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3 mehanisms that may lead to Peptic Ulcer disease
- Ethology- Infections (H. Pulori)
- Hyperproduction of HCL- function of the parietal calls of the stomach
- Inadequate mucosal defense against HCL
- Antimicrobial agents (based on efficiency cure (erradication rate)
- Current reginen of choice (90% erradication rate)
- -2 week combo course with:
- Anti-secretory drug (usually added)
Second line regiments (erradication rate 80-90%)
- Combo of 2 antimicrobial agents:
- Amoxicillin or Clarithromycin
- Antisecretory drug
If you use 1 antimicrobial agent - have a 20-40% erradication rate
What is the reccurrance rate of patients treated only with antisecretory agents?
For those receiving recommended regimen- rate is less then 15%
HCL secretion (parietal cells) is controlled by:
- Actylcholine (increase intracellular Ca++ ion)
- Histamine (activation of adenyl cyclase)
- Prostaglandine E2 and I2 (lower HCL production)
- Gastrin (increase intracellular Ca++ ion)
The agents blocking the secondary messangers acting protein pump
- Dicylomine blocks the cholinergic receptor
- Cimetidine blocks the H2 histimine receptor
- Misoprostol stimulates the prostaglandin receptor
- Omeprazole blocks the proton pump
H2 receptor antagonists Chief clinical use
Inhibitor of gastric acid secretion by reducing intracellular concentration of cyclic AMP.
H2 receptor antagonists Actions
Fully reversible competitive antagonist of histamine receptors completely inhibiting gastric acid secretion, partial inhibition of gastric acid secretion induced by acetylcholine and bethanechol.
H2 receptors antagonists Therapeutic use
All agents are equally effective to promote gastric and duodenal ulcer healing. There may be a recurrance rate of 60-100% per year if H pylori superinfection is present
- Zollinger-Ellison syndrome (gastrin producing tumor)
- Acute stress ulcers
- Gastroesophageal reflux
H2 receptor antagonist agents
- Climetidine (tagamet)
- Ranitidine (zantac)
- Famotidine (pepcid)
- nizatine (axid)
- Metabolized in the kidney- good to use if cant use a drug that is metabolized in the liver
- 30% of dose is metabolized by microsomal enzymes thus 70% excreted unchanged in urine.
- Due to its anti-androgenic and Prolactin stimulation, effect may induce gynecomastia, galactorreha, and decreased sperm count.
- Is a P-450 enzyme inhibitor slowing metabolism of drugs that utlizes the system increasing their serum concentrations.
- -Warfarin, Diazepam, Phenytoin,Quinidine, Carbamazepine, Teophylline, and Imipramine
Longer acting and more potent than Cimetidine
Similar to Ranitidine but more potent
Similar to Ranitidine but principally metabolized in the kidney and bioavailability is near 100%
Inhibits HCL secretion and stimulates mucus and bicarbonate production
- Clinically effective at higher doese and its routine use may be only justified in those patients- Using NAIDS
- Since it produces uterine contraction it is contraindicated during pregnancy.
- Diarrhea and nausea are the most common adverse effects
Inhibitors of proton pump
Supress secretion of H ion into gastric lumen
Actions of inhibitors of proton pump
Inhibits basal and stimulated gastric acid secretion. More then 90% of supression begins 1-2 hours after dose.
Therapeutic use of proton pump inhibitors
- Short term treatment of erosive esophagitis and duodenal ulcer.
- Long term treatment of Zollinger- Ellison Syndrome.
Agents of Proton pump inhibitors
- Omeprazole (prilosec)
- Lansoprazole (prevacid)
- esomeprazole (nexium)
- pantoprazole (protonix)
- Rabeprazole (Aciphex)
Adverse effects of proton pump inhibitors
- Increased incidence of gastric Carcinoid tumor
- prolonged hypochlorhydria
- secondary hypergastrinemia
- increased concentration of viable bacteria
- Omeprazole interferes with oxidaton of Warfarine, Phenytoin, Diazepam, and Cyclosporine
- Weak bases which react with gastric acid and water to form a salt diminsihing gastric acidity,
- Many products varying in chemical composition, neutralizing capacity and sodium content.
