PUD OVERVIEW:

Where is it limited to?

Peptic Ulcer disease is limited to the lesser curvature of the stomach and duodenum

Commonly caused by H.Pylori

Ulcers develop when there is an imbalance defensive and aggressive factors

1. Mucus- secreted by GI cells forming protective barrier
2. HCO3- Neutralizes H+ ions that penetrate mucus, it is produced by the pancreas and is secreted into the duodenum, neutralizing acid from stomach
3. Blood flow- Ischemia can lead to cell injury (and creat ulcer)
4. Prostaglandins:  - stimulates mucus and HCO3 secretion, -promotes vasodilation promoting blood flow, -supresses gastric acid secretion.

Helobacter pylori:

-gram neg. bacteria that produces urease,

-lives between epithelial cells and mucus barrier

-remains in GI tract for years

-Most people with PUD have H.pylori

- Dudodenal uclers are more common with H.Pylori

- Killing the bacteria promotes healing and elimination of BacT decreases recurrence.

NSAIDs and ASA:

-inhibits biosynthesis of prostaglandins

-irritates mucus directly

Gastric Acid:

-Need acid for ulcer formation

Pepsin:

-enzyme in gastric acid

Smoking:

-Delays ulcer Healing

1. Alleviate symptoms (esp. pain)

2. Promote Healing

3. Prevent Complications

4. Prevent recurrance

H.Pylori

What is it?

What Antibiotics are used against it and descrobe MOA

why can't you use just one?

• H.Pylori- gram negative bacterium (2 layers of cytplasmic membrane and thick cell wall)
• 4 types anitbiotics use: Amoxicillin, Clarithromycin (Biaxin), Metronidazole (Flagyll)/Tinidozole(Tindamax), Tetracycle
  
• Amoxicillin - (Broad-spectrum aminopenicillin)-Weakens cell wall, most effective at neutral pH
• Clarithromycin- Macrolide, inhibits protein synthesis, can cause QT interval problems if taken w/ other cyp3A4 inhibitors
• Metronidazole (Flagyll)/Tinidozole(Tindamax)-  prodrug and activated by anerobic bacteria. It's a cyp3A substrate so caution w/drugs that induce the enzyme.
  
• Tetracycline: Broad spectrum, inhibits protein synthesis, bacteriostatic, absorption reduced by food.
  

• Can not use Abx alone because they are not effective alone. Therefore treatment for PUD must use a combo of abx

Bismuth: MOA and SE

(H.Pylori tx)

• Acts topically to disrupt cell wall; binds to enterotoxins
• Inhibits urease activity (urease activity is a test used to check for h.pylori)
• Causes harmless black stool (edu. pts)
• Probably coats stomach (creates protective layer)
• May stimulate prostaglandin, mucus, HCO3 secretion
• Decreases stool liquidity due to salicylate- inhibition of intestinal prostaglandin and Cl- secretion
• Pepto-Bismal--however it is falling out of favor for tx
  

Histamine-2-receptor antagonists:

What do they do? Where are receptors located?

What are the 4 drugs used?

• They promote healing by supressing secretion of gastrc acid
• H2 receptors are located on parietal cells of stomach
• Drugs are: Cimetidine, Ranitidine, Famotidine,Nazatidine (-idine)

Cimitadine: (Tagamet)

MOA?

What does food do to it?

Half-life?

Used in:?

what is the theoritical benifit?

MOA:

-Blocks H2 receptor, decreases volume of gastric juice and H+ ion concentration (DOES not block H-1 receptor(for allergies)).

-Effective against nocturnal acid secretion

-Supresses basal acid secretion and secretion stimulated by gastrin and Ach

-Crosses the blood brain barrier--> CNS effects

FOOD?

- Decreases rate of absorption, but not extent.

Half-life?

-Short- 2 hours

Uses:

-GERD, gastric and duodenal ulcers, Zollinger-Ellison Syndrome, aspiration pneumonitis, heartburn

Theoretical benefit?

reducing both histamine-induced cardiac arrythmias, which are mediated by H2 receptors and anaphylaxis-associated vasodilation, mediated by H1 and H2 receptors

***

• Binds to androgen receptors producing blockade -- causes gynecomastia, decreased libido, and impotence.
• CNS effects : confusion, hallucinations, depression, or excitation.
  
• If given IV-- hypotension and dysrythmias (don't push fast!(
• Mega-drug-drug interactions: Serum concentration of certain drugs (Warfarin, Diazepam, Phenytoin, Quinitdine, Cambazepine, Imipramin) increase due to interaction at the p-450 system in liver.
  

Ranitidine (zantac)

Famotidine (Pepcid)

Nizatidine (axid)

How are they different from Cimetidine?

Peak Levels?

Does it block H1 receptors?

