pharm_gi_antihist_5ht

INH MAST CELL DEGRANULATION

• INH INC IN INTRACELLULAR Ca RELEASE BY IgE BRIDGES
• -----------------------------

• DEGRAN VIA IP3 RECEPTOR
• --------------------------------

• THERA
• 1. inhalation for asthma

2. ophthalmic for allergy

3. nasal for allergy

4. oral for food allergy

Inhb mast cell degran by preventing incr in intracellular Ca++ conc caused by formation of IgE bridges. SAME AS CROMOLYN SODIUM

USED FOR OPHTHALMIC ~ ALLERGIES

OLOPATADINE ALSO BLOCKS H1 RECEPTORS

H1

• INC IP3 --> INC INTRACELL Ca --> CONTRACTION OF:
• 1) POSTCAP VENULES --> LEAK PLASMA --> EDEMA
• 2) BRONCH SMOOTH MUSC
• 3) GI SMOOTH MUSC --> CRAMP & INVOL SHIT

• RESISTANCE ARTERIOLES:
• SYNTH NO --> GUAN CYCLASE --> INC cGMP --> VASODILATION --> DEC TPR --> HYPOTENSION --> REFLEX TACHYCARDIA
• --------------------
• H2

ADEN CYCLASE --> INC cAMP --> VASODILATION --> DEC TPR --> HYPOTENSION

• GASTRIC PARIETAL CELL --> INC cAMP --> INC Ca --> INC ACID SEC, PEPSIN & INTRINSIC FACTOR
• ---------------------------

• H1 = RAPID ONSET OFFSET
• H2 = SLOW ONSET OFFSET

EPI

• H1 BLOCKER -- DIPHENHYDRAMINE
• H2 BLOCKER -- CIMETIDINE

• BROMPHENIRAMINE
• CHLORPHENIRAMINE
• DIPHENHYDRAMINE*
• DIMENHYDRINATE* -- tx motion sick & vertigo (meniere)

*ALSO BLOCK ACh & ARE ANTI-EMETIC

LORATADINE (CLARITIN)

CETIRIZINE (ZYRTEC) -- ACTIVE MET OF HYDROXYZINE

• HYDROXYZINE
• CYPROHEPTADINE

ALSO BLOCK ACh AND ARE ANTI-EMETIC

FEXOFENADINE (ALLEGRA)

• DESLORATADINE (CLARINEX)
• --ACTIVE METABOLITE OF LORATADINE (claritin) CONVERTED BY LIVER

1. Prevents constrictor response to histamine at most smooth muscle (bronchial & GI)

2. Inhb pain & itching caused by histamine at sensory nerve endings

3. Antagonize incr in capillary permb

1. Depresses CNS (sedation, etc)

2. Inhb nasopharyngeal secretion

3. Inh motion sickness (action in vestibular nuclei)

4. Anti-emetic effect!!!

DIPHENHYDRAMINE

TOPICAL ANESTHETIC --> Blocks Na+ ch in aff sensory pain fibers

PD --> Tx central motor d/o caused by antipsych drugs

H1 & ACh BLOCKER

• i.m. or rectal suppository
• (NOT i.v.)

Treatment: motion sickness*

Pre-op sedation

Sedate anxious pts

Prevent post-op n/v

• Treat n/v asst’d w/ GI infxn
• (via rectal suppository)

• Allergic dermatoses
• (e.g. poison ivy, poison oak)

• Acute hypersensitivity rxns
• --------------------------------

TOX

• CNS DEP OR EXCITATION
• DIZZYINESS & TINNITUS
• MUSCARINIC BLOCKER
• (DRY MOUTH, BOWEL STASIS, GLAUCOMA)

H1 BLOCKERS -- NON-SEDATING

LORATADINE

• CETIRIZINE
• FEXOFENADINE

H1 BLOCKER -- DRAMAMINE

"LESS SEDATING" THAN DIMENHYDRINATE

• 1. Promethazine
• 2. Fexofenadine
• 3. Olopatadine
• 4. Hydroxyzine

REST ARE CLASS B

• 1. CNS depression – Anit-musc effect (esp w/ ETOH &
• other drugs → DEC psychomotor performance):
• · Decr alertness
• · Slow rxn times
• · Somnolence

