‫دعواتكم للجميع بالتوفيق والنجاح ‪‬‬
‫‪Zhoory‬‬
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Gastro intestinal disorders
Dyspepsia: pain in the upper abdomen or chest after meal ( burning, fullness, nausea, vomiting)
exacerbated by fatty meals, alcohol, cigarette.
Gastro oesophageal reflux disease (GORD):
When gastric contents come in to prolonged contact with the lower oesophageal mucosa.
Ulcers: lesion of the mucous membrane sometimes accompanied by pus.
Acute ulcers may be caused by:
 digestive action of acid and pepsin
 erosion of gastric mucosa (bile salts & bile acids)
 change in the production of mucosal cells
Three major factors are recognized:
Infection with Gm –ve helicobacter pylori
Increased Hcl secretion and pepsin
Inadequate mucosal defense against gastric acid
Treatment approaches:
 Eradicate H.pylari infection
 Reduce secretion of gastric acid or neutralizing the acid after released
 Providing agents that protect the gastric mucosa from damage
Treatment approaches:
1-Antimicrobial agents amoxycullin + metronidazole + omeprazole + chlarithroycin
2- Histamine receptor blockers (cimetidine, ranitidine)
3- Proton pump inhibitor omeprazole, lansoprazole
4- Mucosal protective agents sucralfate
5- Prostaglandin analogu misoprostol
6- Antacid AL(OH)3 , Mg(OH)2 AL(Mg)OH , NaHCo3 , CaCO3
Role of prostaglandin:
After acid secretion, prostaglandin will activate secretion of HCO3 + Mucous to increase bicarbonate
Mucosal resistance to injury and inhibit Acid secretion.
So, non steroidal anti-inflammatory prone to peptic ulcer because they inhibit prostaglandin and increase
injury because they are irritant.
There are 2 types of acid secretion:
1- Food stimulate 90%
2- 10% stimulated by vagus nerve which stimulate acetyl chaline to give basal acid secretion
Basal acid secretion has a circadian rhythm, in which gastric secretion is highest at midnight and lowest in
the early morning.
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What is the importance of basal acid secretion:
Night time awakening with peptic ulcers pain
It serves as the rational for single night dosing with H2-receptor antagorist or proton pumb inhibitor.
1-Antimicrobial agents
Optimal therapy of patients with peptic ulcer disease (duodenal and gastric ulcers) who are infected with
H.pylori requires antimicrobial treatment.
To document infection:
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Endoscopic biopsy of the gastric mucosa.
Serologic tests
Breath test for urea
If +ve tests eradication of H.pylori results in rapid healing of healing of active peptic ulcers and low
recurrence rates.
Eradication requires combinations of antimicrobial drugs.
Two weak therapy with:
 Bismuth + metronidazole + tetracycline+ omepazole.
 Metronidazole + amoxicillin or clarthromycin + omeprazole
2-H2 receptor antagonists
Gastric acid is secreted from parietal cells located mainly in the upper portion of the stomach.
Parietal cells are stimulated by gastrin, acetyl choline and histamine.
Acts on the mast cells to release histamine
Then histamine acts on the H2 receptor on parietal cells to stimulate acid secretion
So, H2 blocker inhibits gastric acid secretion elicited by:
Gastrin, acetyl choline, H2receptor agonists
H2 receptor antagonists were the result of the intentional modification of the histamine structure and reach
for chemically related substance that would act as a competitive inhibitor of the H2 receptor.
Cimetidine:
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Approved for clinical use 1977 (prototype) by FDA.
It is imidazole ring.
1983 Ranitidine was approved for use (furan ring) in management of duodenal ulcer.
Famotidine was approved (guanidine sulfomamidothiazole derivative)
Although the list of adverse reaction is long, but incidence of these adverse reaction is low and the
reaction is minor e.g headache, dizziness, malaise, diarrhea or constipation, skin rash, pruritus, loss of
lipids & impotamce.
Cimetidine binds to cytochrome P450 and thereby, decrease the activity of hepatic microsomal mixed
function oxidase.
Ranitidine binds less.
They both ranitidine and cimitidine reduce hepatic blood flow.
They are differing markedly in the recommended once a day bed time doses
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famotidine
40mg
94
83%
ranitidine
300mg
95
87%
cimitidine
800mg
85
94%
They are similar in the nocturnal acid suppression comparative healing efficacy after 8 weeks of therapy,
incidence of aside effect and drug interaction.
Uses:
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For treatment of endoscopically or radiologically confirmed duodenal ulcers.
In pathological hypersecreation conditions such as zolinger-Ellison syndrome.
Short term treatment of gastric ulcers.
Stress ulcer, peptic esophagitis & upper gastrointestinal bleeding.
Mechanism:
Competitive inhibitor to H2 receptor of parietal cells leading to reduce the gastric acid output and
concentration.
Under basal condition & gastric acid stimulated by food.
Pharmacokinetic:
Absorption: absorbed rapidly after oral administration.
Small portion is metabolized on its first pass through the liver.
Average bioavilability is 70% when compaired to IV injection.
19% bound to serum protein (Vd = 1.5 L/kg)
48% is excreted unchanged in urine (t½ = 2-3 hrs)
Drug interaction:
 Reduce hepatic metabolism of drug that are metabolized primarily by cytochrom P450 therapy delaying
elimination and increasing blood level of (warfarin, phenytoin, beta adrenergic blocking agents.
Thiophylline & lidocaine)
 Increase in serum digoxin may occur in patients taking cimatidine + digoxine.
Side effects:
Mild and transient: diarrhea, muscular pain, dizziness, rash have been repeated in a few patients.
Exacerbation joint symptoms in patients with pre-existing arthritis are observed in rare occasions.
Mild gynacomastia in 4% patients.
Increase in transaminase & createnine in plasma , reduced withdrawal of the drug.
Dose:
Adult:800 mg at bed time. IV as HCl = 300 mg in 20 ml of 0.9% sodium chloride solution or 300 mg in 100
ml dextrose. by intermittent infusion.
Although usually administered with antacid but it should be administered between doses of antacid to avid
possible inhibition of cimetidine absorption.
Dosage forms:
Tablet: 200, 300, 400, 800 mg
Injection as HCl 300 mg/5 ml single dose , vials as 300 mg/8 ml or multiple dose vials.
Prefilled disposable syrup 300 mg/2ml
White to off-white imptalline powder-unpleasant odor
Solubility 1-200 ml H2O
Used in duodenal ulcers, Zollinger Ellison spud raw (hyper secretary condition safe HCl), also short term
treatment of gastric ulcer (not long termtreatment), stress ulcers, peptic sophagitis, upper GI bleeding
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Ranitidine:
 Asubstiuted furan derivative .
 For short term treatment of duodenal ulcer zollinger disease.
Pharmacokinetic similar to cimetidin oral absorption decreased if given with antacids increased by
food. Bioavibility 50% after oral absorption , 15% bound to plasma protein, Vd = 1.4 L/Kg , 30% excreted
unchanged ,t½ = 2.5 – 3 hrs.
not long acting, no dose response relation ship.
Interaction with Diazipine, Warfarin, Metaprolol, Acetaminophine, Benzodiazepine.
S.E: like cimetidin
Dose:
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300 mg at bed time , in hypersecretory condition 150mg twice daily.
Impaired renal function 150 mg every 12-24 hrs.
Injection 25 mg/ml in 10 ml multi dose vial or in 10 ml multidose vials.
All dosage must be refrigerated & protected from light.
Substituted Furnan ring
Dosage forms:
Injection, single dose vials 2ml (25mg/ml) & multidose vial
Tablets: 150 – 300 mg twice daily
All must be protected from light
Famotidin:
Uses:
Short term treatment of active duodenal ulcer, maintance therapy after the active ulcer has healed, Zollinger
Ellison syndrome.
Duration of inhibition secretion after dose 20 & 40 is 10-12 hrs
Pharmacokinetic:
Absorption incompletely.
F = 40-45% increased by food and decreased by antacid , t½ = 2.5-3.5 hr
Excreted unchanged by renal rout 65-70%, 30% by metabolic routes, So should be used in reduced
doses & longer time intervals in patient with renal insufficiency.
Side effect:
Fever, fatigue, nausea, thrombocytopenia, pain psychic disturbances (depression, anxiety, decreased libido,
bronchospasm, acne, purities)
Dosage form:
Tablet 20-40 mg once a day at bed time , maintenance dose 20 mg each
6 hr in Zollinger Ellison syndrome.
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For short term therapy of active duodenal ulcer as cimetidine.
Bioavailability of oral dose 40-45%, increase by food and slightly decrease by antacid.
Excreted by kidney (should be taken in small doses and at longer time intervals in patients with severe renal
insufficiency).
Dose: oral 40 mg & 820 mg
Dosage form:
Tablet : 20, 40 mg
Injection 10 mg/ml in single & multiple dose powder for oral suspension
Prefilled disposable syringe 300 mg 12 ml
3-Proton pump inhibitors
The final pass way in gastric acid secretion is the exchange of H+ with K+ so hydrogen is secreted by the
paritetal cell in to gastric lumen in exchange with K+.
They are belonging to class of :
Benzimidazoles
Prototype omeprazole
Is An irreversible inhibitor of the proton pump
Uses:
 Active duodenal ulcer, Zolinger Ellison syndrome, gastroesophageal reflex.
 Use with antimicrobial agent to eradicate H.Pylori.
 Short term treatment of erosive esophagitis.
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Pharmacokinetic:
Excreted in urine as metabolites, t½ 0.5-1 hr, duration 24 hr it irreversible inhibit proton pump i.e. 24 hr
duration reflect the time required to generate new H+/K+ ATPase.
Should be taken before meals because they should be protonated (pump) and this can occurs only when
the proton pump is externalized and secreting acid before food proton is passed by the pump and food
will stimulate externalying of pump to secret H+ .
They are more potent when taken before meals and should be taken only orally and more effective 30
min in morning before breakfast.