• Potency: differs from cimetidine in that they are more potent, fewer AE, fewer drug interactions:-Ranitidine 5-10x more potent and Famotidine/Nizatidine 20-50x more potent
• Absorbed at same rate w/without food
• Less CNS effects
• Does not bind to androgen receptors
• Weak CYP inhibition
• Peak levels in about 45-90 mins. 
• IT also doesn't block H1 receptors

PUD tx- PPI use

Omeprazole (Prilosec)**

MOA

AE

Druge-Drug interactions:

• MOA:
• Prodrug‐converted to active form inside parietal cell
• 
  
• -

•  Inhibits basal and stimulated acid release
• Generic form and OTC
• Decreases acid production by 97% in 2 hrs
• Partial recovery 3‐5 days, full recovery weeks
•  Hepatic metab, followed by renal
• Acid labile/unstable‐needs to be protected from stom acid‐enteric coated
• Used for:
•  ulcers, GERD, hypersecretory conditions
•  AE
• ‐HA, diarrhea, N, V; long‐term risk of CA
• Drug interactions:
  
• Atazanavir, ketoconazole,
  itraconazole because increased gastric pH.

Types of PPIs: Isomers, MOA, Pharmacology-

Esomeprazole

Lansoprazole (Dexlansoprazole)

Rabeprazole

Pantroprazole

Esomeprazole (Nexium)—generic in 5/14

S isomer of omeprazole, metabolized slower

Lansoprazole (Prevacid)—Generic in ‘o9

-Dexlansoprazole (Dexilant)
--R‐isomer of lansoprazole
                         --Releases drug in two phases (slow and long acting)

Rabeprazole (Aciphex)—generic 5/13

---Causes reversible inhibition of H+K+ATPase

---Has antibacterial activity

---Metab by CYP450, doesn’t influence metab of other drugs but can increase digoxin levels
---Sprinkle form available for peds (11/13)
Pantoprazole (Protonix)‐Generic available

• No agent is superior for symptoms relief when agent are compared.
• SO you want to choose one formulary; otherwise suggest omeprazole, pantopraole, or lansoprazole because of generic forms.
• *Just use one drug and see how it affects the body
• OTC prilosec is not therapeuticall the same as prescrition due to diff. salt used in formularly (magnesium salts in OTC vs a diff one in prescription)

1. Endocrine-- serum gastrin level elevated (gastric CA in rats, no in humans; "theorectical-trophic risk in gestation, not proven"
2. Nutritional -- can lower B12 abosorption (cobalamine), not though to significantly effect Fe homeostasis
3. Hip Fx -- higher risk for "high dose" (over 1.75 doses/day) or 2.65 for high dose/long terms; theoretically acid inhibition interferes w/Ca+ absorption in small intestines. Not associated w/osteoperosis or bone mineral density loss
4. Community acquired C.diff-- theory base that gastric acidity may be "permissive" to enteric infection (counterintuitive given that acid spreads through acid-resistant spores) *FDA warning on PPIs may be associated w/ c.diff.
   
5. decreases efficacy of Plavix; possibly re: Cyp2C19; worse w/ omeprazole, Pantoprazole is less likely to cause problems
   

• Use of lansoprazole (Prevacid) in children with or without GERD and poorly controlled asthma showed no improvement and not warranted
• Increases respiratory sx, CAP

• Clinical studies show that heartburn relief is not immediate; begins 30-60 minues.
• Prilosec OTC is to be taken for 14 days, may take 1-4 days for full effect (so you can combine other acid reducing agents w/this)

• Serum Antibody tests (specifically looking at IGg)
• Stool tests: look for H.Pylori antigens (this is easy to do and lose cost)
• Breath test: given radiolabeled urea, H.Pylori converts Co2 and ammonia, breath tests measures Co2 levels.
• Endoscopy- BacT staining, culture, urease (looks at GI tissue)--it's the best, but $, invasive, don't need to give to everyone.

Use of triple therapy: aciphex, nexium, prevacid,

* a 7-day tx is as effective as 10-14 day tx*

H.Pylori Tx: "easy-ish" guidlines:

What options do you have?

Combination tx:

• H2RA + 2 Abx [Amoxicillin/Clarithromycin] (Triple Therapy)
•  PPI + 2 abx [Amoxicillin/Clarithromycin] (Triple Therapy)
•  Pepto + 2abx (Teracyline/Flagyl) + H2RA (Quad Therapy)
•  Pepto + 2abx (Teracyline/Flagyl) + PPI (Quad Therapy)
• Triple therapy and combo therapy have similar results!
  

• Combo packs
•  The Helidac® kit contains bismuth subsalicylate chewable tablets, metronidazole tablets, and tetracycline capsules packaged together.
• The Prevpac® 'kit' contains Trimox® (amoxicillin capsules), Biaxin® (clarithromycin tablets), and Prevacid® (lansoprazole capsules) packaged together. (Generic 9/13)
• Pylera™ contains Bismuth/Flag /Tetracycline tab, and omeprazole
• HOWEVER there is a drug shortage...
  