2. Paradoxical CNS excitation in kids & older adults

3. Dizziness & tinnitus

• 4. Anti-Muscarinic effects (esp in older pts):
• · Dry mouth
• · Dry respiratory tract (cough poss)
• · Urinary retention if BPH
• · Exacerbate glaucoma

5. Torsades de pointes

~TIDINE

• FAMOTIDINE
• RANITIDINE
• CIMETIDINE

Inhb both basal & nocturnal acid secretion

• Inhb secretion of gastric acid induced by:
• · Food
• · Coffee
• · Insulin
• · Muscarinic agonists
• · Incr vagal nerve actvy
• · Histamine agonists (betazole)
• · Gastrin (pentagastrin)

• Little physio effects on H2 receptors
• elsewhere in body (mainly inhb acid secretion)
• -----------------------

THERA

1. Gastric & duodenal ulcers

2. Prophylaxis of stress ulcers (trauma, burns)

3. GERD

4. Anaphylaxis

5. Viral warts & other skin lesions (imm systm) – clinical efficacy is anectdotal

PREGNANCY CATEGORY B

All cause n/v, diarrhea, & skin rash

• CIMETIDINE ONLY
• 1. Inhb hepatic CYP450
• · Prevents estr breakdown by CYP450 → gynecomastia, azoospermia & decr libido in ♂
• (Anti-Androgenic effects)

• · Incr t1/2 of other drugs
• (β-blockers, warfarin & diazepam)

• 2. May produce CNS effects
• (from mental confusion to overt psychosis) in:
• · older pts
• · pts w/ prior hx of psychiatric disease
• * pts receiving large doses for a long period

• VASCULAR VASODILATION
• --STIM OF VASC SMOOTH MUSC
• --STIM ENDOTHELIAL CELLS TO MAKE NO
• --PREJUNC INH RELEASE OF NE FROM SYMP FIBERS

• 5-HT1B
• --CONSTR LRG EXTRACEREBRAL ARTS AND ART-VEN ANASTAMOSES
• --CONST CORONARY ART IN Pts w CAD!

• STIM 5-HTB/D
• --INH RELEASE OF PROINFLAM PEPTIDES FROM TRIGEMINAL NERVE

• CNS
• --5HT1A IN HIPPO HYPOPOLARIZES BY OPEN K+ CHANNELS
• --BUSPIRONE

INC IP3 AND INTRACELLULAR FREE Ca++

• PERIPHERY
• --VASOCONSTR
• --PGI2 SYNTH BY VASC ENDOTHEL CELLS
• --PLATELET AGG BY AMPLIFYING TXA2, EPI, THROMBIN
• --BRONCHOCONSTR
• --INC INTESTINAL MOT AND SEC

• CNS
• --DEPRESSION (no stim)

• LUNGS
• --BRONCHOCONSTR IN ASTHMATIC Pts

EMESIS!

• MOTOR
• --STIM OF PREJUNC 5HT3 INC ACh RELEASE FROM INTRAMURAL NEURONS OF GI

• SENSORY
• --BEZOLD-JARISCH CHEMO REFLEX
• (shallow breath and bradycardia)
• --AFFERENT PAIN FIBERS
• --VISCERAL SENSORY FIBERS
• (vagal to chemo trigger zone ctz)
• --EMESIS BY DIR STIM OF CTZ
• --DEC BP
• --INC PAIN & ITCHING IN SKIN

• BLOCKERS
• --METOCLOPRAMIDE
• --ONDANSETRON

• MOTOR
• --STIM AT PREJUNC INC ACh RELEASE IN GI

• BLOCKER
• --METOCLOPRAMIDE

GI VERY SENSITIVE TO 5HT

ACh RELEASE BY VAGUS STIMS 5HT RELEASE IN GI

• RISE IN LUMINAL PRESSURE INC RELEASE OF 5HT FROM ENEROCHROMAFFIN CELLS
• --ACTS 5HT2&3 TO INC TONE AND MOT
• --LOWERS THRESH TO ACT PERISTALTIC REGLEX
• --ENHANCES ACh RELEASE

