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132 Cards in this Set
- Front
- Back
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Treatment for stomach [3]
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PPIs
Antacids Histamine-2-Antagonists |
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Treatment for antiemetic [7]
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Serotonin (5-HT) inhibitor (5-hydroxytryptamine
) Dopamine Receptor Antagonists Histamine -1 Antagonists Steroids Benzodiazepines Cannabinoids Other |
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Antacids-names
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Aluminum Hydroxide
AlternaGEL, Alu-Cap, Alu-Tab, Amphojel, Dialume Aluminum Hydroxide Oral Liquid AlternaGEL Liquid, Amphojel Suspension Aluminum and Magnesium Hydroxide Alamag, Aludrox, Di-Gel, Maalox, Magnalox, Mylanta, Rulox Aluminum and Magnesium Hydroxide Oral Suspension Alamag Suspension, Maalox Suspension, Magnalox Suspension, Magnox Suspension, Mintox Suspension Calcium Carbonate Tablets Amitone, Caltrate 600, Dicarbosil, Equilet, Mallamint, Titralac, Tums Magaldrate Iosopan, Riopan Magnesium Gluconate Almora, Magonate, Magtrate Magnesium Hydroxide Milk of Magnesia, Milk of Magnesia-Concentrated, Phillips Milk of Magnesia |
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Antacids
Treatment for patients with symptoms of mild GERD and are sometimes used to treat peptic ulcer disease (PUD). Raise pH by neutralizing HCl |
Aluminum, calcium, magnesium salts
Raise pH above 5 which inactivates pepsin and produces bile-chelating effects Increases gastric motility by action of gastrin (excepts aluminum hydroxide) Increases lower esophageal sphincter tone Beneficial effect on rate of duodenal ulcer healing and treatment of pain Onset 5-15 minutes and duration 1-3 hours Nonparticulate best because no pulmonary damage is aspirated Single dose can increase gastric fluid volume Must be used in combination therapy to effectively treat PUD Pepsin – digestive enzyme irritating to stomach Lower esoophageal sphincter muscle --- muscle that separates the esophagus from the stomach |
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Sodium Bicarbonate
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Rapid but brief
Systemic alkalosis is possible Useful if alkalinize the urine Chronic use increases sodium load Not tolerated by patients with hypertension or heart disease |
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Magnesium Hydroxide
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Magnesium Hydroxide
Rapid Laxative effect (osmotic diarrhea) Increases magnesium load Neurological, neuromuscular, cardiovascular impairment in patients with renal disease |
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Calcium Carbonate
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Calcium Carbonate
Rapid Chronic therapy causes metabolic alkalosis Increase calcium load Dangerous hypercalcemia in patients with renal disease May cause hypophosphatemia Evoke hypersecretion of hydrogen ions (acid rebound) Carbon dioxide release in stomach (eructation and flatulence) Can cause constipation |
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Aluminum Hydroxide
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Aluminum Hydroxide
Many effects, poor taste, low patient acceptance Increase aluminum concentration Encephalopathy attributed to intoxication with aluminum in patients with renal disease (undergoing hemodialysis) Forms insoluble aluminum phosphates in intestine Marked constipation Can cause hypomagnesemia and phosphorus depletion Sucralfate is complex salt with sucrose sulfate Lacks antacid activity but treats duodenal or gastric ulcers |
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Sucralfate is
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Sucralfate is complex salt with sucrose sulfate
Lacks antacid activity but treats duodenal or gastric ulcers |
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Overdose
For aluminum-containing antacids (Gaviscon, Maalox, Mylanta) |
Bone pain, constipation (severe and continuing), feeling of discomfort (continuing), loss of appetite (continuing), mood or mental changes, muscle weakness, swelling of wrists or ankles, weight loss (unusual)
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Overdose
For calcium-containing antacids (Mylanta, Rolaids, Tums) |
Constipation (severe and continuing), difficult or painful urination, frequent urge to urinate, headache (continuing), loss of appetite (continuing), mood or mental changes, muscle pain or twitching, nausea or vomiting, nervousness or restlessness, slow breathing, unpleasant taste, unusual tiredness or weakness
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Overdose
For magnesium-containing antacids (Gaviscon, Maalox, Mylanta) |
Difficult or painful urination, dizziness or light-headedness, irregular heartbeat, mood or mental changes, unusual tiredness or weakness
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Contraindicated
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Calcibind – binds calcium to prevent formation of calcium containing kidney stones. Calcium antacids overload calcium levels and calcibind not adequate
Isoniazid -- Isoniazid is bactericidal to rapidly-dividing mycobacteria (tuberculosis) , but is bacteriostatic if the mycobacterium is slow-growing. Aluminum hydroxide antacids limits oral bioavailability. Ketoconazole Impairs synthesis of ergosterol, allowing increased permeability in fungal cell membrane and leakage of cellular components.. Requires acidity to dissolve and for absorption Mecamylamine - nicotinic antagonist that is well absorbed from the gastrointestinal tract and crosses the blood-brain barrier. Mecamylamine has been used as a ganglionic blocker in treating hypertension, but, like most ganglionic blockers, is more often used now as a research tool. Best I can find, alkalinization limits the elimination of the drug. Methenamine: as an antibiotic (commonly the hippurate salt, methenamine hippurate), and as a solid fuel tablet used for cooking while camping or hiking. Used as prophylaxis against UTIs. Requires acidic stomach conditions for hydrolysis to acive formaldehyde drug. Sodium polystyrene sulfonate (Kayexalate®, Kionex®) is a medication used to treat high potassium levels. Tetracycline: group of broad-spectrum antibiotics whose general usefulness has been reduced with the onset of bacterial resistance. Despite this, they remain the treatment of choice for some specific indications -- binds easily with magnesium, aluminium, iron, and calcium, which reduces its ability to be completely absorbed by the body. |
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Histamine-2 Antagonists
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Inhibit histamine receptors
Increase gastric pH and reduce volume Treatment for heartburn and peptic ulcers Drugs Sedation like droperidol Cimetidine (Tagamet) Rantidine (Zantac) Famotidine (Pepsid) Can cause sedation |
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Ranitidine (Zantac) is 5-8 times more potent and longer lasting than cimetidine (Tagamet)
Cimetidine inhibts cytochrome p450, has many adverse drug reactions, can interfere with estrogen metabolism |