• Quadruple Tx: ---PPI, bismuth, metronidazole and tetracycline
• ----Can use Helidac® kit but give extra metronidazole to overcome resistance (250 mg t.i.d. with 3 meal time doses of Helidac),
• Cocomittant Tx
•  PPI, clarithromycin, amoxicillin and metronidazole
  b.i.d. instead of q.i.d.

Off Label Regime Being used (d/t abx resistance)

• Use clinical judgment;
• Doxycycline is being substituted for tetracycline;
  Amoxicillin/clavulanate (Augmentin®) 500 mg bid;
• Clindamycin (Cleocin®) 600 mg bid;
• Doxycycline 100 mg bid
• Erythromycin 500 mg bid as clarithromycin substitute

• Sequential treatments being tried--This is New and coming:
• 5 day (PPI BID w Amox 1000 mg BID) followed by
•  5 day (Clarithromycin 500 mg BID / Metronidazole 500
• mg / Tinidazole 500 mg BID+ PPI BID

Other Ulcer Rx:

Mucosal Protective Agents: Sucralafate (MOA, Dosie, Absorption)

Sucralfate (Carafate)**

• Sucrose + Al(OH‐)3
• Binds to actual ulcer
• Actual MOA not known. Thought Sucrose SO4‐binds to +proteins in ulcer base forming physical barrier
• 1 grm q.i.d. on empty stomach
• Minimal systemic absorption: about 90% of each dose eliminated in feces.

Other Ulcer Rx-- Prostaglandin Agents-

Misoprostel (Cytotec)

MOA

Half-Life

Effective in?

AE: (can also be used in pregnancy)

• Misoprostol (Cytotec)
  MOA:
• Analog of prostaglandin E1
   Inhibits acid and protects mucosal lining
  Binds to PG receptor, reduces H‐stimulated cAMP causing modest acid inhibition
  Short half life:
• (30 min) so need frequent dosing.
  Effective for:
• NSAID induced ulcers (they inhibit PG biosynth.)
• Adverse effects:
• stimulates uterine contractions, abdominal pain, Diarrhea.

Antacids- What are they?

What is Potency--ANC: Acid Neutralizing Capacity

What are they used for?

Dosing? and Specific Dosing for Ulcers?

• What are they?
• Alkaline compounds that neutralize
  stomach acid (Acid + base = salt + H2O)
• What is Potency--ANC: Acid Neutralizing Capacity
• Potency = #meq of HCL that can be neutralized by a given
  weight/volume of antacid. ANC: Acid‐neutralizing capacity. Enhances mucosal protection by stimulating PG production
  Poorly absorbed (except HCO‐3)
• What are they used for?
• Used for ulcers. Healing rates = H2RAs
• Provide symptomatic relief but doesn’t accelerate healing.
• Dosing?  Specific Dosing for Ulcers?
  
• Usual dosing 1 & 3 hrs pc and hs
• Gastric ulcers 20‐40meq; duodenal ulcers 40‐80 meq/doseand 

Antacid Types:

CaCo3(Tums)

MOA, AE

• Rapid acting, high ANC, effects of long duration

• Causes acid rebound
• AE: constipation  Releases CO2—eructations and flatulence

1. Rapid onset, effects are short lasting  Liberated CO2, increasing intra abd pressure promotion eructations and flatulence
2. AE: High Na+ content—capacity to cause systemic alkalosis

Antacid Types

Al (Alternagel, Amphogel): MOA AE

Al (Alternagel®, Amphogel®)

• Low ANC, slow acting, effects of long duration
  
• Contain fair amounts Na+
• SE: Consitpation
  

• Rapid acting, high ANC, effects of long duration
• SE: Diarrhe (retains water in intestinal lumen), Caution in use w/ undiagnosed abdominal pain (want to hold off until clear about abd. pain) 

Antacid Combos

Why? What kinds?

• To decrease side effects of “Al3+ only” antacids (constipation) or “Mg2+ only” antacids (diarrhea) the two are combined into one.
• Maalox +, Mylanta-- features TWO antacid ingrediants, Calcium Carbonate and Magnesium hydroxide.

TV marketing Re: Antacids-- e.g. ROLAIDS (ad states give symptom relief better than others)...

However does Acid Neutraliation correlate w/symptom relief clinically?

Other Medication- Antacid

Gas-X -- Simethicone: MOA, what is it?

• Often added to cut the gas
• It's an oral anti-foaming agens to reduce bloating, discomfort and pain caused by excess gas in the stomach or intestinal tract.
  
• It's a mixture of polydimethylsiloxane and silica gel
• May also used alone.
  

Other Combo Antacids:

Tums Dual Action-- what does it contain?

Beano?!

Food Enzyme Dieatary Supplement- MOA

• Alpha‐galactosidase Enzyme derived from Aspergillus niger
• Intended to break down indigestible oligosaccharides found in high‐fiber foods.
  Minimal data to support, but considered safe
• FDA -does not regulate supplements
• DM type II med

Anticholinergics for PUD!

Why is there limited use for it in PUD?