TUMOR OF ENTEROCHROMAFFIN CELLS

SEC 5HT

BRONCHOSPASM BY 5HT2 REC

GI CRAMPING AND DIARRHEA BY 5HT2 REC

STEATORRHEA

UNUSUAL FLUSHING OF SKIN ON TRUNK & NECK BY 5HT2

GREAT INC IN 5HT USES SO MUCH TRYPTOPHAN FOR SYNTH --> NIACIN DEC --> PELLAGRA

Tx w CYPROHEPTADINE or OCTREOTIDE

5HT AG

5-HT1B/1D agonist (+)

1. Cranial vasoconstriction

2. Periph inhb release of inflam peptides from trigeminal nerve

• 3. Central inhb of 2nd-order neurons in trigemino-cervical complex
• ------------------------------

PHARM

• 1. Cerebral blood vessles:
• --Constrict large extracerebral arteries & A-V anastomoses.
• --Effects poss NOT related to efficacy of migraine
• Rx

• 2. Stim of pre-synaptic receptors on trigeminal
• nerve
• → inhb release of pro-inflam neuropeptides which
• stim sensory pain receptors & cause vasodilation & neurogenic extravasation of plasma

• 3. peripheral blood vessels:
• --Slight vasoconst in nL blood vessels
• --Cause arterial spasm in patients with CAD = MI

USE FOR HEADACHES

• 1. Migraine headaches
• -- Rapidly relieves headache & other symptoms
• -- Sumatriptan has short t1/2 (2h) → headache may reoccur after single dose therapy
• -- If pts does NOT resp well to init dose → NO bene to subsq doses

• 2. Cluster headaches
• --Significantly decr severity of pain
• --Also decr functional disability & ipsilateral conjunctival
• injection
• -----------------------------

ADVERSE

1. Rebound headache

2. “Atypical” sensations: tingling, warm/hot, etc.

3. Dizziness & vertigo

4. ­ SBP/DBP

Contraindications:

5. **Severe coronary vasospasm in pts w/ signs & symptoms of CAD or myocardial ischemia

• Do NOT use w/ ergot-type drugs or w/in 24 hours
• of use of any ergot-type drug

5-HT4 agonist (+)

• 5-HT3 antagonist (-)
• (vagal afferent fibers & CTZ)

• D2 dopamine antagonist (-)
• (CTZ)

1. GI stim: 5-HT4 agonist → Enhance ACh release from cholinergic neurons innervating LES & stomach

• 2. Anti-emetic: Block 5-HT3 (Vagal & CTZ) * D2 (CTZ)
• ----------------------

PHARM

• 1. Enhance esophageal clearance of gastric acid
• 2. Incr LES pressure
• 3. Accelerate gastric emptying
• 4. Decr small bowel transit time

(PRO-KINETIC effects like 5-HT4 agonists cisapride & tergaserod)

• 1. Incr LES pressure in pts w/ GERD
• (including infants)
• 2. Accel gastric emptying & incr LES pressure prior to surgery
• 3. Clear stomach & duodenum of food prior to endoscopic exam

4. Enhance gastric emptying in pts w/ diabetic gastroparesis

5. Prevent n/v in pts w/ peptic ulcer, ulcerative colitis & gastric cancer

• Prevent n/v in pts receiving chemo or radiation therapy for cancer
• -----------------------

ADVERSE

1. sedation & fatigue

2. Altered GI absorption of other drugs

• 3. Blockade of central D2 dopa receptors:
• --Incr plasma PRL → (♀) galactorrhea & amenorrhea, (♂) gynecomastia

--Dystonias*, Parkinson’s disease* or tardive dyskinesia, akathisia (esp younger adults & children)

5HT3 BLOCKER

GI -- USED WHEN RADIATION STIMs RELEASE OF 5HT

-setron > metoclopramide b/c does NOT cause acute dystonia or akathisia

--Well-suited for younger adults & children (i.e. groups most likely to get dystonia w/ metoclopramide)

--Combo of dexamethasone (corticosteroid) + odanset more effectv > either drug alone

2. Post-op n/v

3. “Morning sickness” n/v in preg ♀

• VAGAL NERVE ENDINGS & CTZ (INH N/V)
• --------------------

ADVERSE

Constipation

Pregnancy Category B: safety of use in pregnant women has not been established

Little information is available concerning dosage regiments for children less than 3 yrs old

Enters CNS.

