Pharmacology of Disorders of the Pancreas Flashcards
Clinical use of Pancrelipase.
For exocrine pancreatic insufficiency
What can exocrine pancreatic insufficiency be caused by?
- cystic fibrosis
- chronic pancreatitis, or
- pancreatic resection
When secretion of pancreatic enzymes falls below 10% of normal, fat and protein digestion is impaired and can lead to what?
steatorrhea, azotorrhea, vitamin malabsorption, and weight loss.
Describe what coats pancreatic enzymes in order for them to not be broken down in the stomach?
enteric coated preparations
What should a patient take with non-enteric coated preparations of pancreatic enzyme supplements?
They should take concomitantly with acid suppression therapy to reduce acid mediated destruction of the drug within the stomach
How should one take pancrelipase?
should take with each meal and snack
What are some side effects of pancrelipase?
Oropharyngeal mucositis - so capsules should be swallowed, not chewed
Excessive doses may cause diarrhea and abdominal pain
high purine content of pancreas extracts may lead to hyperuricosuria (Gout) 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
How does acute pancreatitis present?
midepigastric abdominal pain and tenderness.
What are some of the major causes of acute pancreatitis?
- an alcoholic or someone with gallstones.
ØHypertriglyceridemia, Trauma, Infection, ERCP
ØMedications such as: ACE inhibitors (captopril ,enalapril etc), thiazides,
didanosine, stavudine, or azathioprine
What does therapy for acute pancreatitis consist of?
§ No feeding (bowel rest)
§ Hydration
§ Pain medications
§ We do not have a medication to reverse pancreatitis.
Necrotic Pancreatitis
§ When the CT shows > 30 percent necrosis of the pancreas, the patient should receive antibiotics such as imipenem.
What are some important lab findings that may clue you into the fact that one has acute pancreatitis?
§Serum, urine amylase, 3-5x normal (↑: 6h,↓: 5d)
§Serum lipase (earlier and more prolonged increase↑)
§Sebi↑, ASAT/ALAT↑
§Leukocytosis, CRP
§Hyperglycaemia (insulin↓, glucagon, adrenalin↑) §Triglyceride↑ (reason and cause)
Is a majority of cases of acute pancreatitis self-limited?
yes; subsides within y days of therapy
What is the best therapy for chronic pancreatitis?
- Diet: alcohol abstinency, protein rich, low fat diet
- Pain killers: NSAID, nitrate, spasmolytics (epidural).
- Exocrine (enzyme support: Pancrelipase ) endocrine (insulin) ,H2 blocker
- Therapy of complications:
§Surgery: pseudocyst resection, to solve stenosi
What are the best pharmaceutical therapies for pancreatic cancer?
FOLFIRINOX (5-fluorouracil, irinotecan, oxaliplatin combination);
GEMOXEL (gemcitabine, oxaliplatin and capecitabine)
What are the side effects of 5-FU?
BMS (bone marrow supression)
N+V
mucositis (lining digestive tract becomes inflamed
diarrhea
hand foot syndrome (redness, swelling and blistering on palms of hands and soles of feet)
MOA of 5-FU.
MOA - Prodrug
Ø After activation to FdUMP it inhibit thymidylate synthase, leading to “thymidine less death” of cells inhibiting DNA synthesis
ØActivation to FUTP – inhibit RNA synthesis
What are uses of 5-FU?
Pancreatic cancer, bladder, breast, colon, anal, head, neck
liver, and ovarian
What can 5-FU be used for topically?
keratoses and superficial basal cell carcinoma
Capecitabine converts to what cancer treating pro-drug?
5FU
What are the names of the alkylating drugs used to treat pancreatic cancer?
cisplatin/oxaliplatin
MOA of alkylating drugs?
Cross-link DNA strands by forming covalent bonds between alkyl groups of the drug and N7 of guanine or O6 of guanine bases of DNA OR
Ø miscoding G-T base pairing
Ødepurination and
Østrand scission
What is a drug used to treat the nausea and vomiting associated with alkylating drugs?
Ondansetron [5HT3 receptor antagonist]
ADR of alkylating drugs?
Ototoxicity, BMS [bone marrow suppression] nephrotoxicity
Oxaliplatin is less or more toxic than cisplatin?
less toxic than cisplatin
Is there ototoxicity or nephrotoxicity associated with oxaliplatin?
no
What are the best uses of Oxaliplatin?
advanced pancreatic and colon cancer. (FOLFOX therapy – 5 FU, Leucovorin, Oxaliplatin)
What ae the DNA Topoisomerase Inhibitiors we went over in this section?
Topotecan and Irinotecan
MOA of DNA topoisomerase inhibitors.
Øproduce DNA damage by inhibiting topoisomerase I.
ØThey damage DNA by inhibiting an enzyme that cuts and religates single DNA strands during normal DNA repair processes.
ØPREVENT relaxation of supercoilded DNA.
Side effects of DNA topoisomerase inhibitors..
BMS, N+V, asthenia
What is Topotecan mainly used for?
second line therapy for advanced ovarian cancer and for small
cell lung cancer.
What is Irinotecan primarily used for?
metastatic colorectal cancer
Explain how genetic variation can affect irinotecan metabolism.
Genetic variation markedly affects irinotecan metabolism. Excessive toxicity is seen in indivituals with variants of UGT1A that result in low glucuronidation activity.
Irinotecan is a prodrug that is converted to what active metabolite?
SN-38
What are 2 major ways to treat DM?
- insulin
- oral anti diabetic drugs
Be able to distinguish between Type 1 and Type 2 diabetes based on age of onset, nutritional status at time of onset, prevalence, genetic predisposition, and defect or deficiency.
What is the cornerstone of DM?
diet modification and exercise routines
This with Type 1 diabetes typically need what as a form of treatment?
insuline replacement
Can weight loss alleviate symptoms of Type 2 diabetes.
Yes it can in some cases
How do we manage Type 2 diabetics?
oral hypoglycemics with or without insulin
How can you monitor Diabetic therapy?
ØPlasma glucose measurements provide a single time point of glucose control.
ØGlycosylated hemoglobin (HbA1c) provides a measure of glucose control over a several-month period (life of erythrocyte).
ØCurrent data recommends relatively tight control aiming for HbA1c of 7% or less (equating to an average blood glucose of 150 mg/dl or less).
Understand this slide on anti-diabetic drugs.