Pirenzepine (Gastrozepine)--MOA, Half-Life, SE

• Why is there limited use?
• Atropine and other classic muscarinic antagonists have limited use for PUD due to systemic SE--(atropine not really used for PUD)
• Pirenzepine (Gastrozepine)
• MOA: Muscarinic antagonist for PUD--Produces “selective” blockade of M receptors that regulate gastric acid secretion
• Half life:  about 10 hrs
• SE: dry mouth, constipation, N, V, Diarrhea

GERD: Gastroesophageal Reflux Disease

Symptom Pattern:

Pathologic Lesion:

*These two make the diagnosis of GERD*

GERD Burden:

• Symptom pattern: heartburn, regurgitation, dysphagia
• Pathologic lesion—erosive esophagitis
   ---Combo of symptoms and esophagitis highly specific (97%) vs pH testing
• GERD burden (GERD‐en?)
   Very common. Affects about 60% of population.
  25% of Americans use antacids/antisecretory meds ≥ 3X/mo
• $10 billion/yr spent on antacids/H2RB/PPI

Non-Erosive GERD: NERD

Prevalence:

Mechanism?

Correlation w/?

Can respond to?

• NERD-- Patients have symptosm of GERD but not the pathologic disease
• Prevalence: 50-70% of those w/ classic GERD sxs; Less likely to have an abnormal ph STUDY like in GERD.
• Mechanism:
• Hypersensitivity, Disordered motility, Pyschological factors
• High Correlation w/ Females, functional GI disorders, mood disorders
• Responds well to mix of Acid redcuing meds, TCAs, anxiolytic, psychotherapy.

• Ca++ channel blockers
•  Nitrates
•  Theophylline
• Anticholinergics (TCAs,
  antihistamines)
•  HRT

• Tetracyclines
• Quinidine
• ASA
• NSAIDs
• Bisphosponates
• K+
•  Fe3+

Lifestyle Measures for GERD

HOB?

Diet?

Smoking?

Sleep?

Wt loss?

Stop meds?

• HOB: Elevate HOB‐yes
• Diet:Don’t eat late; >3 hrs between meal and bedtime; Dietary measures‐-don't really do much for Gerd but-- Avoid fatty foods, caffeine, alcohol, citrus, tomato,peppermint
  Smoking cessation (?)-- it's more assoicated w/PUD not really GERD, but tell pts to stop. 
• Sleep: in left lateral decubitus position‐yes
• Wt. loss-- YES! (BMI correlates with GERD sx)‐Yes
• Meds:  Stop offending meds

NSAIDs--- GERD

New RX meds for RA and OA

• Vimovo® (4/10)--Naproxyn 500 mg+ Esomeprazole 25 mg---(NSAID/PPI)
• Duexis® (4/11)--Ibuprofen 800 mg + Famotidine 26.6 mg ----NSAID/H2RA

New Tx med for GERD:

MOA

Arbaclofen Plarcarbil:

Phase 2b study

• Transported prodrug of R‐baclofen;
• Designed to engage natural nutrient transport mechanisms found on intestinal cell membranes;
• Converted by high‐capacity enzymes to Rbaclofen and natural substances with favorable safety characteristics;
• R‐baclofen is an agonist of GABA receptor

Laxatives-- 5 types

• Bulk--Methycellulose, (Citrucel) psyllium (Metamucil)
• Surfactact--- Docusate (Colace), glycerin supossitories, mineral oil
• Osmotic--MOM, Sorbitol, Lactulose, MgCitrate, NaPhosphate; Balanced polyethylene glycol (GoLytely/Miralax)
• Stimulant-- Biscadoyl (Dulcolax, Correctol); Senna, Aloe, Cascara, Castor oil
• Seratonin Receptor Agonist---Tegaserod-(Zelnorm)

•  Use to ease or stimulate defecation
•  Soften stool
•  Increase stool volume
• Hasten fecal passage through intestine
• Facilitate evacuation from rectum
• Laxative effect: production of a soft, formed
  stool
•  Catharsis: prompt, fluid evacuation of bowel.

Laxatives

1.Bulk

Medication example:

MOA:

Used in?:

AE:

• Medications: Methycellulose, (Citrucel), psyllium (metamucil)
• What are they?: Natural/semisynthetic polysaccharides and celluloses from grains and other plant material
• MOA: Produce soft stool 1‐3 days after onset of tx...Not digested/absorbed, swell in water to form viscous solution or gel Increase volume stretches intestinal wall stimulating peristalsis
• Used in: IBS, diverticulosis, tx diarrhea
• AE: esophageal obstruction if not taken with water (Need to take this med with lots of water and drink quickly)

Surfactant: Laxatives

Examples

MOA

• Docusate (Colace)
• Alter stool consistency by lowering surface
  tension, facilitate penetration of water into feces
• May act on intestinal wall to inhibit fluid
  absorption and stimulate secretion of water and
  electrolytes into intestinal lumen
•  Others: glycerin suppositories, mineral oil

Laxatives: Osmotic!

