Bond preparations: ➢ Sulfasalazine: 5-ASA + Sulfapyridine by AZO bond.

Uses: UC & Rheumatoid Arthritis

SEs: Sulfapyridine SEs: Bone marrow depression & folic anemia ➢ Olsalazine: 5-ASA + 5-ASA

IBD Treatment: 1. Aminosalicylates (5 ASA)

b. Mesalamine Formulations:

1. Pentasa: 5 - ASA TIMED release microgranules into small Intestines (Crohn’s).

2. Asacol: PH – Resin at 6-7 PH → distal ileum & colon

3. Rowasa: Enema in proctosigmoiditis

4. Canasa: Suppository in proctitis

IBD Treatment: 2. Corticosteroids

• In moderate or severe active IBD

• Prednisone & prednisolone are used commonly

• Local hydrocortisone (Enema, Foam, Supp.) in the sigmoid & rectum.

• Budesonide available in 2 forms: 1. Entocort: PH - controlled at 5.5 in distal ileum & proximal colon 2. Uceris: PH - controlled at 7 in Colon.

IBD Treatment: 3. Immunosuppressants:

• Azathioprine & 6 – mercaptupurine

• In Induction & maintenance of Remission

TNFa inhibitors

always end in mab

IBD Treatment: 5. Anti – Integrin therapy:

• Vedolizumab

• In induction & maintenance of Remission in IBD

• May cause hypersensitivity Reaction

IBD Treatment In Pregnancy

• Mesalamine & Cortisone are FDA Cat. B

• Certulizumab Pegol is quite SAFE

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1. Bulk Laxatives

• Fibres, Bran, Methylcellulose, Fybogel

osmotic laxative

lactulose, glycol, epsom salt

Irritant (Stimulant)/ Anthraquinones

• Senna, Bisacodyl (Diphenylmethane),Castor Oil

• MOA: 1. Direct stimulation of mesenteric nerves → ↑ Intestinal transit 2. Local Inflammation → Edema → ↑ WATER