5-HT1 & 5-HT2 antagonist (-)

• H1 & muscarinic antagonist (-)
• -------------------------------

THERA

• Allergic diseases (prim Anti-Hist effect)
• --Allergic rhinitis
• --Conjunctivitis
• --Pruritic dermatoses
• --Prophylaxis of cold urticaria

• Stim appetite (MOA unknown)
• --children & adults
• --Produces variable wt gain/linear growth in infants/children
• --Effectv in some anorexics

• Migraine headache (5-HT­­1???)**
• --Prophylaxis decr intensity/freq of attacks

• Carcinoid syndrome (5-HT1 & 5-HT2)**
• --Decr GI hypermotility
• --Decr hypersecretion
• --Decr diarrhea

Post-gastrectomy dumping syndrome: Partially relieves GI symptoms

PTSD: Soporific agent to prevent nightmares

• MOA
• --Enters CNS
• --5-HT1 & 5-HT2 antagonist (-)
• --H1 & muscarinic antagonist (-)
• -------------------------

S/E result from blockade of muscarinic receptors:

• Exacerbation of:
• --Angle-closure glaucoma
• --BPH
• --GI or GU obstruction

CNS depression (additive w/ other drugs)

Drowsiness& sedation

Paradoxical restlessness & excitation in children

Dry mouth, nose & throat

• Attacks of intense headache
• 1. Often unilateral
• 2. Often exacerbated by normal physical activity
• 3. Asst’d with:
• --anorexia
• --n/v
• --photophobia
• --phonophobia
• Lie “dark quiet room”

May last 4 – 72 hours

• Etiology Theory 1:
• Something → initial cerebral vasoconstriction → oligemia → visual aura

VasoC followed by excessive dilation of extracerebral (meningeal & dural) arteries & arteriovenous (A-V) anastomoses.

Vasodilation → headache

• Etiology Theory 2:
• Release of neuropeptides (VIP, CGRP, etc.)
• from trigeminal nerve endings →

sterile inflam rxn around sensory nerves & extravasation of fluid into mengingeal membranes.

Rx: -triptans

Named for tendency to occur in clusters of time.

• Deep non-throbbing pain, usually involving 1 eye &:
• --Adjacent temple
• --Cheek
• --Forehead
• “Pace the floor in search of relief”

Same part of face or head is involved in every headache

Eye is watery & red w/ partial ptosis (even miosis)

Ipsilateral nostril is congested or hypersecretory

Typically occur during sleep & last 0.5 – 2 hours

Poss in daylight hours, esp in pts drinking ETOH

Remission of headache → exhausted sleep → another attack sometime later

1-4 headaches/day for several week/months before the headaches cease then reappear months later.

~ ♂ Begins in 30s – 40s

• Rx:
• -triptans
• --Inhalation of O2 is effectv Rx & used for home therapy.

Resp poorly to ergotamine compounds.

EMETIC AGENT

Derived from roots & rhizomes (underground stems) of Cephaelis ipecacuanha (“duck penis”)

Stim CTZ

• Causes local irritation of stomach & upper duodenum
• --------------------

PHARM

Clears contents of stomach & upper duodenum

• Effective after overdose of anti-emetic drugs
• (anti-cholinergic: anti-histamines, phenothiazines)
• ----------------------------

THERA

• Oral ingestion of toxic compounds
• (cleaning products or other chem., alcohols, plants, pesticide, etc.)

**Poisoning w/ acetominophen, aspirin, or iron supplements in children.

• Although safefor use at home, best to Rx unwanted oral ingestion in children w/ a trip to ER for gastric
• lavage.
• -----------------------------------------

ADVERSE

Diarrhea

Temporary drowsiness

Sedation

Lethargy

Fever & diaphoresis

Chronic use (bulimia) → emetine-induced cardiomypoathy

• Contraindications for EMESIS:
• (not on exam)