Medications:

MOA:

Polytethylene Glycol MOA

• Colon can’t concentrate or dilute fecal fluid.--Fecal water is isotonic.
• Meds: MOM, Sorbitol, Lactulose, MgCitrate, NaPhosphate
• MOA: These are soluble but not absorbable—increases liquidity of stool due to increase stool fluid
  Balanced polyethylene glycol (GoLytely/MiraLax)
• Balanced isotonic soln, contain inert, nonabsorbable osmotically active sugar with NaSO4, NaCl, NaHCO3, and KCl.
• No significant fluid or electrolyte shifts occur

Laxatives: Stimulant

Medication and its MOA/AE

3 meds!

Bisacodyl (Dulcolax*, Correctol)

• PR/PO
• Acts within 6‐12 hrs
• Avoid po with milk, antacids due to prevent gastric irritation

Senna, Aloe, Cascara:

•  Act on colon to produce soft or semi fluid stool in 6‐12 hrs
• Harmless yellow‐brown urine color

Castor oil

• Works on small intestine. Hydrolyzed in
• upper intestine to ricinoleic acid (irritant)
• Works in 2‐6 hrs
• Produces watery stool
•  Unpleasant taste‐‐‐YUK!

Laxatives: Serotonin Receptor Agonist

What receptor?

MOA?

How to take the med?

Half-life?

AE?

FDA issues?

• Tegaserod (Zelnorm):
• Serotonin 5‐HT4 partial agonist
  that resembles serotonin. No
  binding to 5‐HT3 or dopamine receptors (so no antidepressant or dopamine effects)
•  MOA:
  
• Essentially stimulates peristaltic reflex--Stimulates proximal bowel contraction (Ach and substance P) and distal bowel relaxation (NO and vasoactive intestinal peptide)
• Activates cAMP dependent CL secretion leading to increased stool liquidity
   Bioavailability of 10%
• how to take it?
• Take a.c.
• Effect noted in 48hrs,
• $$$$$$
• AE:
  
• diarrhea, but usually resolves
• FDA pulled from market 3/7, due to CV AE; but has restricted use for IBS

Opioid agonists

• Acts on opioid receptors in GI tract, mediated through an action on the enteric nervous system as well as CNS
• Inhibits presynapitc cholinergic nerves in submucosal and myenteric plexus leading to increased colonic transit time and fecal water absorption

Loperamide

what time of med?

what properties?

Analog of?

Loperamide (Immodium)--Opioid Agonist Laxative

• Non Rx; no analgesic properties; 2 mg 1‐4x/d
• Analog of meperidine‐no abuse

Diphenoxylate (Lomotoil)

What type of med?

SE?

What to be concerened about?
 

Diphenoxylate (Lomotoil)--Opioid Agonist.

-Higher doses have CNS effects,
includes atropine to discourage OD
(Schedule V drug)

-Diphenoxylate: can have CNS effects has potential for abuse (opoid). has atropine (ie: dry mouth) Class 5 drug.

Prepopik Combo

What is it?

MOA?

• New Combo Rx for Bowel Cleansing‐‐
• Combo of Napicosulfate (which acts directly on colonic mucosa to stimulate peristalsis) plus Magnesium citrate in soln (osmotic agent)

 Bile Salt‐Binding Resin
(Cholestyramine, Colestipol)
MOA

What is it?

Anti-Diarrheal: 

MOA:Absorbed in terminal ileum‐bind to bile salts

AE: bloating, flatulence, constipation, fecal impaction

Kaolin & Pectin (Kaopectate*)
What is it?

MOA?

AE?

Availbility?

• Naturally occurring hydrated magnesium aluminum silicate and pectin and indigestible carb derived from apples.
• Act as absorbents of BacT, toxins and fluid decreasing stool liquidity and number
• No significant AE Don’t take within 2 hrs of other meds (bind)
• NO LONGER SOLD.

IBS

Symptoms

Patho

What to treat?

•  Disordered serotonin signaling in GI tract;
• ? Inflammatory disease*
• IBS: crampy abd pain, assoc with diarrhea, constipation or both; >= 12weeks NOS (not otherwise specified)
• Tx directed at relieving pain and improving bowel function
•  Essential tx sx: diarrhea, constipation, pain

Treating IBS

TCA Why?

MOA for IBS?

AE

•  TCA (tricyclic antidepressants, eg amitriptyline,imipramine)
• Low dose alter central processing of visceral afferent information
•  Decreases nociception (TCA: decreases nociception (sensation of pain)
• AE: Anticholinergic effect effects motility and secretion

IBS-- IBS: 5‐HT3‐RA

Name of meds?

MOA?

Efficacy?

Bioavailibility?

Half-life?

Dose?

AE?