Cimetidine will prolong the effects/cause toxic side effects of any other drug requiring p450 metabolism
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Dopamine Antagonists
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Competitive antagonists of dopamine receptors
Anti-emetic properties Reduce post-op nausea and vomiting Drugs Metoclopramide (Reglan) Droperidol (inapsine) Domperidone (Motilium, usually in combination) Other dopamine antagonists (see next page) **anfentanil (opioid analgesic) may also have antagonist activity Cause extrapyramidal (CNS) side effects The best known EPS is tardive dyskinesia (involuntary, irregular muscle movements, usually in the face). Other common EPS include akathisia (restlessness), dystonia (muscular spasms of neck - torticollis, eyes - oculogyric crisis, tongue, or jaw; more frequent in children), drug-induced parkinsonism (muscle stiffness, shuffling gait, drooling, tremor; more frequent in adults and the elderly), Domperidone in combination with metoclopramide, cyclizine (antihistamine), and 5HT3 receptor antagonists |
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Metoclopramide (Reglan)
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Dopamine antagonist and acts on the GI tract as a pro-kinetic (gastrokinetic)
Accelerated gastric clearance of liquids and solids CNS effect causes release of acetycholine from cholinergic synapse in GI wall to give clinical effects Any dopamine effect would be a chemoreceptor trigger zone effect but cholinergic effect more clinically relevent Other uses: Treat diabetic gastroparesis Treat reflux esophagitis (heartburn) Treat patients at risk for aspiration pneumonitis Mendelson’s syndrome, rinsk when pH above 2.5 and 25 mL volume Inhibits plasma cholinesterase Succinylcholine is prolonged Extrapyramidal side effects Other uses because acts on the GI tract to: Relaxes pyloric sphincter, promotes gastric motility, increases lower esophageal sphincter tone, relaxes the small intestine, has anti-emetic effects Should never be given with another drug that also has extrapyramidal side effects. Should not be given to someone with full stomach |
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Cisapride (Prepulsid)
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Gastrokinetic
Stimulates gastric emptying, increases lower esophageal sphincter tone, enhances motilit in intestine a parasympathomimetic which acts as a serotonin 5-HT4 agonist Stimulation of the serotonin receptors increases acetylcholine release in the enteric nervous system |
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Domperidone (Motilium)
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Dopamine antagonist only that has gastrokinetic effect
Benzimidazole derivative Does not cross BBB No cholinergic effect No extrapyramidal effects Effects due to peripheral dopamine antagonist effects. |
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Droperidol (Inapsine)
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Butyrophenone Analog
Dopamine and alpha-1 antagonist neuroleptic (sedated) state extrapyramidal symptons Sometimes can cause hypotension Contraindicated for Parkinson’s Domperidone is not because does not cross BBB Parkinson’s is dopamine deficiency. Exacerbate parkinsons. All dopamine antagonists that cross BBB should be avoided with parkinsons patients (droperidol, metoclopramide, prochlorperzine, alfentanil) |
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Prochlorperazine (Compazine)
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Phenothiazine analog
Potent neuroleptic (sedative) Extra pyramidal side effects Uses: Potent anti-psychotic Other phenothiazine dopamine antagonists: Droperidol, Haloperidol, Chlorpromazine, Promethazine, Prochlorperazine. Phenothiazine analogs usually used for anti-psychotics however they are also potent anti-emetics |
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Dopamine Antagonist Overdose Treatments
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Diphenhydramine IV treats extrapyramidal symptoms.
Anticholinergic activity gives beneficial effects Droperidol, prochlorperazine, metoclopramide Other option is Benztropine (anticholinergic) |
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Histamine-1 Antagonists
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Drugs
Cyclizine (Marezine), Diphenhydramine (Benadryl), Dimenhydrinate (Dramamine) Meclizine (**) Promethazine (Phenergan), Hydroxyzine Many names such as dramamine II, not as many side effects dimenhydrinate so sometimes exchanged Also listed as anti-emetics, also used as sedatives as well. Hydroxyzine – also analgesic and anxiolytic as well |
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5-HT3 Antagonists
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Competitive inhibit serotonin receptors in the CNS and GI tract
Used as an antiemetic Drugs Ondansetron (Zofran) Dolasetron (Anzamet) usually chemotherapy Palonosetron (Aloxi) new Side effects include headache and diarrhea |
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Steroid anti-emetic
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Dexamethasone
Glucocorticoid steroid hormones mechanism not known can be used individually or to augment the effect of 5-HT3 receptor antagonists Other effects include anti-inflammatory and immunosuppressant activities |
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Benzodiazepine Anti-emetic
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Midazolam (Versed)
GABA modulator, Adenosine reuptake inhibitor Also used for anxiolytic, amnestic, hypnotic, anticonvulsant, skeletal muscle relaxant and sedative properties Formulated in open ring form Quick onset and offset Binds GABA activating it for more tightly binding of GABA – Inhibitory pathway. Also inhibited the reuptake of adenosine so more adenosine agonism |
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Cannabinoid Anti-emetics
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Bind to Cannabis receptors
CB1: basal ganglia, limbic system (hippocampus), cerebellum, male and female reproductive systems CB2: Immune system, spleen No receptors in medulla so no effect on respiration or heart Spleen – possibly mediating anti-inflammatory effects. Endocannabinoids (the natural ligand) serve as intercellular 'lipid messengers', signaling molecules that are released from one cell and activate the cannabinoid receptors present on other nearby cells. |
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Trimethobenzamide (Tebamide/Tigan)
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Believed to effect chemoreceptive trigger zone (CTZ)
Because not acting at receptors, less effect |
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Propofol
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Propofol
GABA modulator, CTZ effects Some indication may bind cannabanoid receptor |
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Scopalamine
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Cholinergic Antagonist (anticholinergic/antimuscarinic
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Emetrol
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Mechanism not known
Mixture of glucose, fructose and phosphric acid |
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what are the The Gold Standard for GERD?