1. Petroleum distillates can cause chem “penumonia” (pneumonitis)

2. Corrosive chem (e.g. acids, bases) poss further damage stomach & esophagus

• 3. CNS depressants can obtund pt
• who then aspirates vomit

• 4. Emesis can ppt seizures in pts poisoned with CNS
• stimulants

• SCOPOLAMINE
• DIMENHYDRINATE
• DIPHENHYDRAMINE
• MECLIZINE
• PROMETHAZINE
• METOCLOPRAMIDE
• ONDANSETRON
• DEXAMETHASONE
• DRONABINOL
• APREPITANT

ANIT EMETIC

• ANTI CHOLINERGIC ONLY
• --BLOCKS MUSCARINIC REC IN VESTIBULAR MUC AND RETICULAR FORMATION

PROPHYLAXIS MOTION SICKNESS

• ADVERSE
• --XEROSTOMIA
• --SEDATION
• --PROBS CONCENTRATING
• --AMNESIA
• --FATIGUE

ANTI EMETIC

THC -- MOA UNKNOWN

ANTI EMETIC -- MOA UNKNOWN

STEROID

DEXA TEST FOR HYPERCORTISOL

ANTI EMETIC

NEUROKININ-1 REC ANTAG

BLOCKS ACT OF SUBSTANCE P AT NK-1 REC IN CNS

• PROPHYLAXIS:
• --SCOPOLAMINE
• --DIMENHYDRINATE
• --MECLIZINE

• Tx:
• --PROMETHAZINE

• ONDANSETRON
• METOCLOPRAMIDE
• DIMENHYDRINATE
• MECLIZINE

PROMETHAZINE

DIMENHYDRINATE & MECLIZINE

MENIERE'S Dz

INC GI MOTILITY

INC RELEASE OF ACh BY STIM PREJUNC 5TH4 REC ON CHOLINERGIC FIBERS

INC LES PRESSURE

GASTRIC EMPTYING

• ANTEGRADE MOV OF FOOD
• ----------------------

• THERA
• --PRIOR TO ENDOSCOPY OR SURG
• --ESOPH REFLUX
• --POST-OP EMESIS
• --DIABETIC GASTROPARESIS

BULK LAXATIVE

• Consists of indigestible components of cereal bran,
• fruits, and vegetables

• Attracts H2O to form a hydrogel w/ feces in
• large bowel

(hydration incr bulk by 30x)

Bowel distention → Actv stretch rec → Incr peristalsis via local reflexes

• After 1-3 days of ingestion, methylcellulose
• softens stool & incr:
• ·
• Volume of feces
• ·
• H2O content of feces
• ·
• Colonic
• transit rate
• ·
• Freq of defecation
• --------------------

BULK laxative: NO laxative dependence

Tx Constipation & IBS

BULK LAXATIVE

SIMILAR MOA AS METHYLCELLULOSE

• Attracts H2O to form a hydrogel w/ feces in
• large bowel

(hydration incr bulk by 30x)

NO laxative dependence

• Tx
• --Constipation
• --IBS

BULK LAXATIVE

SIMILAR MOA AS METHYLCELLULOSE

• Hydrophilic, polyacrylic resin that can absorb 60x its
• weight in H2O

• Draws H2O into bowel to expand bulk of
• feces → actv local peristaltic reflexes

NO laxative dependence

• Tx
• --Constipation
• --IBS

• BULK LAX
• LACTULOSE
• DOCUSATE

LAXATIVE -- SYNTHETIC DISACCHARIDE

NOT absorbed by GI tract

Bacteria in bowel degrade lactulose → into lactic, acetic & organic acids

→ Exert an osmotic effect drawing H2O into colon

• → incr bulk of feces
• --------------------------

PHARM

Incr peristalsis via local reflexes (bowel distention)

• Acidification of colonic contents causes ammonia in blood to be trapped & excreted as ammonium ions
• -------------------------------

THERA

NO laxative dependence

Constipation

• ***Portal-systemic encephalopathy of hepatic
• disease

LAXATIVE

STOOL SOFTENER

Emulsifying action softens stool.