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Dose form:
Enteric coated capsule , to protect the drug from premature activation by gastric acid in the stomach.
After absorption in duodenum, they are transported to the acid parietal cell where they are converted to the
active form.
omeprazole
Lanzoprazole
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Tablet 40 mg once daily
Effective in NSAID ulcers taken in
enteric coat, acid lability
Good with impared renal function
Onset 1 hr, duration 24-72 hrs, small
half life.
It has irreversible binding to ATPase
H+/K+
Inhibition of acid secretion peaks in 3
to 4 days & lasts for 5 days after
discontinuing treatment.
They prolong elimination of
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Lipophilic weak base, unstable in acid
(administered as enteric coated released
in small intestine
Prodrug, required protonation for
activation
Given for 30-60 min before food ,t½1.5
hr, duration 24 hrs because it is
irreversible inhibit proton pump.
30-40% more potent than omeprazole
with 30 mg
They are metabolite in liver cytochrom
enzyme so interact with commonly used
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diazepam, Warfarine, phenytoin , and
benzodiazepines.
Not used during pregnancy
Inhibit absorption of acid dependent
drug e.g. ketokenazol
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drugs
No interact with drug
Increase CL of theophylline
Not taken with ketokenazol because they
require low H+for their absorption.
4-Prostaglandins:
Prostaglandin E2 & I2
Pharmacological action:
Inhibit acid secretion , stimulate secretion of mucous and bicarbonate, has a cytoprotective effect
Thus a deficiency of prostaglandin involved in the pathogenesis of peptic ulcer.
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Mesoprostol:
Stable analogue of prostaglandin E1.
The only agents approved for prevention of gastric ulcers induced by NSAIDs.
Less effective than H2 receptor antagonists for acute treatment of peptic ulcers.
It is beneficial only in patient suffering from ulcers complication due to anti-inflammatory agents in
elderly patient.
 Used as routine prophylactic in patient taking NSAIDs
Side effect:
Like other prostaglandin, it produces contraction (not used in pregnancy)
It causes diarrhea and nausea
5-Mucosal protective agents:
They are compounds, known as cyto-protective
They enhance mucosal protection mechanisms
So they prevent mucosal injury, reducing inflammation & help in healing existing ulcers e.g. sucralfate
(complex of AL(OH)3 + sulfated sucrose )
Mechanism of action:
They bind to the +ve charge in protein (glycoprotein) of both normal & necrotic mucosa.
They form complex gel with mucus so create a physical barrier that impair diffusion HCl & prevent
degradation by pepsin.
Simulate prostaglandin ( stimulate mus & Hcc3 faralion)
Inhibit peptic digestion.
Uses:
Far long term therapy to inhibit recurrence (proptective & profylache) of peptic ulcers.
Should not be administered with H2 antagonist or antacid, because it requires H+ far to activation i.e. they
require acidic PH
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Antacid products:
o Antacids are weak bases , react with Hcl to give salt + water.
o The rational for antacid therapy has been to control the pain and to promote the healing of peptic ulcers.
There are several mechanisms by which antacids can reduce ulcer pain:
1-neutralization of acid bring pain relief.
2-elevate gastric PH above the optimum for pepsin activity(pepsin activity is completely inhibited between
PH 4 & 5.
3- tightening of the mucosal barrier & increasing lower esophageal sphincter tone.
Thus the primary effect of an antacid is to neutralize acid , elevating gastric PH and so inactivation of
pepsinogen.
In order for a product to be labeled an '' antacid'' according to FDA , it must consist of:
1-one or more approved active ingredients.
2-each A I must contribute at least 25% of the total acid-neutralizing capacity of the product.
3-the finished product must contain at least 5 mEq/ dose unit of neutralizing capacity and raise the PH of
gastric secretion to 3.5 or greater within 10 minit .
4-no more than 4 active ingredients can be combined in any one product.
This ruling eliminates many marginal or ineffective product which have promoted to the public.
Effect of antacids are temporary and disappear when medication is discontinued why??
Because raising the PH will increase activity of secreting gastric cell (Hcl)
Factors must be considered when selectin an antacid product. :
1-The patient:
Impaired renal function, edema, high blood pressure , allergic to milk products or take certain prescription
drugs.
2-Systemic Vs nonsystemic:
A systemic antacid, such as sodium bicarbonate, is soluble, readily absorbed and capable of producing
systemic electrolyte disturbances, and symptoms of alkalosis.
Non systemic, such as CaCo3, basic aluminium salts, form compounds that are not absorbed and thus do
notexert any systemic effect. So when intensive antacid therapy is indicated only non-systemic agents,
should be employed in order to avoid the potential danger of alkalosis induced by systemic antacids.
3-Neutralizing capacity:
Antacids are compared quantitatively in terms of Acid Neutralizing Capacity
(ANC) which defined as:
The number of milliequivalents of Hcl required to maintain 1 ml of antacid suspension at PH 3 for 2 h in
vitro.
Rate of neutralization varies according to the degree of combination and presence of reactive suspending
agents. So ,ANC and rate of neutralization of various antacids differ enormously .e.g.
 5 ml AL ( amphogel suspension ) will neutralize 6.5 mEq of acid in 60 minute.
 5 ml of (AL Mg OH ) Delcid susp neutralize 42 mEq acid in the same period of 60 min
Dose :
50 mEq /h of antacid is required to neutralize 90% of patients with duodenal ulcers. So , based on the ANC
given above , this would require 6 ml Delcid or 39 ml of amphojel
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Dose interval:
An ideal antacid should be rapid in onset and provide a continuous buffering action (long duration)
e.g. antacid with a rapid onset Mg OH
MgO-CaCO3
Slow onset
Mg trisilicate
AL compound
With an intermediate onset MgAL
Hydroxide
Duration :
Duration of buffering action is determined largely by when the antacid is administrated. If administered
while food in the stomach, the buffering action will lost for 2 h. an additional dose 3 h after Meals will
extend the buffering time by (1 h )
(NB: food delay GE giving more time for antacid to react )
Cost :
When the cost to the patient is a factor, the decision should be based on neutralizing capacity / dose unit
rather than cost / dosage unit
Both physical and chemical nature of antacids suggest a high potential for drug interaction
by:
1-alteration of gastric PH will affect absorption of weak acidic drugs which require low PH for absorption.
2-forming complex e.g Ca+2, Mg +2, AL+ i.e forming complex with tetracycling.
3- systemic antacids may accelerate the excretion of weak acidic drugs (salicylate) and inhibit urinary
excretion of weak basic drugs (amphetamines, or quinidin)
So , it is desirable to administer other drugs at least half an hour before antacid ingestion.
Excess use of antacid may produce adverse side effects:
1-Sod.bicarbonate:
Sodium…. Dose and systemic alkalosis, and contraindicated in patients with hypertension.
2-Mg preparation:
diarrhea
3-Ca carbonate.
Hypercalcemia, renal impairment and acid rebound (stimulate gastric secretion).
4-AL preparation:
phosphate depletion, muscle weakness, bone resarption and constipation.
Examples of antacids
N.B.
*Tablets are more effective if chewed thoroughly and followed with a full glass of water to help dissolution
and dispersion in the stomach.
*Effervescent tablets should be dissolved in water and bubbles should subside before swallowing.
1-Aluminium carbonate gel
Bassal gel (wyeth)
Uses: control hyperacidity
Dosage form : tablets, capsules, suspension
each 10 ml suspension neutralize 25 mEq /Hcl
& 2 tablets or 2 capsules
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2-AL(OH)3 Amphogel
Each 100 gm suspension contains the equivalent of 3.6-4.4 g AL oxide
Suspension may contain:
Rx
Peppermint oil
Glycerin
Sorbitol
Sucrose
Saccharin
Flavors & antimicrobial agents
Incompatibilities:
Complex with tetracycline
Uses: in peptic ulcers.
Non-systemic antiacid.
Weak
1-not elevate PH sufficiently to inhibit peptic activity
2-chronic administration can cause phosphate depletion
3- cause constipation
Dosage forms:
Chewable Tab-capsules, suspension.
3-AL-Mg hydroxide
Megaldrate
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Used as antacid in heart burn, or acid indigestion
Have a rapid action
Uniform buffering action
High acid neutralizing capacity
No alkalanization, or acid rebound
Low sodium content
More effective than AL(OH)3 or Mg(OH)2 as antacid
Neither disturb bowel function or electrolyte balance
Disadvantages: it should not be administered with tetracycline.
Dose: 480-1080 mg taken between meals & one at bed time.
Dosage forms:
Oral suspension, chewable tablets
4-Mg (OH)2 Mg oxid
5-Ca Co3 calcium carbonate
-rapidly acting antacid
-non-systemic
-CaCo3+ Hcl
CaCl 2+Co2
Soluble which is available for absorption from the stomach.
But absorption is limited because about 90% of the CaCl 2 is converted back to insoluble CaCo3 in the
small intestine.
However if enough calcium maybe absorbed over several days of frequent use will induce hypercalcemia.
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Hypercalemia may induce:
Neurologic symptoms, renal calculi, alkalosis.
CaCo3 induce gastric hypersecretion: How???
Ca+2 ion stimulate gastrin which will stimulate gastric secretion (local effect)
Co2 produced stimulate acid secretion.
Dosage forms: tablet(chewable), suspension.
Dose: 350,420, 500 mg. susp.
Tablets 0.5-1.5 gm taken every 2h – to 4 h after meals
Limitation factors of CaCo3 as antacid:
Constipation
Interact with tetracycline.
Acid rebound
Milk alkalin syndrome
6-Sodium bicarbonate
(rapid onset & short onset)