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PPI's
Not the traditional ant-acids More selective than H2 blockers Much more effective than the H2’s Have unique ability to decrease the amount of HCl produced |
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PPI Use and Treatments
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GERD Gastro Esophageal Reflux Dis.
PUD Peptic Ulcer Disease ZES Zollinger Ellison Syndrome Barretts’ Esophagitis Helicobactor Pylori Preventitive use |
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GER vs. GERD
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GER is a normal physiological process that occurs multiple times a day without producing mucosal damage
Normal instances of acid regurgitation without symptoms GERD results from the failure of the normal antireflux mechanism that protects against frequent and abnormal amounts of GER Irregular occurrences of acid regurgitation can lead to esophageal ulceration, peptic stricture and BE |
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GERD Epidemiology
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GERD affects men and women equally
Increasing age is an important factor in prevalence of GERD complications Decreasing prevalence of H. pylori may be contributing to increasing prevalence of GERD GERD significantly impairs quality of life GERD-associated prevalence of EE: 7% in U.S. 2% - 10% in Europe GERD associated morbidity: 5% esophageal ulcerations 4% - 20% peptic strictures 8% - 20% BE |
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Heartburn Symptoms and GERD Treatment Options
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Lifestyle modifications
Head of bed elevation Avoidance of tight-fitting clothes Weight loss Restriction of alcohol Elimination of smoking Dietary therapy Refraining from lying down after meals Avoidance of evening snacks before bedtime Over-the-counter medications Antacids Davison® H2RAs PPI Prescription medications Prokinetics H2RAs PPIs Sugery |
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PPI’s Are Effective in Individual Patients’ Acid-Related Disorders
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Heal all grades of EE
Most erosions heal in 4 to 8 weeks Heal EE in BE patients Treats patients with pathological hypersecretory conditions including ZES Heal NSAID-associated gastric ulcers in patients continuing NSAID use PREVPAC eradicates H. pylori to reduce the risk of duodenal ulcer recurrence Individual results may vary |
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PROTON PUMP INHIBITION
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PPI’s suppress acid secretion by selectively inactivating the proton pump - the final stage of acid production. The inhibited proton pump is unresponsive to the stimuli – histamine, gastrin, and acetylcholine.
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Mechanism of Action PPI's
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Proton pump inhibitors reduce gastric acid secretion through inhibition of H+/K+-ATPase in gastric parietal cells. By inhibiting its function ppi’s prevent formation of gastric acid.
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Metabolism PPI's
excretion PPI's |
All are metabolised in the liver by the cyp2c19 and cyp3a4 pathways.
Almost all excretion is done through the kidneys for all 5 of the ppi’s |
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Esophagitis and Erosive Esophagitis
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Esophagitis is the inflammation of the lower esophagus from regurgitation of acid gastric contents, usually due to malfunction of the lower esophageal sphincter
Erosive esophagitis is indicated by endoscopic evidence of damage (erosions) in the lining of the esophageal mucosa |
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erosive esphagitis
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Endoscopic evidence of damage (erosions) in the lining of the esophageal mucosa
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GERD
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Results from the failure of the normal antireflux mechanism to protect against abnormal amounts of GER. GERD is a spectrum of disease usually producing symptoms of heartburn and acid regurgitation
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GER
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A normal physiological process which occurs in virtually everyone, multiple times a day without producing symptoms or signs of mucosal damage
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Zollinger-Ellison syndrome
PPI’s Heal EE and Treat ZES |
Zollinger-Ellison syndrome is a disorder where increased levels of the hormone gastrin are produced, causing the stomach to produce excess hydrochloric acid. Often, the cause is a tumour of the pancreas producing the hormone gastrin. Gastrin then causes an excessive production of acid which can lead to peptic ulcers (in almost 95% of patients)
Gastrin works on stomach parietal cells causing them to secrete more hydrogen ions into the stomach lumen. In addition, gastrin acts as a trophic factor for parietal cells, causing parietal cell hyperplasia. Thus, there is an increase in the number of acid secreting cells and each of these cells produces acid at a higher rate. The increase in acidity contributes to the development of peptic ulcers in the stomach and duodenum. High acid levels lead to multiple ulcers in the stomach and small bowel. |
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Prevalence of Zollinger-Ellison Syndrome
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Estimated to be 0.1 to 3 patients per million population
0.1% to 1% of patients in the U.S. who present with peptic ulcer disease Age range of affected persons varies from 7 years to 90 years Mean age at time of diagnosis is 50 years Men with ZES predominate over women by ratios varying from 2:1 to 3:2 PPI’s Are Indicated for: Short-term treatment for healing and symptom relief of all grades of erosive esophagitis Maintaining healing of erosive esophagitis. Controlled studies were conducted for up to 12 months Long-term treatment of pathological hypersecretory conditions, including ZES |
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NSAID Use in the United States
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It is estimated that 14 million people in the U.S. use NSAIDs daily
In endoscopic studies, the incidence of new gastric ulcers (GU) ranges from 10% to 40% NSAID-related complications are responsible for 10,000 to 20,000 deaths annually Estimated >100,000 hospitalizations per year NSAIDs are among the most commonly used medications in the United States – especially among the elderly. 70% of people over 65 years take NSAIDs at least weekly, and 34% take NSAIDs at least daily. A major factor limiting their use is gastrointestinal toxicity. Endoscopic studies reveal that gastric or duodenal ulcers develop in 15% to 30% of patients who regularly take NSAIDs and bleeding is a concern. It has been estimated that more than 100,000 patients are hospitalized and ~16,500 die each year in the United States as a result of NSAID-associated gastrointestinal events (15th leading cause of death in the United States). |
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The treatment of NSAID-associated gastric ulcer in patients who continued NSAID use. Controlled studies did not extend beyond 8 weeks.