• An anionic surfactant:
• Detergent action decr surface tension of feces to allow penetration of H2O

IRRITANT purgative

• Irritant action → Incr accum of H2O & electrolytes in lumen of colon & enhances colonic peristalsis by
• actvn of local reflexes

• Produces soft semi-fluid stool w/in 6-12 hrs of p.o.
• dosing

• Suppositories exert purgative effect w/in 15-60 min
• ----------------------------------

THERA

• IRRITANT purgative agent selective
• for colon

Cathartic agent

• Evacuate bowel prior to radiological or sigmoidscopic exam (eliminates shadows in large bowel on imaging)
• ---------------------------

• ADVERSE (BAD!)
• --GI colic
• --Laxative dependence
• --Dehydration & electrolyte imbalance (K+ loss)

*Osmotic (saline) purgative agents

Hypertonic soln create osmotic forces

→ draws H2O into large bowel → bowel distention → actv stretch rec → incr peristalsis via local reflexes

PROD SOFT SEMI-FLUID STOOL 6-12 hrs AFTER p.o. DOSING

• Mg OH
• --CONSTIPATION
• --CATHARTIC AGENT
• --EVAC BOWEL PRIOR TO RAD OR SIGMOSCOPE

• PEG
• --EVAC BOWEL PRIOR TO RAD OR SIGMOSCOPE

• ADVERSE (BAD!)
• --GI COLIC
• --LAX DEPENDENCE
• --Dehydration & electrolyte imbalance

• EXPAND LRG BOWEL:
• --BULK LAXATIVES
• --DOCUSATE & LACTULOSE

• MUSCARINIC REC ANTAG INH SPASM
• --DICYCLOMINE

LACTULOSE

• DIPHENOXYLATE
• &
• LOPERAMIDE

SLOW COLONIC TRANSIT TIME BY DIRECT/INDIR INH OF GI MOT DESPITE INC GI MUSC TONE

BOWEL STASIS ALLOWS ABS OF FLUIDS & CONSOL FECES

• DIPHENOXYLATE
• --SUBTHERA DOSE OF ATROPINE SULFATE TO INH ABUSE

• LOPERAMIDE
• --DOC

RESIN ABS EXCESS H2O IN BOWEL

FORMS GEL WHICH HELPS CONSOL STOOL

ANTI-DIARRHEAL -- PEPTO BISMOL

• Anti-ulcer MOA:
• --Astringent action protects irritated GI mucosa by contracting surface layer of mucus

--Demulcent action coats irritated mucosa

--Incr PG synth & alkali secretion

--Anti-proteolytic action counteracts breakdown of mucus coat by pepsin & H. pylori protease

--Antibacterial effects

• Anti-bacterial MOA
• --Binding to –SH groups of microbial proteins to destroy their 3o structure

--Prev microorg binding to epithelium by decr their adherent properties

• Bismuth NOT absorbed
• --But 90% of salicyclate absorbed

• Bismuth exerts a synergistic anti-bac effect when
• como w/ other antibiotics
• --------------------

• ADVERSE
• --Salicylate toxicity
• --Decr absorption of tetracyclines
• --Stool becomes radio-opaque (interferes w/ x-rays) & turns gray black **do not confuse w/ melena

"SAY CIAO TO ULCERS" ...?

CLARITHROMYCIN

AMOXICILLIN

OMEPRAXOLE

CURE DEPENDS ON ERADICATION OF H. PYLORI FROM GI TRACT

95% CURE RATE

DOC FOR GASTRIC & DUO ULCERS

• ANTI-ULCER
• --Antacids
• --Weak bases which are only slowly solb in H2O
• --Onset of acid-neutralizing action in 10-15 min
• --pH of gastric contents temply rises to 3-4

• Products vary as much as 6-7 fold in their acid neutr
• capacity

• Liquids are more potent and effective than tablets.
• ------------------------

THERA

Gastric & Duodenal ulcers

• Prophylaxis of STRESS ulcers
• --Given via NG tube w/ gastric pH
• monitoring
• --Adjunctv Rx w/ H2 antag

Heartburn: symptom relief

• GERD: symptomatic relief
• ------------------------------

ADVERSE

Al cmpds: constipation

Mg cmpds: diarrhea

Al &/or Mg toxicity can occur in pts w/ renal insufficiency

Prevent GI absorption of tetracylcines, FQs, iron & isoniazid

~TIDINES

H2 BLOCKER

Incr gastric pH to 3-4

• Does NOT alter:
• --LES pressure
• --Gastric motility or emptying
• --pancreatic & biliary secretion