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Potent and effective antacid
Should not be used in chronic therapy (large doses may lead to systemic alkalosis )
Sodium bicarbonate elevate PH above the desired PH (4-5), gastrin will stimulated acid rebound.
Also acid may be released by gastric distention that result from Co2 released. During the reaction
between NaHCo3+ Hcl.
Thus although NaHCo3 is a potent antacid, it may stimulate further acid secretion.
Therefore effervescent NaHCo3 should be used only occasionally, for relief from over eating or indigestion.
It is contraindicated for use in chronic therapy
Dose: 300 mg to 16 g daily
Gastric antacid mix:
1- Combine fast & slow reacting antacid to obtain a product with a rapid onset & relatively sustain action.
2-Lower the dose of each component and minimizing the possibility of certain adverse effect.
3-Use one component to antagonize one or more side effects of another components (laxative verses
constipation)
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Laxatives
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dehydration
Immobilety
poor diet & fuid intake
irritable bowel syndrom
endocrine disorders
electrolyte disturbance
mechanical obstruction
drug
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Increase dietary
fiber
Increase mobility
ensure fluid intake
antidepressant
anticholinergic
AL+³,Ca+² salts
Opioids alkaloid
What is a laxative products ???
Laxative facilitate the passage and elimination of feces from colon and
rectum
What is constipation??
Infrequent as difficult evacuation which results from: the abnormal
slow movement of feces through the colon , dry and hard feces
accumulate in the descending colon
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Causes of constipation:
1-neglecting to respond to the defecation urge
2-failure to acquire the habit of regular defecation
3-faulty eating habits
4-enviromental changes
5-mental stress
6-excessive ingestion of food that harden stood
7-prolonged use of drug such as AL(OH)ɜ or CaCoɜ and anticholinergic
Laxative drug are classified according to their mechanism
of action into:
stimulant
Saline &
hyperosmotic
Bulk forming
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Anthraquinones
Cascara
Senna
Bisacodyl
phenolphthaline
 Methy cellulose
 Carboxy methy
cellulose
 Polycarbophil
 psylliumseeds
Emollient or
fecal softner
Dioctyl
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sodium
sulfosuccinate
 Mg citrate
 mgSo4
 glycesin
(suppository)
lubricant
Mineral oil
emulsion
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A-stimulant laxatives
Mechanism of action:
They increase the propulsive peristaltic activity of the intestine by:
a-local irritation of the mucosa
b-by selective action as direct action on the intramural nerve plexus of intestinal smooth muscle, thus
increasing motility.
Contraindication:
Abdominal pain, nausea or vomiting which are symptoms of appendicitis
The more commonly employed agent are:
1-Anthraquinone laxatives: e.g. senna and cascara
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these glycosides are absorbed in the small intestine, circulated through the portal system in the
general circulation.
excreted in bile, urine , saliva, colonic mucosa and milk of lactating women.
2- senna leaves:
Dried leaflet of senna, which contain aloe-emodin glycoside
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Evacuation of the bowels within 6-12h after administration.
may impart a yellowish brown color to acid urine and a reddish color to alkaline urine
Dose: 2 g
Dosage forms: Senna extract (naturally occurring glycoside )
Senna syrup
Tablet (one or two tablets daily at bed time) tablet contains 20 mg of sennasoids A&B
3-Bisacodyl (fleet bisacodyl)
Active constituents: phenol 4,4'(2-pyridinyl methylene)bis-diacetate ester
Uses:
 contact laxative which act directly on the colonic mucosa to increase peristalsis through out the
large intestine
 administered as orally or rectally for constipation.
 for evacuation of bowel prior to surgery or radiologic examination.
 it is effective over night or within 6-10h
Side effect: abdominal cramps
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Dose:10-30 mg orally or 10 mg rectal
Dosage forms: suppositories 10 mg
Enteric coated tablet
N.B.{ THE tablet should not chew or break or taken with antacid or milk}
4- phenolphlhalin: (irritant laxatives)
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acts within 4-8 h after ingestion
may cause allergy in susceptible individuals (skin rash and may cause anaphylactic schock)
may change color of urine and faeces (change color of alkaline urine red)
Dose: 60 mg oral (preferably at bed time)
Dosage forms: tablet, solution
5-castor oil:
lipolysis
Classified as stimulant laxative because lipolysis in small intestine to the castor oil
Ricinoleic acid ,Which is short chain fatty acid which stimulates peristalsis and inhibit absorption of
H2o and electrolyte from the small intestine.
N.B. chronic use is not recommended since absorption of nutrients may be reduced.
Dosage form: liquid as aromatic castor oil
Rx vanillin+ castor oil + cinnamon –saccharin + clove oil
B- Bulk forming Laxatives
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They include a wide range of natural and semisynthetic poly saccharides and cellulose
derivatiative that are only partial digested.
The undigested partions are lipophilic and swell in the presence of H2o to form aviscous solution
or gel.
This viscous gel increase intraluminal pressure,stimulate peristalsis and produce a soft gelatinous
stool.
Onset time: 12-24h or sometime require 3 days
Patient consultations:
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Each dose shoud be taken with a full glass of H2o
These drugs interact and combine with other drugs, such as salicylate, digitalis .
They should not as a general rule , be taken with other drugs or gastrointestinal obstruction.
Examples:
 Carboxy methyl cellulose agar
 Methyl cellulose
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 Plantago seed
Advantage : free from systemic sid effect.
C-Lubricant laxatives
Example:
Mineral oils (liquid paraffin)
Mechanism of action:
Lubricate the intestinal tract and soften the fecal contents and fascilitate passage of feces
Side effects
o Decrease absoprption of oil soluble vitamin(lipoid a vitaminosis)
o Aspiration causes pneumonia (contraindicated for infants and elderly patients)
Dose: 15-30 ml once aday
for children above 6 year 5-20 ml
dosage form: Emulsion
D-Fecal softners (delayed effect)
They represent the most recent approach to the management of constipation and fecal impaction
e.g. surface active agents or wetting agents which are non absorbable and relatively non toxic
Mechanism of action:
By lowering surface tension, they permit the intestinal fluids to penetrate the fecal mass more readily
and thus ,produce soft easily passed stools.
e.g.Docusate Sodium or Ca+² or K+
advantages:
o useful in preventing constipation.
o Dose not cause peristaltic stimulation ,so used in patient in whom cathartic medication is
contraindication.
o They are free from side effects and contraindication.
o Useful for constipation in geriatric and pediatric.
Dose: 50-500 mg daily or 100mg 2or 3 time daily.
Dosage form: tablets and capsules 50,60,100 mg, solution 50mg
N.B. 1-2 days of treatment is necessary before an effect is observed.
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E-Saline Laxatives or Hyperosmotic
Example:
sulfates
Mg salts
phosphate
Tartarate
s
Mechanisms:
When given orally in hypertonic solutions ,they draw water from tissues in to the intestine increase peristalsis
and induce aperfuse watery stool. Also, Mg stimulates release of endogenous cholecystokinin ,pancreozymine(
ahormone which cause accumulation of fluids and electrolytes within human small intestine.
So, laxative action of Mg salt may result from their ability to diminish the net absorption of fluid and
electrolytes.
Side effects:
o
o
20 % of Mg ion may be absorbed after oral administration ,if renal function is impaired accumulation of Mg
ion will be toxic
Chronic use of saline laxatives may also result in excessive dehydration
Dosage forms: Mg citrate oral solution, Mg So4 powder (10-15 g) dissolved in a glss of H2o
Type of constipation
Treatment options
Acute
chronic
Senna (stimulant)
Bulk forming laxatives
lactulose
Elderly patients
Acute
chronic
Glycerin supositories
Senna
lactulose
Patient who used laxative should remined of the following points:
1-laxative are not for long-term use, if they are not effective for one week, a physician should
consulted.
2-phenalphthalin discontinued if skin rash appears.
3-Saline laxative should not be given orally to child under 6 year.
4-paraffin or mineral oil not given to child under 6 years, and taken at bed time to minimize
interference with absorption of fat soluble vitamine.
5-paraffin oil also should not be given orally to elderly patients or infant (aspiration cause
pneumonia)
6-dioctyh sodium succinate should never be used with mineral oil.
7-saline laxative should not be given to infant (dehydration)
17
Anxiolytic drugs
Anxiety:
Is a state of tension- fear arise from unknown sources
Symptoms:
Tachycardia, sweating , trembling , palpitations, headaches, muscle aches , nervous tension.
i-Benzodiazepine
 Are the most widely used anxiolytic drugs
 They have largely replaced barbiturates and meprobamate in the treatment of anxiety since they are:
a-more effective
b-safer (lethal dose is over 1000 times greater than the therapeutic dose)
Mode of action:
they bind to specific ,high affinity sites on the cell membrane which are separated but adjacent to
the GABA receptor , the binding of benzodiazepine to their receptors enhances the affinity of GABA
Receptors for their neurotransmitter ,resulting in a more frequent opening of adjacent chloride
channels which results in enhanced hyperpolarization and further inhibition of neuron firing.
They have NO analgesic action , NO antipsychotic activity , NO effect on autonomic N.S
Uses:



Reduce anxiety
Hypnotic at higher doses
Anticonvulsant (muscle relaxant)
Pharmacokinetics:
Absorption: Lipophilic_ absorbed rapidly after administration
Distribution: Widely distributed (go to blood brain barrier)
Metabolism: Biotransformed in liver to an active metabolites with long half-life than the parent drug
N.B. this metabolites may be significantly in elderly and newborn or in sever liver
disease
Duration:
half- life of the drugs are very important clinically, because benzodiazepine can be divided into
short , intermediate and long acting ,the longer active agent form active metabolite with long halflife
So, pharmacokinetic considerations are very important in choice of drug
Excretion: in urine as glucouronide or oxidized metabolites
18
Dependence:
 Psychological and physical dependence can develop if high doses of the drug are given over a
prolonged period of time.
 Abrupt discontinuation result in withdrawal symptoms including:
Confusion, anxiety, agitation , restlessness, insomnia,( for long t½, symptoms not occur until a
number of days after discontinuation).
Adverse effects:
Drowsiness and confusion , early morning insomnia.
Drug interaction:
Alcohol , CNS depressants, other anxiolytic hypnotic, TCAD-opiates, analgesic ,antihistaminic , non
prescription sleep aids and cold remedies( all will produce serious side effect)
1-Alprazolam (xanax)
Uses: short term relief of anxiety
Kinetics:




Peak after oral administration 1-2h
Steady state after 2-3 days
Elimination: is rapid after discontinuation
Half-life 12-15h
So, chronic therapy should not be discontinuated abruptly (severe withdrawal symptoms)
Has no active metabolites
Dose: 0.25-0.5 T.I.D
Dosage adjustments: according to the needs of the patient
Dosage form: tablet 0.25, 0.5 and 1 mg
2-chlordiazepoxide (Riposan)
Uses: preoperative apprehension anxiety
Pharmacokinetic:
 t½ 8-20h
 accumulation occurs for the parent drug and for the three active metabolites
demoxepam t½ 37h
desoxydemoxepam 44h
19
these metabolites contribute to the overall activity of the drug
Excretion: in urine unchanged and conjugated
Adverse reactions: like other benzodiazepines
Dose: 5-10 mg 3 to 4 time daily
Dosage forms: capsule 5,10,25 mg
Tablet , powder for injection and Ampoul.
Warning: not taken in the following:




Excessive depressed patients
Elderly
Pregnant and lactating women
Renal and hepatic disorders
3-Diazepam (Valium) Roch
Uses: anxiety, acute alcohol withdrawal , skeletal muscle spasm , for management of Epilepsy
(muscle relaxant)
Pharmacokinetics:
Absorbed well after oral administration (rapid onset) lipid soluble
Elimination is slow t½ 20- 50 h
It has an active metabolite (demethyl diazepam) Which accumulate and reach steady state after 7
days
It takes long time to achieve maximum sedative and antianxiety effects
Dosage form: injection 10 mg / 2 ml , Tablets 2,5,10 mg and sustained release capsule 15 mg.
Benzodiazepines Antagonist:
Flumezenil GABA receptor antagonist