Reducing the risk of NSAID-associated gastric ulcers in patients with a history of a documented gastric ulcer who require the use of an NSAID. Controlled studies did not extend beyond 12 weeks. |
PREVACID Addresses the Need for Healing GU and Reducing the Risk of Recurrence
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Prevalence of H. pylori
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H. pylori infection is commonly acquired in childhood
Typically found in socially disadvantaged or large immigrant populations In developing countries children are infected by age 10 years In the United States, 10% of white, middle- and upper class populations of 50 years or younger are infected |
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There are 5 PPI’s
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They all have the same end result in decreasing the amount of hydrochloric acid secreted form the parietal cells.
However each has it’s own receptor cite and structure Prevacid- Lansoprazole Protonix- Pantoprazole Nexium- Esomeprazole Prilosec- Omeprazole Aciphex- Rabeprozle |
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Drug/Drug Interactions PPI's
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PPIs interact with few drugs. The absorption intothe body of some drugs is affected by the presence of acid in the stomach, andbecause PPIs reduce acid in the stomach, they may affect the absorption of thesedrugs. Specifically, PPIs reduce the absorption and concentration in the bloodof ketoconazole (NIZORAL) and increase the absorption and concentration of digoxin (Lanoxin). This may lead to reduced effectiveness of ketoconazole and anincrease in digoxin toxicity. PPIs can reduce the break-down of some drugs bythe liver and lead to an increase in their concentration in the blood.Omeprazole is more likely than the other PPIs to reduce the break-down of drugsby the liver. For example, omeprazole may increase the concentration in theblood of diazepam (Valium), warfarin (Coumadin) and phenytoin (Dilantin).
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PPi Side Effects
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Inhibit absorption of Ca++
Studies have shown an increase in osteoporosis type fractures with longterm use of ppi’s. Clostridium Difficile (C-Diff) Even without a prior use of antibiotics |
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History of Heparin
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One of the oldest drugs currently still in widespread use
Discovered in 1916 but did not enter clinical trials until 1935 Heparin’s discovery can be attributed to the research of Jay McLean and William Henry Howell |
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HEPARIN
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Unfractionated heparin is composed of a mixture of highly sulfated glycosaminoglycans that produce their anticoagulant effects by binding to antithrombin, which is normally present as a naturally circulating anticoagulant.
This binding with heparin enhances by about 1,000 times the ability of antithrombin to inactivate a number of coagulations enzymes-X, XII, XI, and IX. |
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Heparin Clinical Uses
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Effective in the prevention and treatment of venous thrombosis and pulmonary embolism
Prevention of mural thrombosis after myocardial infarction (MI) Treatment of patients with unstable angina and acute MI Prevention of coronary artery rethrombosis after thrombolysis. |
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heparin Administration
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Heparin is given parenterally, as it is degraded when taken by mouth
It can be injected intravenously or subcutaneously Intramuscular injections are avoided because of the potential for forming hematomas Because of its short biologic half-life of approximately 1 hour, heparin must be given frequently or as a continuous infusion. |
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Heparin Side Effects
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Hemorrhage is the most common side effect of heparin therapy. The risk increases with the intensity of anticoagulation required, preexisting coagulation defects, and concurrent use of other drugs that impact on coagulation, and the need for instrumentation.
Hemorrhage due to heparin is minimized by dosage control based on laboratory measurement of heparin effect. Serious concurrent illness and chronic heavy consumption of alcohol increase the risk of heparin-induced bleeding. |
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Thrombocytopenia
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Can be divided into two syndromes due to heparin administration…Slaughter and Greenberg
The most common syndrome is mild, occurring in 30% to 40% of heparin-treated patients manifesting as platelet counts of <100,000 cells. Even exposure to heparin flush has been associated with acute heparin-induced thrombocytopenia. The platelet count usually returns to baseline within 4 days after heparin is discontinued A second, more severe and life-threatening syndrome develops in 0.5% to 6.0% of patients manifesting as severe thrombocytopenia <50,000 cells. This severe response usually develops after 6 to 10 days of heparin therapy and is probably due to formation of heparin-dependent antiplatelet antibodies that trigger platelet aggregation and resulting thrombocytopenia. |
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Allergic Reactions-Heparin
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Heparin is obtained from animal tissues
Caution should be used in its administration to a patient with a preexisting history of allergy Fever, urticaria, and cardiopulmonary changes occasionally occur after administration of heparin |
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Reversal of Heparin-Induced Anticoagulation
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Protamine
The specific antagonist of heparin’s anticoagulant effect. Strongly alkaline The positively charged alkaline protamine combines with the negatively charged acidic heparin to form a stable complex that is devoid of anticoagulant activity. These heparin-protamine complexes are removed by the reticuloendothelial system. |
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Low-Molecular-Weight Heparins
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Enoxaparin and dalteparin are low-molecular-weight heparins derived from standard commercial-grade unfractionated heparin by chemical depolymerization to yield fragments approximately one-third the size of heparin.
These fragments are heterogenous in size, with a mean molecular weight of 4,000 to 5,000 daltons. |
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Spinal and Epidural Hematomas
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The risk of spontaneous hematoma formation may be increased in the presence of low-molecular-weight heparin.
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Danaparoid
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A glycosaminoglycuronan that is derived from porcine intestinal mucosa and consists of a mixture of heparin sulfate, dermatan sulfate, and chondroitin sulfate.
Elimination is predominately through the kidneys Effective in decreasing the incidence of DVT following hip arthroplasty. Minimal risk of immune-induced thrombocytopenia. |
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Fondaparinux
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A synthetic anticoagulant composed of the five saccharide units that make up the active site of heparin that binds antithrombin.
