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132 Cards in this Set

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Treatment for stomach [3]
PPIs
Antacids
Histamine-2-Antagonists
Treatment for antiemetic [7]
Serotonin (5-HT) inhibitor (5-hydroxytryptamine
)
Dopamine Receptor Antagonists
Histamine -1 Antagonists
Steroids
Benzodiazepines
Cannabinoids
Other
Antacids-names
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
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
Sodium Bicarbonate
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
Magnesium Hydroxide
Magnesium Hydroxide
Rapid
Laxative effect (osmotic diarrhea)
Increases magnesium load
Neurological, neuromuscular, cardiovascular impairment in patients with renal disease
Calcium Carbonate
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
Aluminum Hydroxide
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
Sucralfate is
Sucralfate is complex salt with sucrose sulfate
Lacks antacid activity but treats duodenal or gastric ulcers
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)
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
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
Contraindicated
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.
Histamine-2 Antagonists
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
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
Dopamine Antagonists
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
Metoclopramide (Reglan)
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
Cisapride (Prepulsid)
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
Domperidone (Motilium)
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.
Droperidol (Inapsine)
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)
Prochlorperazine (Compazine)
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
Dopamine Antagonist Overdose Treatments
Diphenhydramine IV treats extrapyramidal symptoms.
Anticholinergic activity gives beneficial effects
Droperidol, prochlorperazine, metoclopramide
Other option is Benztropine (anticholinergic)
Histamine-1 Antagonists
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
5-HT3 Antagonists
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
Steroid anti-emetic
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
Benzodiazepine Anti-emetic
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
Cannabinoid Anti-emetics
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.
Trimethobenzamide (Tebamide/Tigan)
Believed to effect chemoreceptive trigger zone (CTZ)
Because not acting at receptors, less effect
Propofol
Propofol
GABA modulator, CTZ effects
Some indication may bind cannabanoid receptor
Scopalamine
Cholinergic Antagonist (anticholinergic/antimuscarinic
Emetrol
Mechanism not known
Mixture of glucose, fructose and phosphric acid
what are the The Gold Standard for GERD?
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
PPI Use and Treatments
GERD Gastro Esophageal Reflux Dis.
PUD Peptic Ulcer Disease
ZES Zollinger Ellison Syndrome
Barretts’ Esophagitis
Helicobactor Pylori
Preventitive use
GER vs. GERD
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
GERD Epidemiology
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
Heartburn Symptoms and GERD Treatment Options
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
PPI’s Are Effective in Individual Patients’ Acid-Related Disorders
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
PROTON PUMP INHIBITION
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.
Mechanism of Action PPI's
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.
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
Esophagitis and Erosive Esophagitis
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
erosive esphagitis
Endoscopic evidence of damage (erosions) in the lining of the esophageal mucosa
GERD
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
GER
A normal physiological process which occurs in virtually everyone, multiple times a day without producing symptoms or signs of mucosal damage
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.
Prevalence of Zollinger-Ellison Syndrome
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
NSAID Use in the United States
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).
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
Prevalence of H. pylori
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
There are 5 PPI’s
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
Drug/Drug Interactions PPI's
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).
PPi Side Effects
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
History of Heparin
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
HEPARIN
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.
Heparin Clinical Uses
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.
heparin Administration
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.
Heparin Side Effects
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.
Thrombocytopenia
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.
Allergic Reactions-Heparin
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
Reversal of Heparin-Induced Anticoagulation
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.
Low-Molecular-Weight Heparins
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.
Spinal and Epidural Hematomas
The risk of spontaneous hematoma formation may be increased in the presence of low-molecular-weight heparin.
Danaparoid
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.
Fondaparinux
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.
Oral Anticoagulants
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
Coumadin MOA
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
Coumadin PK's
Rapidly and completely absorbed
Peak concentrations 1 hour after ingestion
97% protein bound
Negligable renal excretion
Long elimination half-time
Clinical Uses-coumadin
Venous thromboembolism
Prevention of systemic embolization
Prosthetic heart valve
A-fib
Prevention of stroke
Recurrent MI
Prevention of death in patients with acute MI
Coumadin S/A
Bleeding
May increase incidence of intracranial hemorrhage after CVA
Skin necrosis
Crosses placenta- embryologic changes
Thrombolytics
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
Direct Thrombin Inhibitors
Suppress platelet function
Treatment of arterial and venous thrombotic disease
Hirudin, Ximelagatran, Argatroban, Bivalirudin
Adenosine Diphosphate Inhibitors
Prevention of arterial thrombosis
Inhibit platelet aggregation
Aspirin, Clopidogrel and Ticlopidine, Dipyridamole, Dextran
Platelet Glycoprotein IIb/IIIa Antagonists
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
Chemotherapy
Alkylating Agents
Antimetabolites
DNA Topoisomerase Inhibitors
Antibiotic
Antimitotic
Hormone Treatment
Monoclonal Antibodies
Aromatase Inhibitors
Gonadotropin Releasing Drugs
Progestin
Chemotherapy (drugs) generally works to kill cancer cells by...
by affecting the cell DNA. The phase of the cell cycle during which the drug works depends on the chemotherapy type.
Alkylating agents: Kill cancer cells by
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.
Antimetabolites: Block cell growth by
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).
Microtubule inhibition:
The taxanes (Taxol® and Taxotere® are examples) interfere with the cell's structure, blocking cell division.
Nitrosoureas:
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).
Antitumor antibiotics:
Act by binding with DNA and preventing RNA creation. Examples include doxorubicin (Adriamycin®) and mitomycin-C.
Plant (vinca) alkaloids:
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.
Hormonal manipulations:
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.
3 main mech's of anticancer drugs
-act on DNA
-act on miotic spindle
-act on steriod hormones
anticancer
act on DNA how
damage dna
inhibit synthesis of functions
anticancer drugs