• Serotonin 5‐HT3‐receptor antagonists
• (Alosteron)[Lotronex]
• Blocks receptors in gut on way to spinal cord inhibiting sensation of N, pain and bloating‐slows colonic transit
• More effective in women
• 50‐60% bioavailability
• 1.5 hr half life
• Dose 1 mg qd‐b.i.d.
•  AE: constipation requiring
• hospitalization, ischemic colitis
•  FDA warnings in 2002—special use rules

IBS--Antispasmodics (anticholinergics)

Name of meds?

MOA:

AE at low doses and high doses?

• Dicyclomine (Bentyl), Hyoscyamine
• (Anaspaz,Cytospaz)
• Inhibit muscarinic cholinergic receptors in the
  enteric plexus and on smooth muscle
• Low doses, minimal ANS effects, but high doses
  have anticholinergic effects (dry mouth, visual
  disturbance, urinary retention)

• IBS-- how to treat Gas/Bloat
  

• IBS-Gas/Bloat: Antigas measures--Antispasmodics, Antidepressants, Probiotics? Rifaximin--(non-absorbable Abx-tx BacT overgrowth.
  

• IBS-Mixed D/C: Bulking agents, Antidepressants, ? Probiotics

IBS: Constipation---

what is Lubisprostone and Linaclotide

• IBS-Constipation: Fluids, exercise, Bulking agents, Laxatives, Tegaserod, ? Probiotics, Lubiprostone(activates gut luminal Cl channels; increases fluid in intestine); Linaclotide (agonist of guanylate cyclase type-C receptor on intestinal surface increasing fluid secretion and transit)

IBS- How to treat Diarrhea?

What is probiotics?

Probiotics:

What is it? How is it marketed? What has it?

FDA?-- OTC probs?

MOA?

Probiotics

• Live, nonpathogenic microorganism (BacT/yeast) “marketed” as dietary supplements.
• Yogurt is most familiar source (either Lactobacillus bulgaricus and Streptococcus thermophiles)
• No FDA approval for any indication.
• ----Dietary supplements; quant/quality/purity are uncertain.
• MOA: Thought to inhibit bacterial toxins, Lower pH, and inhibit growth of pathogenic bacteria such as E. coli and C. diff; might physically or chemically prevent adhesion and colonization of pathogenic BacT

Pro-Biotics:

AE:

Drug Interactions:

• AE: gas, bloating, diarrhea, eructations (Usually mild/transient) Infectious complications have occurred esp. in highly immunosuppressed and/or critically ill
• Drug interactions:
•  ---Antibiotics can inactivate bacteria‐derived probiotics
• ---Florastor® not used with oral systemic antifungal meds

IBD: Crohn’s & Ulcerative
Colitis

What medications?

Terminal ileum inflammation
 5‐aminosalicylates (Sulfasalazine)[Azulfidine]

Immunomodulators: IBD

^{Immunomodulators: IBD}

^Types:

^MOA:

• Glucocorticoids:(dexamethasone, budesonide)
•  Immunomodulators(Azathioprine)[Imuran]
• 
  
• ^{MOA:  Generally act on T lymphocytes to suppress production of IL‐2, interferon and other cytokines— ultimately suppresses T cells and proliferates B cells}

5‐aminosalicylates (Sulfasalazine)[Azulfidine]
Metabolism

Efficacy

AE

• Metab by intestinal BacT—5‐ASA and sulfapyridine
• Suppresses Prostaglandin synthesis and migration of inflammatory cells into area
• Effective for acute mild‐mod episodes
• AE: N, fever, rash, arthralgia, hematologic disorders

Anti-emeitc: 5HT3 receptor blocker:

What types of meds?

What center of brain?

SE?

Useful?

Drug Shortage?

• 5HT3 receptor blocker works in CTZ vomiting center.
• Types of Meds: (Ondansetron, Granisetron, Bolasetron)
  SE: HA, Diarrhea, dizziness
  Uses: Useful for chemo tx induced and post op N/V
• Drug Shortage: Single IV dose off
  market 2013 due to serious cardiac rhythm

Aprepitant (Emend)

What is it?

MOA?

Drug Interactions?

• Anti-emetic
• MOA: Substance P/Neurokinin1 Antagonist
  Prolonged duration of action, prevents
  delayed NV and acute NV
• Drug Interactions: Combined with other drugs-Inhibitor and inducer of CYP3A4

• Suppresses emesis by blocking 5HT (Seratonin Receptor); increases upper GI motility by enhancing actions of Ach
• Use: GERD, DM, gastroparesis, N/V re:chemo/OR
• SE: EPS,BBW: Tardive dyskinesia, sedation

• Anti-emetic
• Cisapride (Propulsid)- limited use—last resort GERD, severe chronic constipation, pseudo-GI obstruction, gastroparesis

Dronabinol (Marinol) (Sched III)

and

Nabilone (Cesamet ) (Sched II)

Medical Marijuana-Nausea

Works on the cerebellum zone at the Cannabinoid Receptor.

Phenothiazines

What is it

MOA?

SE?