Administered SC, fondaparinux is rapidly absorbed and has an elimination half-life of 15 hours, making it acceptable for once daily dosing. Eliminated through the kidneys Clinical uses include prevention of DVT and pulmonary embolism. |
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Oral Anticoagulants
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Derivatives of 4-hydroxycoumarin
Warfarin is most frequently used Predictable onset and duration of action Excellent oral bioavailability Disadvantages Delayed onset Difficult reversal for surgical procedures-discontinue 1-3 days previous Frequent lab draws-PT |
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Coumadin MOA
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Inhibits vitamin K epoxide reductase, blocking conversion of vitamin K epoxide to vitamin K
Subsequent depletion of vitamin K results in the porduction of hemostatically defective vitamin K-dependant coagulation proteins Prothrombin Factors VII, IX, X Platelet activity is not altered by oral anticoagulants |
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Coumadin PK's
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Rapidly and completely absorbed
Peak concentrations 1 hour after ingestion 97% protein bound Negligable renal excretion Long elimination half-time |
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Clinical Uses-coumadin
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Venous thromboembolism
Prevention of systemic embolization Prosthetic heart valve A-fib Prevention of stroke Recurrent MI Prevention of death in patients with acute MI |
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Coumadin S/A
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Bleeding
May increase incidence of intracranial hemorrhage after CVA Skin necrosis Crosses placenta- embryologic changes |
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Thrombolytics
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Convert the endogenous proenzyme plasminogen to the fibrinolytic enzyme plasmin
Goal is to restore circulation through a previously occluded artery or vein Risk is spontaneous bleeding, especially intracranial hemorrhage Streptokinase, Alteplase, Anistreplase |
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Direct Thrombin Inhibitors
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Suppress platelet function
Treatment of arterial and venous thrombotic disease Hirudin, Ximelagatran, Argatroban, Bivalirudin |
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Adenosine Diphosphate Inhibitors
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Prevention of arterial thrombosis
Inhibit platelet aggregation Aspirin, Clopidogrel and Ticlopidine, Dipyridamole, Dextran |
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Platelet Glycoprotein IIb/IIIa Antagonists
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Act at the corresponding fibrinogen receptor that is important for platelet aggregation
Block fibrinogen binding to platelet glycoprotein IIb/IIIa receptors that is final common pathway of platelet aggregation Clinical uses Acute coronary syndrome Unstable angina MI Abciximab, Eptifibatide, Tirofiban |
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Chemotherapy
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Alkylating Agents
Antimetabolites DNA Topoisomerase Inhibitors Antibiotic Antimitotic Hormone Treatment Monoclonal Antibodies Aromatase Inhibitors Gonadotropin Releasing Drugs Progestin |
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Chemotherapy (drugs) generally works to kill cancer cells by...
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by affecting the cell DNA. The phase of the cell cycle during which the drug works depends on the chemotherapy type.
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Alkylating agents: Kill cancer cells by
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directly attacking DNA. This type of drug is used for many types of cancer, including chronic leukemias, lung cancer, breast cancer, ovarian cancer and others. Cyclophosphamide (Cytoxan®) is a commonly used alkylating agent.
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Antimetabolites: Block cell growth by
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interfering with activities such as the making of DNA. This type of drug is used for cancers such as acute and chronic leukemias, breast cancer, some cancers of the gastrointestinal tract, and others. An example of a commonly used antimetabolite is 5-fluorouracil (5FU).
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Microtubule inhibition:
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The taxanes (Taxol® and Taxotere® are examples) interfere with the cell's structure, blocking cell division.
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Nitrosoureas:
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Block changes necessary for DNA repair. These drugs are used to treat brain tumors, lymphomas, multiple myeloma, and melanoma. Examples include carmustine (BCNU) and lomustine (CCNU).
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Antitumor antibiotics:
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Act by binding with DNA and preventing RNA creation. Examples include doxorubicin (Adriamycin®) and mitomycin-C.
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Plant (vinca) alkaloids:
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Derived from plants, these anti-cancer agents block cell division. They are used to treat a variety of cancers, including lymphoma, some leukemias, testicular cancers, lung cancer, and others. Vincristine and vinblastine are examples.
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Hormonal manipulations:
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Although the exact mechanism of action is not well understood, drugs in this class are effective in the management of cancers such as breast cancer. Tamoxifen is a well-known example, and is used for estrogen dependent cancers of the breast.