Agents of Antacids
Aluminum or magnesium salts
Adverse effects of Antacids
- Constipation (aluminum) (maalox and mylanta)
- diarrhea (magnesium) (gaviscon, mylanta)
Mucosal protective agents
- Sucralfate (carafate)
- Colloidal bismuth
Complex of aluminum hydroxide and sulfated sucrose which forms a complex gel with mucus impairing diffusion of HCL.
- Inhibits pepsin
- Increase mucus secretion
Vomiting reflex center
- Chemoreceptor trigger zone (caudal end of 4th ventricle) Responds to chemical stimuli in blood of CSF
- Vomiting center (lateral reticular formation of medulla)- Coordinated the mechanical (motor) mechanism of vomit
Although nausea and vomits are not exclusive of chemotherapy, 70-80% of patients will experience this symptom. 10-40% experience the symptoms before therapy due to anticipation.
Agents or their metabolites may activate the center by the releasing and the actons of several neuroreceptors (Dopamine and Serotonine)
Idiosyncratic response (smell, color, etc)
Emetric Potential of chemotherapeutic drugs
Strong emetric potential
(some used for leukemia)
Moderate Emetric Potential
Mild Emetric Potential
Drugs used to control chemotheraphy induced emesis
- Substituted benzamines
Block dopamine receptors. Effective against low or moderate ematogenic agents (fluorourcil, doxorubicin)
Side effects- Sedation, hypotension and extrapyramidal symptoms
Substituted benzamines (Metoclopramide)
Effictive at high dose against highly ematogenic agents (eg Cisplastin)
Side effects- Sedation, diarrhea, and extrapyramidal symptoms limit high doses
Moderatly effective antiemetic
Benzodiazepines (lorazepam, alprazolam)
Requires a perscription- pt can get dependent
- Low potency antiemetic agents
- Beneficial properties include: Sedative anxiolitic and amnesic, useful in anticipatry vomits
Corticosteroids (dexamethasone, methylprednisolone)
Useful against mild to moderate emetogenic drug. May be involved in prostaglandin blockage.
Canabinoids (mary jane) (dronabinol, nabilone)
- Mariuana derivatives
- Seldom used due to side effects: Dysporia, hallucination, sedation, vertigo, and disorientation.
Block pripheral and central receptors. May be administered as a single does PO or IV and effective against all grades
- Ondansetron is also effective as post operative nausea and vomits
- Headache is most common side effect
Antiemetric Activity- High drugs
- Serotonin antagonists
- Substituted benzamide
Antiemetric activity- Moderate
Antimetic activity- Low
Percent response fron drug combos
- Dexamethasone, Ondansetron = 91%
- Dexamethasone, Diphenhydramine, Metoclopramide, Droperidol = 76%
- Lorazepam, Dexamethasone, Metoclopramide = 63%
- Diphenhydramine, Dexamethasone, Metoclopramide = 58%
- Activated attapuigite
- Bismuth subsaticylate
Decreased motility (diphenoxylate, loperamide) (meperidine analogs) with Opiod like action= inhibits acetylcholine release, and decreases peristalsis
Side effects of Antidiarrheals
- Drowsiness, dizziness, and abdominal pain
- May cause Toxic megacolon contraindicated in children and patients with colitis.
Adsorbents (kaolin, pectin, methycellulose, and activated attapulgite
- adsorption of toxins, or coating mucosa (protective)
- -May interfere with absorption of other drugs
Agents that modify fluid or electrolyte transport
- NSAIDS (indometacine, asperine) by inhibiting prostaglandin synthesis.
- Pepto Bismol (bismith subsalicilate (choice for traveler's diarrhea)
Castor oil, Senna, Aloe, Phenolphthalein, Bisacodyl, Hydrophilic colloids, Methylcellulose, Psyllium seeds, Bran, Magnesium hydroxide, Polyethylene glycol, Lactulose, Docusate sodium, Mineral oil, Glycerine suppositories
- Increase movement of food along GI
- Irritants- Castor oil brake down to rinolinoleic acid which is very irritant and increases peristalsis.
- Bulking agents (most effective)- Methylcellulose, psyllum seeds
Stool softeners- Mineral oil and Glycerine suppositories
Drugs that are effective against microorganisms through "selective" toxicity without affecting the host cells.