Phenothiazines

Antiemeitc
Receptor: D2 Blocker (Dopamine) at the CTZ zone
SE: EPS, anticholinergic, effects, hypotension,
sedation

Benzodiazepines

What kind of meds as antiemetic?

MOA:

Useful for?

• (Lorazepam/Diazepam)
• MOA: BZD receptor in brain (Benzodiazepine Receptor)
• Use: Suppress anticipatory V in chemo

Muscarinic Antagonist (Scopolamine) and
Antihistamines (Dimenhydrinate, meclizine,
myclizine

What are they used for (GI lecture)

MOA

SE

Anti Emetics

MOA:Block M and H1
SE: sedation, dry
mouth, blurred
vision

Diet plays a major role in ulcer management?

True or False

False

No convincing evidence that ulcer diets, or caffeinated beverages promote ulcer
formation or interfere with recovery.

 False
 There is no hard evidence
 If patient notices association/exacerbation then common sense would tell them to
stop.

ETOH and Water are the only two substances directly absorbed by stomach

• (Possibly )True, (more than likely False)
  Dogs and cats have their own special type of Helicobacter in their stomach. As pups, dogs catch it from their mother and have gastritis. When they grow up the Helicobacter appears to be pretty harmless. However, DOG AND CAT HELICOBACTERS HAVE BEEN FOUND IN HUMANS. Actual clinical disease has not been shown. Suggest not letting pets lick you or your children on the face and mouth

HMG CoA reductase inhibitors

MOA

Place in Therapy

• MOA: Inhibition of HMG CoA reductase-- rate limiting enzyme in cholesterol biosynthesis----Decreases plasma LDL-C by 18-55%
• -------Increases HDL- 5-15%, lowers TG: 7-30%
• Place in Therapy: First line for LDL-C reduction for most patients; Outcome data show reduce major CV events, CHD mortality, coronary procedures, stroke, and total mortality.

The four benefit groups are

1. anyone with LDL >190mg/dL

2. Those w/ ASCVD without Class II-IV HF or hemodialysis.

3. age 40-75; LDL: 70-189; with DM--without clinical ASCVD

4. Anyone 40-75 y.o. without clinical ASCVD or DM with LDL 70-189 and ASCVD risk >7.5% in 10 years.

STATINS

Highest Potency to Lowest Potency?

And special consideration for each--

HIV patients--Which drugs to use and why?

1. Rosuvastatin (not metabolied well in asian populatins-- give them in lowered dose)
2. Atrovastatin (most studies back up use of this drug-- lots of drug-drug interactions)
3. Simvastatin (also many drug-drug interactions)
4. Pitavastatin (newest statin)
5. Pravastatin (not used very much, prescribed if pts on polypharmacy)
6. Fluvastatin (same as pravastatin)
7. Atrovastatin, Simvastatin, Lovastatin (ASL)- have highest drug-drug rxn because use same CYP enzyme as most drugs)
8. Paravastatin and Fluvastatin used with HIV pts, because they are on a protease inhibitor which interacts with statins; however these drugs are lower potency and have less drug-drug interactions and used in this pt population; despite the fact they don't work very well.

Atrovastatin (40-80mg)

Rovustatin (20-40mg)

1. Atrovastatin (10-20mg)
2. Rosuvastatin (5-10mg)
3. Simvastatin
4. Pravastatin
5. Lovastatin
6. Fluvastatin

Pravastatin

Lovastatin

**not really recc. unless patient can't tolerate statins**

Statins:

Adverse Effects

• HA, GI disturbances (infrequent but possible)
• RARE occurance of Myopathy/Rhabdomylosis (1-5%): --Early signs: muscle weakness and pain (check creatning kinase levels); Advanced signs (darkening of urine-because crt can't be broken down; most likely to occur at higher dose and if overlapping with meds that also can cause this SE. DOSE DEPENDENT
• Hepatoxicity: Dose dependent, also rare; Requires basic monitoring of LFTs (we do a baseline and then annually)
• Feb 2012 warning that increases memory loss, confusion, dementia like symptoms with elderly-- cardiologist havn't changed their practice with this warning though--keep in back of your mind.
  

Statins

Drug interactions/Contradictions

• Fibrate-- (gemfibrozil or niacin)--cholesterol meds --increased risk of myopathy (more risk wehn combined with statin)
• ---Avoid potent CYP3A4 inhibtors w/simvastatin, lovastatin, and atrovastatin (e.g. azole antifungals (ketoconazole), erythmromycin, HIV protease inhibitors (ritonivir)
• Caution w/HIV pts.--should use a lower potency statin.
  