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3 main mech's of anticancer drugs
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-act on DNA
-act on miotic spindle -act on steriod hormones |
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anticancer
act on DNA how |
damage dna
inhibit synthesis of functions |
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anticancer drugs
act on steriod hormones how? |
agonize or antagonize
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anticancer drugs
damage dna how? |
alkylatin
free radical formatino |
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anticancer drugs
inhibit synthesis for function of DNA how? |
antimetabolites
topoisomerase inhibitors |
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anticancer drugs
alkylating agent MOA exps |
miscoding of DNA
crosslinking of DNA nitrogen mustard agents-(guanosine, Active aziridinium intermediate_ -Mechlorethamine -Melphalan -Chlorambucil -cyclophosphamide others Ethyleneimine Hexamthylmelamine. Thiotepa Alkyl Sulfonates Busulfan Nitrosoureas Carmustine, Lomustine, Semustine, Streptozotocin Triazenes Dacarbazine, Temozolamide (next slide) Bioreductive Alkylating agents Mitocycin C Platinating Agents Cisplatin, Carboplatin, Oxaliplatin (next slide) |
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anticancer drugs
Cisplatin |
DNA alkylating reagent
The damaged DNA induces repair mechanisms, which activate apoptosis when repair proves impossible Causes fall in GFR and development of acute tubular necrosis wi 3-5 days possibly due to retention of platinum. Increase in blood urea, nitrogen, creatine, proteinuria, hyperuricemia, can lead to renal failure Also can cause neurotoxicity, nausea and vomiting, ototoxicity, alopecia, hypomagnesaemia, hypokalaemia and hypocalcaemia Toxicities possibly may be protected with mannitol, furosemide |
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cancer agents Anti-Metabolites
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5-flouracil
6-mercaptopurine Folate Analogs Methotrexate Pyrimidine Analogs Fluorouracil, Cytarbine, Gemcitabine Purine Analogs Mercaptopurine, Thioguanine, Fludarbine, Pentastatin, Cladribine, Hydroxyurea |
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cancer agents
DNA Synthesis Inhibitors |
Topoisomerases can fix these topological problems and are separated into two types separated by the number of strands cut in one round of action:
Type I topoisomerase cuts one strand, passes the other through it then reanneals the cut strand. Type II topoisomerase cuts both strands, and passes an unbroken double strand through it then reanneals the cut strand. |
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cancer agents
DNA Synthesis Inhibitors Anthracyclines (Doxorubicin, Daunomycin, Idarubicin, Epirubicin) |
Mechanisms of Action
Anthracycline intercalating agent Also shown to inhibit the activity of topoisomerase |
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cancer agents
DNA Synthesis Inhibitors Doxorubicin (Adriamycin) |
Toxic to the heart
dose-dependent decline in mitochondrial oxidative phosphorylation. Reactive oxygen species, generated by the interaction with iron damage the myocytes causing myofibrillar loss and cytoplasmic vacuolization Non-specific st-T wave changes Premature ventricular and atrial contractions Irreversible QRS voltage depression (up to 30%, dose dependent) Affects 2-32% of patients with up to 61% mortality Mortality associated with cumulative dose |
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cancer agents
DNA Synthesis Inhibitors Actinomycins |
Dactinomycin
Mechanisms of Action inhibits DNA and RNA synthesis by binding to (3’-5’) dGdC resulting in intercalation Binds DNA at the transcription initiation complex and preventing elongation by RNA polymerase. |
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anti cancer drugs
DNA Synthesis Inhibitors Other Topoisomerase Inhibitors |
Anthracenediones
Mitoxantrone (topoisomerase II inhibitor) Epipodophyllotoxins Etoposide (topoisomerase II inhibitor) Teniposide (toposisomerase II inhibitor) Dactinomycin (Transcription Initiation Complex binding) Camptothecins Irinotecan (Topoisomerase I inhibitor) Topotecan (Topoisomerase I Inhibitor) |
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anti cancer drugs
Anti-tumor Antibiotic Agents From microbial fermentations |
Bleomycin
Mechanisms of Action (Iron activated) DNA strand scission oxidation inhibits incorporation of T in DNA Toxic to pulmonary system (10-25% of patients). Cause decrease in pulmonary functions all the way to severe pulmonary fibrosis. Concentrated preferentially in the lung because the enzyme that inactivates beomycin (a hydrolase) is deficient deficient in the lung Pulmonary capillary endothelial damage that progresses to injury with necrosis of type I and type II alveolar cells And Produces reactive oxygen metabolites (superoxide anions). Attract and activate nuetrophils and macrophages which cause tissue damage |
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Bleomycin Toxicity
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Toxic to pulmonary system (10-25% of patients).
Cause decrease in pulmonary functions (severe pulmonary fibrosis). Concentrated preferentially in the lung inactivating enzyme (hydrolase) is deficient in the lung Can cause Pulmonary capillary endothelial damage that progresses to injury with necrosis of type I and type II alveolar cells Produces reactive oxygen metabolites (superoxide anions) that Attract and activate nuetrophils and macrophages which cause tissue damage |
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anti cancer drugs
Anti-mitotic Agents Vinblastine – Vinca Alkaloid |
Bind to Tubulin and interferes with the formation of microtubules.
Other: Vincristine, Vinorelbine |
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anti cancer drugs
Anti-mitotic Agents Taxol (Paclitaxel) |
Taxene Class of anti-cancer agent
Includes other agents such as docetaxel Natural product Found in the Pacific Yew tree Interferes with the normal function of microtubule growth Also used for the prevention of restenosis (recurrent narrowing) of coronary stents Allergies to drugs such as cyclosporine, teniposide and drugs containing polyoxyethylated castor oil may indicate increased risk of adverse reactions Dexamethasone is given prior to beginning treatment to mitigate some of the side effects. Common side-effects include nausea and vomiting, loss of appetite, change in taste, thinned or brittle hair, pain in the joints of the arms or legs lasting 2-3 days, changes in the color of the nails, tingling in the hands or toes. More serious side effects such as unusual bruising or bleeding, pain/redness/swelling at the injection site, change in normal bowel habits for more than 2 days, fever, chills, cough, sore throat, difficulty swallowing, dizziness, shortness of breath, severe exhaustion, skin rash, facial flushing and chest pain can also occur |
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anti cancer drugs
Anti-mitotic Agents Colchicine |
Originally used to treat rheumatic complaints, gout (primary current use), cathartic and emetic effects, anti-cancer, pericarditis
Colchicine inhibits microtubule polymerization by binding to tubulin |
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anti cancer drugs
Hormone Therapy (Signal Transduction Modulators) |
There are certain hormones that can attach to cancer cells and can affect their ability to multiply. The purpose of hormone therapy -- also called hormonal therapy or hormone treatment -- is to add, block or remove hormones