Short half-life (rapid onset) short duration
Should be taken I.V infusion (intermittent)
Frequent administration is necessary to cause withdrawal in dependence peoples
20
ii-barbiturates
Mode of action:
 Interfere with Na+ /K+ transport across the cell membrane
 Potentiate GABA action
Drug interactions:
i-They induce the hepatic microsomal enzyme
they increase rate of metabolisms of coumarin , TCAD , Oral contraceptive , digoxin ,phenytoin ,
corticosteroid.
So, patient on both barbiturates and one of these agents may develop adverse effects ,if the
barbiturates is discontinued during chronic therapy.
ii-concomitant use of barbiturates and other CNS depressants will additive the depressant effect .
iii-A patient treated with coumarin may hemorrhage if barbiturates is stopped and anticoagulant
dosage is not readjusted.
Adverse drug reaction:
Agitation , confusion , nightmares , insomnia , respiratory depression , bronchospasm ,
hypersensitivity and skin rashes
Pharmacokinetic:




Absorbed orally (salt absorbed rapidly than free acids)
Widely distributed
Metabolites in liver
Excreted via kidney in urine
(liver disease decrease their elimination , kidney insufficiency given rise to accumulation of polar
metabolites)
They have been replaced by benzodiazepines due to:






They have low therapeutic index.
Physical dependence.
Induce drug metabolizing enzymes
Induce tolerance
A very severe withdrawal symptoms
Liability to cause coma in toxic doses
They are classified according to their duration :
1-Ultrashort:
Thiopental : Which acts within seconds and has a duration of about 30 minutes. Used as I.V dosage
form for induction of anaesthesia
2-Short acting:
Amobarbital ,Secobarbital: Which are effective as sedative and hypnotics
21
3-Long acting:
Phenobarbital used in treatment of Epilepsy.
Over dose may cause Respiratory depression.
Adverse effects:



CNS impaired concentration.
Drug hangover (after effect)
Impaired ability to function normally for many hours after awaking , nausea and dizziness occur.
Poisoning: cause death by taking over dose, sever depression of respiration with central
cardiovascular depression and shallow infrequent breathing.
Treatment:
1.
2.
3.
4.
5.
22
artificial respiration
Purging the stomach of its contents
Hemodialysis
Make urine alkali
Using adsorbent (Charcoal)
Antidepressants
 Used for mild to sever depression
 Produce response in 40-70% of patients
 They have similar efficacy , however they differ in :
Adverse effects
Mechanism of action
Medication interactions
Cost
So, selection of pharmacologic agent for patients should be based on:




Specific symptoms the patient is experientially.
Adverse effects of the medications.
Medications interactions.
Ability of the patient to afford the medication.
Pathophythiology of depression:


Genetic
Biogenic amine theories i.e. decrease level of norepinehrin ,5-hydroxy tryptamine (serotonin) and
dopamine in the brain.
Symptoms include:
Loss of interest , change appetite , weight gain or loss, insomnia or excess sedation, recurrent thought of
suicide , suicide attempt.
i-Monoamine oxidase inhibitors
drug
phenelzine
Isocarboxazide
Indications:


Starting dose(mg/day)
10
20
Dose range (mg/day)
15-90
20-40
Weight gain
+++
++
Have numerous adverse effects , food & drug interactions
Indicated only in patients refractory to other medication (other antidepressants)
Mechanism of action:
Inhibit and inactivate MAOxdase enzyme by forming irreversible complexes with them
Pharmacokinetics:
 Absorbed orally ,effects require 2-4 weeks of treatment
 Enzyme regeneration require several weeks after termination of antidepressant agent MAO inhibitors
therapy
So, switching after termination of MAO inhibitors two weeks delay must be allowed
23
Adverse effects:





Tyramine toxicity (food interaction)
Hypertensive crises
Serotonin syndrome (when level of 5-hydroxytryptaine become too high)
Weight gain
Suicidal tendency
MAO inhibitor and SSRIs should not co administered due to risk of life threatening serotonin syndrome.
Both require wash out periods of 6 weeks before administering the other.
ii-selective serotonin reuptake inhibitors (SSRI)
They are currently available in the U.S. for treatment of depression
Drug
fluoxetine
paroxetine
sertraline


Starting dose mg/day
10-20
10-20
25-50
They are considered first line for treatment of depression.
Used for anxiety, Panic disorder , Obsessive convulsive disorder.
Mechanism of action:
Block reuptake of serotonin.
Adverse effects:
Nausea , vomiting , sedation , sexual dysfunction ,agitation , weight loss.
Pharmacokinetics:
May inhibit cytochrom 450. So, may interact with other medication. some has long t½
N.B. Abrupt discontinuation has been associated with withdrawal symptoms such as : night mares ,
nausea, anxiety.(with the exception of fluoxetine)
Fluoxetine has little risk of causing syndrome upon discontinuation because its long t½
SSRIs should slowly tapered when discontinued to prevent this syndrome.
24
iii-Tricyclic antidepressants
indications:



Are not usually indicated first line for the treatment of depression ,due to their numerous adverse
effects.
May be considered for patients with a history of response to TCAs or patient refractory to other
medications.
Should be avoided in ::
patient with suicidal ideation .
patients with cardiovascular conditions.
urinary retention.
closed angle glaucoma.
Mechanism of action:



Inhibiting reutake of 5-HT, NE , Dopamine.
Have effect at α – adrenergic ,histamine and cholinergic receptors
Individual TCAs have different affinities for these receptors (so different side effects)
Adverse effects:
Blurred vision , orthostatic hypotension , dry mouth , weight gain , tendency to suicidal.
Pharmacokinetics:






Lipophilic (absorbed orally)
Half life 4-17 h
Suffer first pass effect (low and in consistent availability)
Metabolized by hepatic microsomal enzyme
Conjugated with glucorinic acid ,secreted via kidney
They have anarrow therapeutic range 5-6 time the maximal dose
Examples:
tertiary amine
Amitryptyline
Imipramine
Trimipramine
Doxepin
Secondary amine
Nortriptyline
Desipramine
Precaution:
Patient should avoid the following:
 Avoid all medications including OTC.
 Alcohol beverages.
 Limit amount of caffeine
 Concurrent use of MAOIs or SSRIs a minimal (4 days should elapse between discontinuation of MAOIs
and starting TCAs therapy & vice versa
25
Amitryptyline HCL (Treptizole) (Amilril roch)
Pharmacokinetics:





Absorbed orally
Bioavailability 31-61% (first pass effect)
t½ 31-46 h
metabolized to one active metabolite (nortriptyline)
excreted in urine as an active metabolite (25-50%)
Dose: 75 mg oral in divided dose or 50 -100 mg once at bed time ,intra-muscular 20-30 mg.
Imipramine HCL
Dose : 30-40 mg not over 100 mg
Dosage form: Tablet 10 ,25, 50 mg , injection 25 mg /2 ml.
Uses : used in enuresis in childhood and elderly as an oral dose of 25 mg once a day one hour before bed
time.
Revesion:
 SSRIs is a good – first line agent particularly in patient who are benefit from simulating side effect of
SSRIs
 Amitryptine would not be good if the patient hyper somnolence and has weight gain also not
recommended in patient at risk of suicide.
 MAOIs not recommended as first line therapy.
 Antidepressant must be given 4-6 week befor it is considered a therapeutic failure.
 MAOIs are reversed for refractory depressed patient.
 Serotonin syndrome result when starting MAO immediately after another antidepressants (increase
serotonin level)
 Two weak wash out period is recommended .
 Fluoxetin require 5 weak ( because it long acting active metabolite)
26
Principles of oncology
Tumors arise from a single abnormal cell,Which continues to divide indefinitely.
Types of cancer:
Benign: slow growing resemble normal cells
Malignant: proliferate more rapidly , have an atypical appearance , invade and destroy surrounding
tissues and are harmful if left untreated.
They are classified by the location from where the tumor cell arise.
A) Solid tumors:
1-Carcinomas are tumors of epithelial cells e.g. lung, colon , breast.
2-Sarcomas –tumors of connective tissue such as bone( e.g. Osteosarcoma), muscle (e.g.
leiomyosarcoma).
B)Hemological malignancies:
1-Lymphomas: tumors of the lymphatic system and include Hodgkin-non Hodgkin.
2-Leukemias: are tumors of blood forming element and are classified as acute and chronic.
Cause:





Virus e.g. HB virus
Environmental
Medication
Life style
Genetic
Warning signs (by American cancer society)
Caution
C: Change in bowel or bladder habits
A: Asore that dose not heal
U: Unusual bleeding or discharge
T: Thickening or lump in the breast or elsewhere.
I: Indigestion or difficulty swallowing.
O: Obvious change in a wart.
N: Nagging chough or horseness.
27
Guideline for screening:
Goal of screening is to detect cancers early , when the disease is curable , and to reduce mortality.
Staging:
Is the categorizing of patients according to the extent of their disease .the stage of the disease is
used to determine prognosis and treatment.
TNM CLASSIFICATION:
a)T: indicates tumor size and is classified from 0 to 4 (zero indicate absence of tumor regional)
b)N: presence and extent of regional lymph node spread and is classified from 0-3 (zero
indicating no regional lymph node involvement.
c)M: indicate the presence of distance mitastases and is classified as 0 (for absence) or 1 (for
presence of distant metastases)
e.g.
**T2N1M0 (moderate size tumor with limited nodal disease and no distant mitastases)
Cell life cycle:
Knowledge of the cell life cycle and cell cycle kinetics is essential to the understanding of the
activity of chemotherapeutic agents.
Phases of the cell cycle:
M, G1, S, G2, G0.
Tumor doubling time:
Is the time for the tumor to double in size.
As the tumor get larger, its doubling time gets longer, because it contains a smaller population
of actively dividing cells owing to restriction of space , nutrient availability and blood supply.
Chemotherapeutic agents:
May be classified according to their effect on cell cycle kinetics.
Combinations of chemotherapy agents that are active in different phasese of the cell cycle may
result in greater cell kill.
1)Phase specific agents.
2)Phase non specific agents.
1)Phase specific agents:
Are most active against cell that are in a specific phase of the cycle.
These agents are most effective against tumors with a high growth fraction.
e.g M phase
vinca alkaloids
G1 phase
prednisone
S phase
antimetabolites
G2 phase
bleomycin
28
2)Phase non specific agents:
Are effective while cells are in the active cycle but do not require that the cell in a particular
phase. These agents generally show more activity against slow growing tumors.
e.g. alkylating agents and antibiotics also, they are effective in all phases.
Chemotherapy dosing:
Based on body weight , body surface area or AUC.
Combination therapy:
Factor to be considered :
1-antitumor activity.
2-different mechanisms of action.
3-minmally overlapping toxicities.
Reasons for combination therapy:
 Preventing resistance.
 Cytoxicity to restingand dividing cells.
 Biochemically enhancement the effect.
Acronyms: used to designate chemotherapy regimens .
e.g. C M F refere for combination of
C: cyclophosphamide , M: methotrexate , F: fluorouracil
Also, P O M P
P: prednisone , O: oncovin or vincristin, M: methotrexate, P: procarbazine.
Administration:
I.V. most commonly
Oral ,S.C , intrathecal , intraareterial , intraperitoneal , intravesical , continuous I.V. infusion
e.g. Methotrexate : oral solution, tablet, I.M. ,I.V. and intrathecal.
N.B. drugs should not be administered intrathecal route without specific information
supparting intrathecal administration.
Growth fraction = G1+S+G2+M
G0+G1+S+G2+M
IN tumors, growth fraction between 0.2-0.7 this will be greater in the more rapidly proliferating
tissue and tumors.
Those tumors with a large growth fraction are more succeptible to chemotherapy than those
with a low fraction e.g.
o Acute leukemia in children
o Hodgkin's disease
o Breast cancer
29
Example of neoplasm that respond poorly are:
Bronchogenic carcinoma , uterus and cervix carcinoma
Since growth fraction are higher in small recent tumors so, efficiency is enhanced by early
treatment.
i-antimetabolites
they are structurally reated to normal cellular components.
They interfere with the availability of normal purine or pyrimidine inhibiting their synthesis or
completing with them in DNA or RNA synthesis.
They are cell cycle specific.
1-Methotraxate(related to folic acid)
Site of action:
Inside the cell (transfere by active transport mechanism and have a high affeinity to
dihydrofolate redactase.
Mechanism:
Inhibit dihydrofolate redactase.
Therapeutic application:


Leukemia , lymphatic leukemia , breast cancer.
Treatment is followed by administration of Leucouerin to rescue the bone marrow.
Pharmacokinetic:



Absorbed orally from GIT
doses not penetrate blood brain barrier so, intrathecally administered
Metabolism :by hydroxylation at position 7, it form less water soluble derivative and this may lead to
crystalluria .
So, it is important to keep urine alkaline and well hydrated to avoide renal toxicity.
Excretion : parent & 7-hydroxy metabolite excreted by the kidney.


Adverse effects :
Stomatitis , bone marrow depression , alopecia , vomiting , leucopenia ,thrombocytopenia and
anemia
These side effects reversed by administing leucourin.
Uses:
Psoriasis
Joints and severe rheumatoid arthritis
Trophoblastic tumors
Leukemia
30
Dosage forms:
Oral solution ,capsule ,tablet , intrathecal (not penetrate BBB) ,intraarterial (to achive a local
high concentration)
2-Mercapopurine(M phase & S phase)
Mechanism:
Prevent conversion of purine bases in to nucleotides
Side effects:
Bone marrow depression , leucopenia , thrombocytopenia.
Uses:
In leukemia and immunosuppressive in psoriasis , arthritis.
Need Use of allopurinol to inhibit formation of urater crystals and oliguria.
Pharmacokinatics:
Availability by oral route 37% (first pass effect)
Dose : 2.5 mg/kg/day, 80-100 mg/m²/day
Dosage form: Tablet
3-5-Fluorouracil
Uses:
Tpically in actinic keratosis endometrial carcinoma. \side effect:
Side effect:
Mainly leucopenia , which is recovered if the dose is lowered
Rout of administration:
Not orally (cause severe toxicity to GIT )
I.V. is required 12mg /kg/day
Topically cream 1-5% & solution
Pharmacokinetics:
60% metabolized to Co2 which is exhaled
15% is excreted in to urine
It is a prodrug.
ii-Alkylating agents
They are polyfunctional (related to mechanism of action e.g. alkylating group react with
neucleophilic :N centers in many different kinds of molecules , guanine in DNA is the most
reactive target.
Their bi or tri functional character allows them to cross – link double stranded DNA ,Thus
preventing the strands from separating for replication.
31
1-Mechlorethamine HCL (Nitrogen Mustard)
Cell non specific
Used in combination known as MOPP
M : mechlorethamine , O: oncovin , P: procarbazine ,P: prednisone
Used for Hodgkins disease
Dosage form:
I.V. infusion (reconstileted powder) very unstable should be reconstituted before
administration –cause bilistering & vesicle formation (Extravasations)
2-Cyclophosphamide
Prodrug ,need hepatic enzyme for activation
Administered orally and parentrally
Stable in GIT.
Used in Hodgkin's lymphomas and in rheumatoid arthritis as immunosuppressive.
Side effects:
Leucopenia and cardiotoxicity ,long term use : bladder fibrosis (2 mercapto ethan sulfonate
protect the bladder from fibrosis)
Pharmacokinetics:
Absorbed orally
Widely distributed
Metabolized by liver enzyme to phosphamide mustard + acrolin (whish responsible for fibrosis
of the bladder)
Dosage forms:
Injection 100 , 200 , 500 mg / ml
Tablets 25 , 50 mg
Second malignancy appears after therapy
iii-Microtubule inhibitors
Vinca alkaloids (plant origin)
1-Vincristine sulphate(Oncovin)
And Vinblastine ((M phase))
Mechanism :
Microtubule inhibitors (thus prevent partitioning of DNA in to two equal part)
Pharmacokinetics:
Metabolized in liver
Excreted in urine
Dosage form: I.V injection (Extravasations) administrated as intermittent infusion.
Uses:
Hodgkin's and other rapidly proliferating neoplasm.
32
Side effect:
Hyperurcemia due to conversion of purine base in to uric acid so, used with allopurinol.
iv-Antibiotics
Mechanism:
they interact with DNA Leading disruption of DNA function.
They are miscellaneous group with respect to mechanism of action e.g.
Daunorubicin
inhibit DNA synthesis
Mitomycin
alkylating agent
Bleomycin
antimetabolite
1-Bleomycin So4
Obtained from culture of stretomyces vertiallus
It has very little effect on bone marrow (this is related to its low distribution to bone marrow)
Used in Hodgkin's disease
1% dies due to pulmonary complication( if patient recive more than 400 unit)
Pharmacokinetics:
Absorbed poorly orally and inactivated in gut and liver so, must be administered parentrally
Eliminated via kidney.
Dosage form: injection I.V, S.C, Intrapleural.
Dose: 0.2-0.8 units.
2-Doxorubicin HCL (Adriamycin)
Antibiotic isolated from culture of stretomyces.
Change urine colar red.
Administration alone not in combination.
Severe bone marrow depression ( as a neutroopenia , cell count as 1000/mm³. So, monitoring
of leucocytes and RBCs is essential.
Administration of antioxidant (bis piperazine) protect against cariditoxicity.
Pharmacokinetics:
Not absorbed orally ,So administred I.V. infusion (Extravasations)"due to the drug is irritant"
Solution injected in to a sod.Chloride or Dextrose solution (intermittent infusion)
33
v-Steroids hormones
1-prednisone
Antiinflamatory corticosteroid
Bind to a receptor that triggers the production of specific proteins which affect cellular growth.
Used in Hodgkins and nonHodgkins lymphoma
Used orally
2-Tamoxifen
Active in treatment of estrogen-receptor positive breast cancer.
Binds to estrogen receptor and result in deplation of estrogen receptor.
Dosage form: oral.
‫تم بحمد هلل وتوفيقه‬
zhoory
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