pharm_gi_antihist_5ht

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soren101
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pharm_gi_antihist_5ht
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2012-03-23 00:07:14
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pharmacology histamine serotonin gi
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pharm GI histamine 5HT
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  1. CROMYLN SODIUM
    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
  2. OLOPATADINE
    &
    KETOTIFEN
    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
  3. H1 AND H2 RECEPTOR SECOND MESSENGER SYSTEM
    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
  4. DOC FOR LARYNGEAL EDEMA
    EPI
  5. DOC FOR HYPOTENSION
    • H1 BLOCKER -- DIPHENHYDRAMINE
    • H2 BLOCKER -- CIMETIDINE
  6. H1 BLOCKERS
    ORAL NON-Rx SEDATING
    • BROMPHENIRAMINE
    • CHLORPHENIRAMINE
    • DIPHENHYDRAMINE*
    • DIMENHYDRINATE* -- tx motion sick & vertigo (meniere)

    *ALSO BLOCK ACh & ARE ANTI-EMETIC
  7. H1 BLOCKERS
    ORAL NON-Rx NON-SEDATING
    LORATADINE (CLARITIN)

    CETIRIZINE (ZYRTEC) -- ACTIVE MET OF HYDROXYZINE
  8. H1 BLOCKERS
    ORAL RX SEDATING
    • HYDROXYZINE
    • CYPROHEPTADINE

    ALSO BLOCK ACh AND ARE ANTI-EMETIC
  9. H1 BLOCKERS
    RX NON-SEDATING
    FEXOFENADINE (ALLEGRA)

    • DESLORATADINE (CLARINEX)
    • --ACTIVE METABOLITE OF LORATADINE (claritin) CONVERTED BY LIVER
  10. EFFECTS OF H1 BLOCKADE
    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
  11. EFFECTS OF CHOLINERGIC BLOCKADE
    1. Depresses CNS (sedation, etc)

    2. Inhb nasopharyngeal secretion

    3. Inh motion sickness (action in vestibular nuclei)

    4. Anti-emetic effect!!!
  12. ONLY ANTI-HISTAMINE THAT HAS LOCAL ANESTHETIC EFFECT AND USED TO Tx PARKINSON'S
    DIPHENHYDRAMINE

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

    PD --> Tx central motor d/o caused by antipsych drugs
  13. PROMETHAZINE
    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)
  14. DOC FOR SEASONAL ALLERGIES
    H1 BLOCKERS -- NON-SEDATING

    LORATADINE

    • CETIRIZINE
    • FEXOFENADINE
  15. MECLIZINE
    H1 BLOCKER -- DRAMAMINE

    "LESS SEDATING" THAN DIMENHYDRINATE
  16. H1 BLOCKERS WITH "PREGNANCY C" RATING
    • 1. Promethazine
    • 2. Fexofenadine
    • 3. Olopatadine
    • 4. Hydroxyzine

    REST ARE CLASS B
  17. S/E OF ALL H1 BLOCKERS
    • 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
  18. H2 BLOCKERS
    ~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
  19. H2 BLOCKERS ADVERSE
    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
  20. 5-HT1 RECEPTOR ACTIONS
    • 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
  21. 5-HT2 RECEPTOR ACTIONS
    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
  22. 5-HT3 RECEPTOR ACTIONS
    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
  23. 5-HT4 RECEPTOR ACTIONS
    • MOTOR
    • --STIM AT PREJUNC INC ACh RELEASE IN GI

    • BLOCKER
    • --METOCLOPRAMIDE
  24. EFFECTS OF 5-HT RELEASE IN GUT
    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
  25. CARCINOID TUMORS AND 5-HT
    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
  26. SUMATRIPTAN MOA AND PHARM
    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
  27. SUMATRIPTAN THERA AND ADVERSE
    • 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
  28. METOCLOPRAMIDE MOA AND PHARM
    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)
  29. METOCLOPRAMIDE THERA AND ADVERSE
    • 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)
  30. ONDANSETRON
    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
  31. CYPROHEPTADINE MOA AND THERA
    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
  32. CYPROHEPTADINE ADVERSE
    • 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
  33. MIGRAIN HEADACHES
    • 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
  34. CLUSTER HEADACHES
    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.
  35. IPECAC
    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
  36. ANTI EMETIC AGENTS
    • SCOPOLAMINE
    • DIMENHYDRINATE
    • DIPHENHYDRAMINE
    • MECLIZINE
    • PROMETHAZINE
    • METOCLOPRAMIDE
    • ONDANSETRON
    • DEXAMETHASONE
    • DRONABINOL
    • APREPITANT
  37. SCOPOLAMINE
    ANIT EMETIC