FDA Catagory Antimicrobial fetal risk
- A- No risk
- B- only studies on animals, suggest potential toxicity
- C- Animal fetal toxicity demonstrated; human risk undefined
- D- Human fetal risk present, but benefits outweigh risks
- X- Fetal risk present, does not outweigh benefits; contraindicated in pregnancy.
B category drugs
- B- Lactams
- B- Lactams with inhibitors
C Catagory drugs
D Category drugs
- Aminoglycosides (except gentamicin)
Detecting the microbial agents
- Direct microscopic visualation
- Cultivation and Identification
- Detection of microbial antigens
- Detection of microbial RNA or DNA
- Detection of host immune response
Begin therapy after identification and sensitivity
Therapy is begun before ID and sensitivity determined
Why would you begin therapy before the identification and sensitivity is determined
May be detrimental to life
- Broad cover against bacterial infection
- Effective against gram + and - anaerobes.
- Combo of antibiotics or single broad spectrum
You will get culure results and sensitivity depending on if it is gram + or -, or mixed flora
Agent selection is by:
- Patient history
- Immune Status
- Community vs Hospital acquired (nosocomial)
- Site of infection
Site of infection
- Antibiotic has to reach the area
- Difficult sites to reach sanctuaries
- -Prostate gland
- Immune status
- Renal function (aminoglucosides)
- Hepatic function (erythromycin)
- Pregnancy (all agents cross the placenta)
- Age (all functions diminish with age)
- Site of Infection
- Renal function
- Hepatic function
- Neutropenia- lack of adequate number of neutrophils
- GI function
- Underlying diseases
- Concomitant drugs
- Desired route of administration
- Activity against pathogen
- Ability to arrive in site of infection
- Potential drug interactions
- Dosing frequency
- Stability at different temperatures
Cost of therapy
- Often, several drugs have similar effectiveness but different costs.
- ex Clarithromycin costs $120, and Tetracycline is $5
Drug function- 2 ways
- Drugs that arrest growth and replication of bacteria limiting spread of infection while immune system works.
- These agents DONT kill the microorganism
- ex- Chloramphenicol
- Agents that eliminates (KILL) microorganism
- ex- Penicillin
ID sensitivity of organism
- Take a culture in the media
- MIC- Minimum inhibitory conc= lowest conc of an antibiotic that inhibits bacterial growth.
- MBC- Minimum bactericidal concentration= The lowest conc of antiboitic that kills 99.9% of bacteria.
LOOK AND UNDERSTAND GRAPHS ON SLIDES 15,16,17
Spectrum of therapy
- Particular actibity of the drug
Single or limited group of organism (Isoniacid)
- Effective against gram + and gram - organism
- Wide variety of microbial species
- Teyracycline, Chloramphenicol
It is wise to use only one agent with higher specificity for the organism decreasing superinfection and emergence of resistant organism
Drug combo advantages
Synergism (combo is more efficient than either used separately (B- lactams and Aminoglycosides)
Disadvantages to drug combos
Some agents work only while organism is growing. If combined with bacteriostatic agent it becomes ineffective.
- Bacterias are resistant when the agent fails to halt its growth by the maximal level of antibiotic tolerated by the host
- Genetic alteration- Spontaneous mutation, Transfer of drug resisance by R factors (plasmids)
- Modification of target site (eg Staph aureus)
- Decrease accumulation (Decreased permeability for agent)
- Enzymic inactivation (B- lactamase resistant organism)
Complications of therapy
- Direct toxicity
Reaction to drig or metabolites is frequent (eg Penicillin)
High levels in serum may be toxic to the host (Aminoglycoside produce ototoxicity)
Therapy may alter the normal flora allowing overgrowth of opportunistic organisms
- Situations in which antibiotics are used for prevention.
- Restricted to situations where its use outweighs its potential risk.
examples on when to use prophylactic antibiotics
- 1- Prevention of strep infections in pts with a history of rheumatic heart disease. Pts may require years of treatment.
- 2- Pretreatment of patients undegoing dental extractions who have implanted prosthetic devides, such as artificial heart valves, to prevent seeding of the prosthesis.