• Reoccurrence common after cessation
• of therapy
• --------------------

THERA

Gastric & Duodenal ulcers

Prophylaxis of STRESS ulcers

Given i.v. to keep gastric pH ≥4

Heartburn: symptom relief

GERD: inhb gastric acid secrtn

• Zollinger-Ellison syndrome
• --Drug tolerance develops
• --Failure rate of Rx 25-50%
• *triad of gastric acid hypersec, severe peptic ulceration, and non-beta cell islet tumor of pancreas (gastrinoma)
• -----------------------------------

ADVERSE

CIMETIDINE ONLY

• 1. Inhb hepatic CYP450
• · Prevents estr breakdown by CYP450 → gynecomastia, azoospermia & decr libido in ♂ (Anti-Androgenic effects)

· Incr t1/2 of other drugs (β-blockers, warfarin & diazepam)

• 2. May produce CNS effects (from mental confusion to overt psychosis) in:
• · older pts
• · pts w/ prior hx of psychiatric disease*
• *pts receiving large doses for a long period

ANTI-ULCER

PPI: proton pump inhibitors (-prazole)

• Inhb gastric H+/K+ ATPase → Acid sec blocked for 24-72 hrs
• ----------------------------

PHARM

Inhb basal & nocturnal acid secretion (& secrtn by all other stim)

Incr gastric pH to 4-5 → partially inhb absorpn of protein-bound B12 (but NOT → megaloblastic anemia)

Reactv incr in plasma gastrin conc in 5-10% pts but gastric enterochromaffin cell hyperplasia & carcinoid tumors have NOT been reported w/ prolonged use

• NO effect on LES pressure, gastric
• emptying or GI motility

Does NOT inhb release of IF from gastric parietal cells. (but ­pH partially inh absorption of protein-bound VB12)

• Does NOT cause megaloblastic anemia
• ----------------------------

THERA

• ***Zollinger-Ellison syndrome:
• --Occurs in 0.1% of pts w/ duodenal ulcers

• --Hypersecretn of gastrin fr a malignant pancreatic gastrinoma → hypersecrtn of gastric acid w/ ulceration &
• diarrhea

• --Rx Omeprazole
• § Larger dose
• § No drug tolerance
• § After healing, suppr therapy may be req
• § Heals ulcers in 30% of Z-E pts whose sympt are NOT
• controlled by Rx w/ H­2 anatag

Gastric & Duodenal ulcers

***DOC: GERD: inhb gastric acid secrtn (Rx Omeprazole)

ANTI-ULCER

Stable analog of PGE1

Stim PGE1 receptors on gastric parietal cells → inhb acid secretion

NSAID → decr of cycloprotectv PGE’s.

• Older pts asymptomatic (no pain or dyspepsia) → present to ER w/ severe GI bleeding
• ------------------------------

PHARM

Blocks incr in secretion caused by histamine, pentagastrin, aspirin, food & coffee

Protective effect on gastric mucosa*

• NO effect on:
• --basal acid secretion
• --LES pressure
• --Plasma gastrin
• --Gastric emptying
• --------------------

THERA

• **DOC: prophylaxis of NSAID-induced gastropathy
• --Prevents GI ulceration & bleeding
• --Does NOT affect pharm of NSAIDS
• --Only use in high risk pts, e.g. those age 60+, smokers or pts w/ prior hx of ulcers or GI bleeding

• **DOC: prophylaxis of corticosteroid-induced
• gastropathy
• --prevents GI ulceration caused by chronic
• immunosuppressive Rx
• ----------------------------------

• ADVERSE
• --Diarrhea in 5-15% pts
• --Potent abortifacient: DO NOT used in ♀ of child-bearing potential without adequate contraception

ANTI-ULCER

Coating agents

• H2O-insolb complex of aluminum hydroxide & sucrose
• sulfate which polymerizes (when pH < 4) →

• Forms a sticky viscous gel which forms a protective layer on the ulcer
• ----------------------

PHARM

Gel binds tightly to ulcerated gastric mucosa

Gel refluxed into lower esophagus aids in Rx GERD

Polymerized gel does NOT dissolve in duodenum (pH >7)

Polymerized gel poorly permb to HCl, pepsin, trypsin & bile salts

• Does NOT neutralize stomach acid or inhb
• acid secretion
• ------------------------------
• THERA