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

    PROPHYLAXIS MOTION SICKNESS

    • ADVERSE
    • --XEROSTOMIA
    • --SEDATION
    • --PROBS CONCENTRATING
    • --AMNESIA
    • --FATIGUE
  38. DRONABILOL
    ANTI EMETIC

    THC -- MOA UNKNOWN
  39. DEXAMETHASONE
    ANTI EMETIC -- MOA UNKNOWN

    STEROID

    DEXA TEST FOR HYPERCORTISOL
  40. APREPITANT
    ANTI EMETIC

    NEUROKININ-1 REC ANTAG

    BLOCKS ACT OF SUBSTANCE P AT NK-1 REC IN CNS
  41. DOC MOTION SICKNESS

    PROPHYLAXIS vs. Tx
    • PROPHYLAXIS:
    • --SCOPOLAMINE
    • --DIMENHYDRINATE
    • --MECLIZINE

    • Tx:
    • --PROMETHAZINE
  42. DOC MOTION SICKNESS FOR PREGOs
    • ONDANSETRON
    • METOCLOPRAMIDE
    • DIMENHYDRINATE
    • MECLIZINE
  43. DOC N/V FROM INFLUENZA
    PROMETHAZINE
  44. DOC VERTIGO OF VESTIBULAR ORIGIN
    DIMENHYDRINATE & MECLIZINE

    MENIERE'S Dz
  45. METOCLOPRAMIDE
    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
  46. METHYLCELLULOSE
    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
  47. PSYLLIUM
    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
  48. CALCIUM POLYCARBOPHIL
    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
  49. LAXATIVES THAT DON'T CAUSE DEPENDENCE
    • BULK LAX
    • LACTULOSE
    • DOCUSATE
  50. LACTULOSE
    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
  51. DOCUSATE
    LAXATIVE

    STOOL SOFTENER

    Emulsifying action softens stool.

    • An anionic surfactant:
    • Detergent action decr surface tension of feces to allow penetration of H2O
  52. BISACODYL
    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)
  53. MAGNESIUM HYDROXIDE
    &
    POLYETHYLENE GLYCOL
    *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
  54. IBS Tx
    • EXPAND LRG BOWEL:
    • --BULK LAXATIVES
    • --DOCUSATE & LACTULOSE

    • MUSCARINIC REC ANTAG INH SPASM
    • --DICYCLOMINE
  55. Tx OF PORTAL SYSTEMIC ENCEPHALOPATHY OF HEPATIC Dz
    LACTULOSE
  56. ANTI-DIARRHEAL OPIATES
    • 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
  57. CALCIUM POLYCARBOPHIL
    (anti-diarrheal)
    RESIN ABS EXCESS H2O IN BOWEL

    FORMS GEL WHICH HELPS CONSOL STOOL
  58. BISMUTH SUBSALICYLATE
    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
  59. ANTI-BIOTIC TRIPPLE THERAPY
    "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
  60. Al & Mg HYDROXIDES
    • 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
  61. CIMETIDINE
    RANITIDINE
    FAMOTIDINE
    (anti-ulcer)
    ~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
  62. OMEPRAZOLE
    &
    ESOMEPRAZOLE (s-isomer)
    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)
  63. MISOPROSTOL
    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
  64. SUCRALFATE
    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
  65. METHYLPREDNISONE
    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
  66. MESALAMINE
    IBD

    NSAID

    CAPSULE SLOWLY RELEASES 5-ASA AS MOVES THROUGH BOWEL
  67. OLSALAZINE
    IBD

    NSAID

    2 5-ASA MOLs JOINED BY AZO BOND CLEAVED BY BAC ENZs IN LRG BOWEL
  68. DRUGS THAT DISSOLVE GALLSTONES
    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
  69. DRUGS FOR PRIMARY BILIARY CIRRHOSIS
    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
  70. TX OF HYPERLIPOPROTEINEMIA
    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%

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