act on steriod hormones how?
agonize or antagonize
anticancer drugs

damage dna how?
alkylatin

free radical formatino
anticancer drugs

inhibit synthesis for function of DNA how?
antimetabolites

topoisomerase inhibitors
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)
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
cancer agents Anti-Metabolites
5-flouracil
6-mercaptopurine
Folate Analogs
Methotrexate
Pyrimidine Analogs
Fluorouracil, Cytarbine, Gemcitabine
Purine Analogs
Mercaptopurine, Thioguanine, Fludarbine, Pentastatin, Cladribine, Hydroxyurea
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.
cancer agents

DNA Synthesis Inhibitors

Anthracyclines
(Doxorubicin, Daunomycin, Idarubicin, Epirubicin)
Mechanisms of Action
Anthracycline intercalating agent
Also shown to inhibit the activity of topoisomerase
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
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.
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)
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
Bleomycin Toxicity
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
anti cancer drugs

Anti-mitotic Agents
Vinblastine – Vinca Alkaloid
Bind to Tubulin and interferes with the formation of microtubules.
Other: Vincristine, Vinorelbine
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
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
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
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:
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
cancer Therapy Concerns
Selectivity
Resistance
combination therapy
Solid Tumors
no blood supply
no oxygen supply (hypoxic)
Insulin Stimulation
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
Type I Diabetes (Juvenile Diabetes)
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
DM 1 Treatment
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
Insulin Formulations (pg 479)
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
Type II Diabetes
Insufficient production of insulin
Resistance to action of insulin
Mechanism not understood
Increased risk of high glucose, coronary heart disease, increased blood pressure, gout
DM II Treatment
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
Sulfonylureas:
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
Meglitinides:
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.
Riguanides:
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.
Thiazolidinediones:
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.
Alpha-Glucosidase Inhibitors:
Alpha glucosidases are responsible for breaking down carbohydrates in the diet. No carbohydrate breakdown, no glucose to be absorbed.
Incretin Memetics:
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.
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.
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
PPAR drugs
troglitazon
rosiglitazon
pioglitazon
Clinical Uses of Antidepressants
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
Selective Serotonin Uptake Inhibitors
Fluoxetine, Sertraline, Paroxetine, Fluvoxamine, Citalopram, Escitalopram, Bupropion, Venlafaxine, Trazodone, Nefazodone
Tricyclic and related cyclic compounds
Amitriptyline, Amoxapine, Clomipramine, Desipramine, Doxepin, Imipramine, Nortriptyline, Protriptyline, Trimipramine, Mirtazepine
Monoamine Oxidase Inhibitors
Phenelzine, Tranylcypromine, Isocarboxazid
SSRIs
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
triCyclics
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
MAOIs
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.
Benzodiazepines for psycho
Buspirone (BuSpar) common for more general and mild. Partial serotonin agonist.
Lithium
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
Antipsychotic Drugs Treatment of
Schizophrenia
Mania
Depression with psychotic features
Organic psychoses
Antipsychotic Drugs
Phenothiazines
Thioxanthenes
Dibenzodiazepines
Butyrophenones
Diphenylbutylpiperidines
Benzisoxazole
Antipsychotic Drugs MOA, S/A
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)
Antiepileptic Drugs
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
Parkinson’s Treatment
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