More effectv duodenal > gastric ulcers

Healing rate NOT affected by smoking

Prevents relapseB/c acid pH req’d for activn → do NOT use w/ H2 antagonists, omeprazole or antacids

Prophylaxis of NSAID-induced gastropathy: decr heartburn & epigastric burning/pain

• GERD
• --Protects irritated tissue & prev further damage
• --Healing in 90% of pts & is asst’d w/ restoration of motor func in lower esophagus

• **DOC: prophylaxis of STRESS ulcers b/c Rx
• w/o incr gastric pH
• --Erosion of GI tiss w/in 24 hrs in 90% pts w/ burns, shock, sepsis or severe trauma
• --Fr mucosal isch w/ normal acid secretion exacerbating erosion & ulceration
• --Superficial ulceration → Minimal blood loss tho poss substantial in time.
• ----------------------------

ADVERSE

• RARE but can cause:
• --Aluminum toxicity in pts w/ renal failure
• --Hypophosphatemia in chronic alcoholics

IBD

• CORTICOSTEROID
• --INH SYNTH OF PGs & LTs
• --LOCALLY ALTER IMMUNE FUNC

• GIVEN VIA
• --ENEMA
• --FOAM
• --SUPPOSITORIES
• --p.o. FOR EXTENSIVE COLONIC Dz OR Dz INV SMALL BOWEL

IBD

NSAID

CAPSULE SLOWLY RELEASES 5-ASA AS MOVES THROUGH BOWEL

IBD

NSAID

2 5-ASA MOLs JOINED BY AZO BOND CLEAVED BY BAC ENZs IN LRG BOWEL

URSODIOL

• Incr ratio of bile acids & phospholipids : chol by:
• --Decr chol synth (inhibit HMG CoA reductase)
• --Decr GI absorption of chol
• --Decr biliary secretion of chol

• Promotes form of liquid crystalline phase
• at surface of gallstones which incr sol of chol

• Gallstones no longer form & existing stones are dissolved
• --------------

THERA

• **DOC: Dissolving gallstones
• --50-80% success rate in pts w/ radiolucent chol stones
• --Maintain prophylactic therapy indefinitely (b/c
• 50% reoccurrence w/in 5 years)

• SURGERY for pts w/ severe or recurrent biliary colic
• or cholecystitis (NOT Ursodiol)

• **DOC: Primary biliary cirrhosis
• ---------------------------------------

PATHO OF GALLSTONES

Chol in bile normally in soln via form of micelles w/ bile acids & phospholipids (e.g. lecithin)

When ratio of bile acids & phospholipids to chol < 10:1 → cholesterol gallstones

Bile supersat w/ chol → chol ppts as crystals

10-15% US population has gallstones

URSODIOL

**DOC: Dissolving gallstones

**DOC: Primary biliary cirrhosis Continuous daily therapy

Slow progression of disease

• Incr time before hepatic transplantation
• is required

• Immunosuppr therapy with corticosteroids has NOT been effectv in preventing Dz progression
• -------------------------------

PATHO OF BILIARY CIRRHOSIS

• Autoimmune disease in which T cell & eosinophils
• → gradual destruction of bile ducts

• DIAGNOSIS:
• --INC plasma alkaline phosphatase
• --INC plasma γ-glutamyltransferase aka GGT
• (γ-glutamyl transpeptidase)
• --(+) AMA titer (anti-mito Ab)
• --ANA (+) or (-)

• May become part of a larger autoimmune dz, which affects salivary glands & thyroid.
• --(+) ANA also

PSYLLIUM

• MOA Same MOA as:
• --Bile acid sequestrants (coelstipol & cholestyramine)
• --Inhb GI abs of chol (ezetimibe & stanols)
• --------------------

• PHARM
• --Psyllium binds to bile acids → incr fecal excr of bile acids
• --Loss of bile acids → decr intrahepatic conc of sterol pool → upreg of LDL rec
• --Incr in hepatic LDL receptors → decr plasma
• LDL chol
• ----------------------------

THERA

• Chronic ingestion of psyllium:
• --Decr total chol by 5-15%
• --Decr LDL by 10-20%