1. Gastropharmacology: miscellaneous
Domina Petric, MD

2. Pancreatic enzyme supplements

3. Introduction
Exocrine pancreatic insufficiency is most commonly caused by:
cystic fibrosis
chronic pancreatitis
pancreatic resection
When secretion of pancreatic enzymes falls below 10%, fat and protein digestion is impaired, resulting in steatorrhea, azotorrhea, vitamin malabsorption and weight loss.

4. Pancreatic enzyme supplements
Contain a mixture of amylase, lipase and proteases.
PANCREATIN is an alcohol-derived extract of hog pancreas with relatively low concentrations of lipase and proteolytic enzymes.
PANCRELIPASE is an enriched preparation.
Pancrelipase has approximately 12 times the lipolytic activity and more than 4 times the proteolytic activity of pancreatin.

5. Pancreatic enzyme supplements
Pancrelipase is available in both non-enteric-coated and enteric-coated preparations.
Formulations vary in amounts of lipase, amylase and protease.
Pancrelipase enzymes are rapidly and permanently inactivated by gastric acids.
Non-enteric-coated preparations (Viokase tablets or powder) should be given with proton pump inhibitors.

6. Pancreatic enzyme supplements
Enteric-coated formulations are more commonly used.
Pancrelipase preparations are administered with each meal and snack.
Dosing should be individualized according to the age and weight of the patient, the degree of pancreatic insufficiency and the amount of dietary fat intake.

7. Pancreatic enzyme supplements
Therapy is initiated at a dose that provides 20,000-30,000 IU of lipase activity in the prandial and postprandial period.
Suboptimal response to enteric-coated formulations may be due to poor mixing of granules with food or slow dissolution and release of enzymes.
Gradual increase of dose, change to a different formulation or addition of acid suppression therapy may improve response.

8. Pancreatic enzyme supplements
For patients with feeding tubes, microspheres may be mixed with enteral feeding prior to administration.
The capsules should be swallowed.
If chewed, pancreatic enzymes may cause oropharyngeal mucositis.
Excessive doses may cause diarrhea and abdominal pain.

9. Pancreatic enzyme supplements
The high purine content of pancreas extracts may lead to hyperuricosuria and renal stones.
Several cases of colonic strictures were reported in patients with cystic fibrosis who received high doses of pancrelipase with high lipase activity.

10. Bile acid therapy for gallstones

11. Ursodiol
Ursodiol (ursodeoxycholic acid) is a naturally occurring bile acid that makes up less than 5% of the circulating bile salt pool in humans.
After oral administration, it is absorbed, conjugated in the liver with glycine or taurine, and excreted in the bile.
Conjugated ursodiol undergoes extensive enteropheatic recirculation.

12. Ursodiol The serum half-life is approximately 100 hours.
With long-term daily administration, ursodiol constitutes 30-50% of the circulating bile acid pool.
A small amount of unabsorbed conjugated or unconjugated ursodiol passes into the colon.
There is either excreted or undergoes dehydroxylation by colonic bacteria to lithocholic acid.
Lithocholic acid is potentially toxic for liver.

13. Pharmacodynamics
The solubility of cholesterol in bile is determined by the relative proportions of bile acids, lecithin and cholesterol.
Ursodiol decreases the cholesterol content of bile by reducing hepatic cholesterol secretion.
It also stabilizes hepatocyte canalicular membranes through a reduction in the concentration of other endogenous bile acids or through inhibition of immune-mediated hepatocyte destruction.

14. Clinical use
Ursodiol is used for dissolution of small cholesterol gallstones in patients with symptomatic gallbladder disease who refuse cholecystectomy or are poor surgical candidates.
At a dosage of 10 mg/kg/d for months, dissolution occurs in up to 50% of patients with small and noncalcified gallstones.
Small gallstones: less than 5-10 mm.

15. Clinical use
Ursodiol is also effective for the prevention of gallstones in obese patients undergoing rapid weight loss therapy.
Ursodiol mg/kg/d is helpful for patients with early-stage primary biliary cirrhosis, reducing liver function abnormalities and improving liver histology.

16. Adverse effects
Ursodiol may rarely cause bile salt-induced diarrhea.

17. Drugs for variceal hemorrhage treatment

18. Portal hypertension
Most commonly occurs as a consequence of chronic liver disease.
It is caused by increased blood flow within the portal venous system and increased resistance to portal flow within the liver.
Splanchnic blood flow is increased in patients with cirrhosis due to low arteriolar resistance that is mediated by increased circulating vasodilators and decreased vascular sensitivity to vasoconstrictors.

19. Portal hypertension
Intrahepatic vascular resistance is increased in cirrhosis due to fixed fibrosis within the spaces of Disse and hepatic veins, as well as reversible vasoconstriction of hepatic sinusoids and venules.
Consequences of portal hypertension: ascites, hepatic encephalopathy, development of portosystemic collaterals, especially gastric or esophageal varices.

20. Portal hypertension
Varices can rupture, leading to massive upper gastrointestinal bleeding.

21. Somatostatin, octreotide
In patients with cirrhosis and portal hypertension, intravenous somatostatin (250 mcg/h) or octreotide (50 mcg/h) reduces portal blood flow and variceal pressures.
Their activity may be mediated through inhibition of release of glucagon and other gut peptides that alter mesenteric blood flow.

22. Somatostatin, octreotide
These agents are effective in promoting initial hemostasis from bleeding esophageal varices.
They are generally administered for 3-5 days.

23. Vasopressin
Vasopressin (antidiuretic hormone) is a polypeptide hormone secreted by the hypothalamus and stored in the posterior pituitary.
It is a potent arterial vasoconstrictor.
When administered intravenously by continuous infusion, vasopressin causes splanchnic arterial vasoconstriction that leads to reduced splanchnic perfusion and lowered portal venous pressures.

24. Vasopressin
Vasopressin is no longer used to treat acute variceal hemorrhage.
For patients with acute gastrointestinal bleeding from small bowel or large bowel vascular ectasias or diverticulosis, vasopressin may be infused to promote vasospasm.
Vasopressin is infused into one of the branches of the superior or inferior mesenteric artery through an angiographically placed catheter.

25. Adverse effects
Systemic and peripheral vasoconstriction can lead to hypertension, myocardial ischemia or infarction and mesenteric infarction.
These effects may be reduced by coadministration of nitroglycerin.
Nitroglycerin may reduce portal venous pressures by reducing portohepatic vascular resistence, and the coronary and peripheral vascular vasospasm caused by vasopressin.

26. Adverse effects Nausea and abdominal cramps.
Diarrhea due to intestinal hyperactivity.
Antidiuretic effects lead to retention of free water: hyponatremia, fluid retention and pulmonary edema.

27. Terlipressin
It is a vasopressin analog that appears to have similar efficacy to vasopressin with fewer adverse effects.

28. Beta-blockers
Beta-blockers reduce portal venous pressures via a decrease in portal venous inflow.
This decrease is due to a decrease in cardiac output (β1 blockade) and to splanchnic vasoconstriction (β2 blockade) caused by the unopposed effect of systemic catecholamines on α receptors.
Nonselective β blockers (propranolol and nadolol) are more effective than selective β1 blockers in reducing portal pressures.

29. Katzung, Masters, Trevor. Basic and clinical pharmacology.
Literature
Katzung, Masters, Trevor. Basic and clinical pharmacology.