• CI: Pregnancy (Cat x)--if wants to get pregnant switch med to a different class  and Active Liver disease (can be hepatoxic)

AIM high: adding niacin w/low HDL-C and High TG

ACCORD- adding fenodibrates in patient w/DM

**did not show any real decrease in risk factors for CVD

**In general; the stance is Adding non-statin doesn't decrease ASCVD risk reduction w/acceptable safety margin***

Niacin (nicotinic acid) [Niacor, Niaspan]

MOA

Anti-cholesterol

Niacin is OTC, Nisaspan is Perscription

MOA:

–Inhibits VLDL production, which ↓ LDL- C (5-25%)

–↑ HDL (15-35%)

–↓ TG (20-50%)

Niacin (Nicotinic acid)- Niacor or Niaspan

SE

• Facial flushing, facial itching, and GI distress
• Intense facial flushing neck, face, ears--> occurs in practically all patients-->prostaglandin mediated effect. (Can give ASA 325mg 30 min prior to dose; or use Niaspan (because this medication is extended release and releases med in a steady state vs Niacor (OTC-vitamin B3) which has more peaks--so SE are less intence.) May also prescribe at night to sleep through it.
  
• Hyperuricemia (occurs transiently--watch for gout; is pt has active gout don't start the medication)
• Hyperglycemia
• Hepatotoxcicity (Check LFTs)
• Rhabdomylosis (less than w/statins--higher risk if prescribed with stating)
  

Bile Acid Resins

What are the names of medications?

Bile Acid Resins

What is unique about Colesavelam (Welchol)?

It has less bloating,fewer interactions

this is newer RX and better tolerated.

Bile Acid Resins:

MOA

• These work in the gut and not the liver. The bile acid resins bind to bild acid (metabolites of cholestrol) in the intesting and prevent it from becoming reabsorbed.
  
• Reduces LDL, increases HDL, MAY increase TG!!!
• Cholestyramine comes in a powder
• Welchol are capsules, but need to take 4x day--anther reason why they are not used often.
• This is good option for those with a poor diet and can not tolerate statins
  

Bile Acid Resin

SE:

CI:

• Causes constipation and bloating (because it works in the gut! Need to titrate slowly)--- another reason not really used (need to advise patients to drink fluids, take in fiber or prescribe a stool softener with it. ---
• May form complexes with other medications and decrease its efficacy--decrease the absorption of other drugs! (other drugs my get extreted inactiely) BETTER to take other meds 1 hour before this dose or 4 hours after
• CI: in patients w/ elevated TG, esp. >400 (try to prescribe with TG <150)
• CI: history of obstruction--- can cause severe constipation
  

Fibrates

Drugs:

gemfibrozil (Lopid, generic); fenofibrate (Tricor, others generic); Fenofibric acid (TriLipix)

Fibrates:

MOA

Stimulates lipoprotein lipase to increase lipolysis--this decreases TGs

Inhibits liver production of VLDL (TGs)

Increases efficiency of hepatic reuptake of lipoproteins.

Very effective in decreasing TGs, not every good in decreases LDLs

Fibrates:

SE--

• Rashes and GI disturbances are the most common SE
• Hepatoxicity (like statins, nicotinic acid)--check LFTs!
  
• Gallstones
• Myopathy/Rhabdomylosis (like statins, but less than them (I believe like nicotinic acid as well)--- crt kinase to?

Fibrates

CI:

• Medication is hepatoxic and is also excreted through kidneys THEREFORE CONTRAINDICATED IN: ACTIVE LIVER DISEASE AND SEVERE RENAL DISEASE.
• Because can cause GALLSTONES--CI in those with gallbladder dx!

Fibrates:

Drug Interactions:

• Displaces warfarin from plasma albumin-- so increases warfarin in system and anticoagulant effects-- (need to Monitor INR (there is an increased risk of bleeding), may need to lower dose)
• Increased myopathy risk if combined w/statins or Niacin; Rhabdo occurs more with gemfibrozil rather than fenofibrate

Ezetimibe (Zetia)

MOA

Anti-cholesterol

Newer Agent

Works in the gut, inhibits cholesterol absorption in the gut!

• ezetamide/simvastatin: Vyotrin---decreases LDL and TG increases HDL...
  
• ezetamide/atrovastatin---same thing as the other combo!
• Why a new combo:
  a new combo, just because it is seen to lower LDL levels.

Controversy with

Ezetimibe ?

Ezetimibe

AE:

Omega-3 Acids (Fish Oil; Lovaza)

Preperations?

What is EPA and DHA?

Omega-3 Acids

MOA

Omega-3- Acids

Places in Therapy

Recommended Doses--avoid which fish?

• Mainly to decrease TG and inflammation (anti-inflammatory properties)
• Take fish oil supplements or increase fish intake:
  •1-2 servings/week fatty fish or fish-oil supplements
• -- RECOMMENDED DOSES:
• •AHA 2003 Guidelines
  –Eating at least 2 servings of fish/week
  •Fish with high concentration of EPA/DHA (mackerel, halibut, herring, salmon, albacore tuna, trout)
  –Average goal of 1 gram of EPA and DHA/day
  •Eating fish carries some risk of mercury poisoning
  Can consider fish-oil supplements and avoiding fish known to have high risk (golden snapper, swordfish)
• Prescription grade for Omega-3 has less chance of mercury poisioning.
  

Prescription Omega-3 fatty acid!