There are several common hormone therapy drugs used for breast cancer: Tamoxifen Fareston Arimidex Aromasin Femara Zoladex Antiestrogens Tamoxifen, Toremifene, Raloxifene oral selective estrogen receptor modulator (SERM) Antiandrogens Flutamide, Bicalutamide, Nilutamide |
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anti cancer drugs
Hormone Therapy (Signal Transduction Modulators) Tamoxifen |
Tamoxifen and several of its metabolites are thought to act as estrogen antagonists, by competitively binding to estrogen receptors on tumor and other tissue targets, producing a nuclear complex that decreases DNA synthesis.2,3 This mechanism appears to have cytostatic effects, causing cells to accumulate in G0 and G1 phases.2 Tamoxifen may also have cytotoxic activity; tamoxifen may induce apoptosis independent of estrogen receptor expression.4,5 It is also recognized that tamoxifen acts as an estrogen agonist on endometrium, bone and lipids.3
PHARMACOKINETICS: |
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anti cancer drugs
Antibodies |
Monoclonal Antibodies
Rituximab Trastuzumab (Herceptin) Herceptin, also known as Trastuzumab, is currently the only clinically approved 1monoclonal antibody for the treatment of Human Epidermal Growth Factor 2 (HER2)-positive metastatic breast cancer |
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cancer Therapy Concerns
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Selectivity
Resistance combination therapy Solid Tumors no blood supply no oxygen supply (hypoxic) |
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Insulin Stimulation
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Glucose transporters translocated to plasma membrane allowing increase glucose “diffusion” into cells
Glucose metabolism shifted toward storage as glycogen (inactivate glycogen synthetase) Stimulate cellular uptake of AA, phosphate, potassium, magnesium Stimulate protein synthesis and inhibition of proteolysis Regulate gene expression via insulin regulatory elements in target DNA areas |
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Type I Diabetes (Juvenile Diabetes)
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The body does not produce Insulin
Exogenous Insulin is the only effective treatment for Type I diabetes Increased risk of heart disease, blindness, nerve damage, and kidney damage 1. the stomach changes food intop glucose 2. G enters the bloodstream 3. pancreas makes little or no insulin 4 little or no insulin enters blood stream 5. glucose builid up in the bloodstream |
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DM 1 Treatment
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Early treatment
Insulin from beef or pork pancreas Allergy, immunoresistance Current Recombinant DNA produced insulin Rapid/Short – normal meal-stimulated mimic Slow/Long – nocturnal mimic |
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Insulin Formulations (pg 479)
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Rapid
Regular Crystalline zinc (CZI) Very Rapid Lispro (Analog) Insulin Aspart (Synthetic) Intermediate Acting Lente (NPH) Long Acting Ultralente Glargine Regular – crystalized with zinc chloride |
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Type II Diabetes
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Insufficient production of insulin
Resistance to action of insulin Mechanism not understood Increased risk of high glucose, coronary heart disease, increased blood pressure, gout |
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DM II Treatment
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Sulfonylureas
Stimulate insulin secretion, hypoglycemia is a risk Glyburide, Glipizide, Glimepride, Tolbutamide, Chlorpropamide, Acetohexamide Meglitinides Stimulate insulin secretion, hypoglycemia is a risk Repaglinide, Nateglinide Biguanides Inhibit glucose production by the liver, hypoglycemia NOT a risk Metformin Thiazolidinediones Increase sensitivity to insulin for glucose uptake, hypoglycemia NOT a risk Rosiglitazone, Pioglitazone Alpha-Glucosidase Inhibitors Slow digestion and absorption of carbohydrates from diet, hypoglycemia NOT a risk Acarbose, miglitol Incretin Memetics Exantide (Byetta, very expensive) Combination Therapy Common |
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Sulfonylureas:
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experimental animals appears to be the stimulation of insulin secretion from the beta cells of pancreatic islet tissue and is thus dependent on functioning beta cells in the pancreatic islets. In humans glipizide appears to lower the blood glucose acutely by stimulating the release of insulin from the pancreas, an effect dependent upon functioning beta cells in the pancreatic islets. The mechanism by which glipizide lowers blood glucose during long-term administration has not been clearly established.
Amaryl (glimepiride, Aventis)-once-a-day sulfonylurea |
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Meglitinides:
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lowers blood glucose by stimulating the release of insulin from the pancreas. It achieves this by closing ATP-dependent potassium channels in the membrane of the ß cells. This depolarizes the ß cells and causes voltage-gated calcium channels to open. The resulting calcium influx induces fusion of insulin-containing vesicles with the cell membrane, and insulin secretion occurs.
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Riguanides:
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Metformin hydrochloride is an antihyperglycemic agent, which improves glucose tolerance in patients with type 2 diabetes, lowering both basal and postprandial plasma glucose. Its pharmacologic mechanisms of action are different from other classes of oral antihyperglycemic agents. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose, and increases peripheral glucose uptake and utilization. Unlike sulfonylureas, metformin does not produce hypoglycemia in either patients with type 2 diabetes or normal subjects (except in special circumstances, see PRECAUTIONS) and does not cause hyperinsulinemia. With metformin therapy, insulin secretion remains unchanged while fasting insulin levels and day-long plasma insulin response may actually decrease.
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Thiazolidinediones:
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Rosiglitazone is a highly selective and potent agonist for the peroxisome proliferator-activated receptor-gamma (PPAR_). In humans, PPAR receptors are found in key target tissues for insulin action such as adipose tissue, skeletal muscle, and liver. Activation of PPAR_ nuclear receptors regulates the transcription of insulin-responsive genes involved in the control of glucose production, transport, and utilization. In addition, PPAR_-responsive genes also participate in the regulation of fatty acid metabolism.
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Alpha-Glucosidase Inhibitors:
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Alpha glucosidases are responsible for breaking down carbohydrates in the diet. No carbohydrate breakdown, no glucose to be absorbed.
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Incretin Memetics:
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The amino acid sequence of exenatide partially overlaps that of human GLP-1. Exenatide has been shown to bind and activate the known human GLP-1 receptor in vitro. This leads to an increase in both glucose-dependent synthesis of insulin, and in vivo secretion of insulin from pancreatic beta cells, by mechanisms involving cyclic AMP and/or other intracellular signaling pathways. Exenatide promotes insulin release from beta cells in the presence of elevated glucose concentrations. When administered in vivo, exenatide mimics certain antihyperglycemic actions of GLP-1.