- 3- Prevention of tuberculosis or menigitis among individuals who are in close contact with infection pts.
- 4- Treatment prior to certain procedures to prevent infection.
- 5 Treatment of the mother with zidovudine to protect the fetus in the cause of HIV infected, pregnant women.
Classifications of antimicrobial agents
- Inhibitors of metabolism (Sulfonamides, Trimethoprim)
- Inhibitors of cell wall synthesis (B-Lactams, Vancomycin)
- Inhibitors of protein sysnthesis ( Tetracyclines, Aminoglycosides, Macrolides, Clindamycin, Chloramphenicol)
- Inhibitors of nucleic acid function or synthesis (Fluroroquinolones, Rifampin)
- Inhibitors of cell membrane function (Isoniazid, Amphotericin B)
Cell wall inhibitors
- These agents are active against proliferating microorganisms
- The most important members are the B-lactam antibiotics since the ring is esential for antimicrobial activity.
Cell wall inhibitors
- B lactam antibiotics:
- Other antibiotics:
Interfere with transpeptidation or cross-linkage, last stage of cell wall synthesis.
- Rationale: Makes bacterial wall less stable and osmotically fragile, therefore bactericidal in nature
- Ineffective against organisms that don't synthesize peptidoglycans as: mycobacteria, protozoa, fungi, viruses.
- Penicillins bound to preiplasmic "receptors" where bacterial enzymes work to produce and modify its wall.
- Many bacteria produce autolysins for remodeling the wall.
- In presence of Penicillins they "synergistically" destroy its wall.
Obtained from the mold. Penicillum chrysogenum
- Differ from the substrate R group:
- Natural Penicillins: Antistaphylococcal
- Semi-synthetic: Extended spectrum, Antipseudomonal.
- Crystalline penicillin G (IV)
- Penicillin V (po)
- Aqueus procaine penicillin G (IM)
- Benzathine penicillin G (IM)
Antistaphylococcal Penicillins (COMND)
- Methicillin (IV)
- Nafcillin (IV)
- Isoxazloyl penicillins (IV)
- Oxacillin (IV)
- Cloxacillin (PO)
- Dicloxacillin (PO)
- Ampicillin (IV or PO)
- Amoxicillin (IV or PO)
- Carbenicillin (IV)
- Ticarcillin (IV)
- Piperacillin (IV)
- Azlocillin (IV)
- Mexlocillin (IV)
Pen G. (benzylpenicillin)
- used IV or IM- effective against Gram + and - organisms but is susceptible to inactibation by B-lactamase penicillinases.
- Not resistant to acid (not used orally)
Therapeutic applications for Penicillin G
- Streptococcus sp. (pneumoniae, pyogens, viridans)
- Neisseria sp (gonorrhea, meningitides)
- Clostridium perfringes
- Bacilus antracis
- Corynebacterium diphteriae
- Treponema pallidum
Similar spectrum to Pen G. but more acid stable (used in oral indections by anaerobes)
Penicillinase resistant agents use restricted for resistant organisms (COMND)
- extended spectrum
- Spectrum similar to Pen G.- but more effective against Gram (-)
Can be natural or acquired
Organism lacking peptidoglycan cell wall
- Plasmid transfer (significant problem)
- B-lactamase activity (constitutive vs. acquired)
- decreased permeability to drug
- altered penicilin binding proteins
- Route determned by stability to gastric acid and severity of infection
- PO- oral
- Depot (IM) Procaine, Pen G, and Benzyl Pen G)
- IV (antipseudomonal)
Most are incompletly absorbed after oral intake (except amoxicillin)
Distribution of Penicillin
Free drug is distributed well including the placenta but the hemato-encephalic barrier is limited to acute stages of disease
Matabolism of Penicillin
Excretion of Penicillin
Primary route is renal tubular secretion and glomerular filtration
Adverse reactions of Penicillin
- Hypersensitivity (most important) 5% of patients (penicilloic acis reacts with proteins (hapten))
- Nephritis (eg. Methicillin)
- Neurotoxicity (may produce seizures if injected intrathecally)
- Platelet dysfunction (antipseudomonal)
- Caution toxicity- usually administered as Na+ or K+ salts (avoided by ising the most potent which allow for lower doses)