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PPARg controls how certain cells heed insulin's instructions to lower blood sugar levels. Patients with a mutant version of the PPAR gamma gene have a 25% higher risk of developing adult-onset diabetes, in which cells stop responding to insulin's orders. Existing diabetes drugs such as Thiazolidinedione are found to be PPARg agonist. They resensitize the body to insulin by turning on the PPARgamma receptor. In turn, that can cut C-reactive protein, a marker for inflammation, by up to 40%. However, these PPARgamma drugs make patients fatter and have undesirable side effects that include heart failure, liver failure and even death.
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By activating PPAR_:
insulin resistance is decreased ; adipocyte differentiation is modified ;VEGF-induced angiogenesis is inhibited (abstract). Leptin levels decrease (leading to an increased appetite) ;Levels of certain interleukins (e.g. IL-6) fall ;Adiponectin levels rise |
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PPAR drugs
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troglitazon
rosiglitazon pioglitazon |
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Clinical Uses of Antidepressants
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Unipolar and Bipolar Depression
Panic Disorder Social Phobia Post-Traumatic Stress Syndrome Neuropathic Pain Migraine Prophylaxis Obsessive Compulsive Disorder Bulimia Childhood Attention-Deficit Hyperactivity Disorder |
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Selective Serotonin Uptake Inhibitors
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Fluoxetine, Sertraline, Paroxetine, Fluvoxamine, Citalopram, Escitalopram, Bupropion, Venlafaxine, Trazodone, Nefazodone
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Tricyclic and related cyclic compounds
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Amitriptyline, Amoxapine, Clomipramine, Desipramine, Doxepin, Imipramine, Nortriptyline, Protriptyline, Trimipramine, Mirtazepine
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Monoamine Oxidase Inhibitors
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Phenelzine, Tranylcypromine, Isocarboxazid
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SSRIs
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broadly prescribed, drug of choice mild/moderate
Inhibit reuptake of Serotonin High therapeutic index (advantage over the tricyclics) Some risk of suicidality Low sedative effect, anticholinergic potency and orthostatic hypotension risk except for Trazodone and Nefazodone Fluoxetine is a potent inhibitor of cyp P-450 Even must be careful moving between fluoxetine (Prozac) and an MAOI. Some have long _ life’s |
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triCyclics
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Highly effective
Act as several transporters and receptors but MOA most likely block reuptake of serotonin and/or NE Some have significant sedation, anticholinergic potency and orthostatic hypotension risk but some do not. Tolerance to the anticholinergic and OH can develop Narrow therapeutic index (coma, intractable myocardial depression or ventricular cardiac dysthythmias |
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MAOIs
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Becoming limited in use (hypotension, narrow TI, difficult dosing) but works when other dont
Irreversibly Inhibit Monoamine oxidase enzyme the metabolizes biogenic amines (maintain high neurotrasmitter concetrations at synapse) Low sedative and anticholiergic potency but cause significant orthostatic hypotension Inhibit metabolism of amines in food (tyramine free diet) and drugs (catecholamines, serotonin) Important other interactions Opioids: elevated excitatory reactions with meperidine due to further increased serotonin levels (meperidine has some SSRI properties morphine might be better with coadministration). Also hypotension and depression of ventilation because of limited MAO metabolism of meperidine. Sympathomimetics: exaggerated hypertensive response due to limited metabolism. Direct acting drug better than indirect but reduce dose of all. |
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Benzodiazepines for psycho
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Buspirone (BuSpar) common for more general and mild. Partial serotonin agonist.
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Lithium
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Treatment of choice for bipolar. Many side effects and many interactions (Tables 17-8,9)
Thiazide diuretics: increased lithium load NSAIDs: increased lithium load Aminophylline: decreased lithium Neuroleptic: exacerpate extrapyramidal symptoms Anticonvulsants: additive neurotoxicity Beta antagonists: Decrease lithium tremor NMB: prolong duration |
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Antipsychotic Drugs Treatment of
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Schizophrenia
Mania Depression with psychotic features Organic psychoses |
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Antipsychotic Drugs
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Phenothiazines
Thioxanthenes Dibenzodiazepines Butyrophenones Diphenylbutylpiperidines Benzisoxazole |
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Antipsychotic Drugs MOA, S/A
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Mechanism
Possibly blockade of dopamine receptors in basal ganglia and limbic portions of the forebrain Side Effects Serious Extrapyramidal Cardiovascular (decrease in BP due to alpha antagonism and direct vasodilation and direct cardio depression) Fendolopam was dopamine agonist antihypertensive Neuroleptic Malignant Syndrome Antiemetic (good) |
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Antiepileptic Drugs
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Control seizures by decreasing excitability or enhancing inhibitory neurotransmission
Alter membrane ion currents Effect activity of inhibitory GABA neurotransmitter As a class, many kinds of drug-drug interactions Some highly protein bound Competition for binding sites Some cyp P-450 inducers Often increased doses needed for thipental, propofol, midazolam, opioids, NMB Some cyp p-450 inhibitors Different drugs have different side effects Protein binding – toxic levels of the antiepileptic or of other drug |
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Parkinson’s Treatment
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Objective: enhance the inhibitory effect of dopamine or decrease the excitatory effect of acetylcholine
Requires centrally acting drugs (cross BBB) Treatment options Levodopa (prodrug of dopamine that does not cross) Given concomitantly with peripheral decarboxylase inhibitor to limit peripheral metabolism Can also give with Catechol-O-Methyltransferase (COMT) inhibitors Several drug interactions (antipsychotics antagonize dopamine, MAOIs increase dopamine levels, anticholinergics act synergistically, pyridoxone increases carboxylase levels) Synthetic Dopamine Agonists (bromcriptine, pergolide) Anticholinergic Drugs (trihexyphenidyl, benztropine) Amantadine (antiviral) Selegiline (selective/irreversible monoamine oxidase B inhibitor) Nonpharmacologic Transplantation of fetal mesencephalic tissue Posteroventral pallidotomy BBB – like nearly all in this presentation |
