DRUG-INDUCED

PANCREATITIS
Christina Ford PharmD, PGY1
Lutheran Hospital
February 26, 2020
cford3@lutheran-hosp.com
Introduction: About Me
Objectives
◦ Recall pancreatitis anatomy and pathophysiology

◦ Identify clinical manifestations of pancreatitis

◦ Discuss mechanisms for drug-induced pancreatitis

◦ Critique a patient case for pancreatitis etiology

◦ Design a treatment plan for a patient with drug-induced pancreatitis

Why is this lecture important to you?

Images courtesy of www.graphicsfuel.com

Pancreatitis Anatomy and Physiology
 Gastrointestinal
System:

Pancreas Anatomy

• Endocrine and exocrine

function

https://www.drugs.com/health-guide/pancreatitis.html#print
Pancreas: A&P
Endocrine function Exocrine function
Islets of Langerhans (alpha, beta, delta cells) Acini and ductules
• Insulin • 2.5 L/day isotonic fluid
• Glucagon • Water, electrolytes, pancreatic enzymes
• Somatostatin Enzymes
• Polypeptide hormones 1. Amylolytic
2. Lipolytic
3. Proteolytic
4. Nucleolytic
5. Trypsin inhibitor

https://qph.fs.quoracdn.net/main-qimg-d19f116dec16122a983d4fa1480e3fad Bolesta. Pharmacotherapy ch. 39

 Pancreas: A&P
• Amylolytic amylase

• Lipolytic lipase, procolipase,

prophospholipase A2, carbosylesterase

• Proteolytic trypsinogen,
chymotrypsinogen, procarboxypeptidase,
proelastase

• Nucleolytic ribonuclease and

deoxyribonuclease

• Trypsin inhibitor: Found in pancreatic

juice to protect pancreas from own
A&Phttp://www.animatedpancreaspatient.com/en-pancreas/slides/exocrine-pancreatic-insufficiency-epi/app05-slides-ch4_slide_04$jpg
enzymes

Bolesta. Pharmacotherapy ch. 39

Pancreatitis Overview
Pancreas becomes inflamed
and painful

Multiple etiologies and

varying risk factors

http://4.bp.blogspot.com/_rx09liKwknc/S7PI6TaJRpI/AAAAAAAAAAU/JboOQhre
WvE/s320/Dibujo14.jpg Medications result in ACUTE
pancreatitis (vs Chronic)

Bolesta. Pharmacotherapy ch. 39

 Pancreas: A&P

https://simple.wikipedia.org/wiki/Gallstone

https://i.ytimg.com/vi/GfZ4fD9_4Hk/maxresdefault.jpg
https://www.sciencenews.org/article/hidden-inactive-
ingredients-medications-trigger-allergies

Bolesta. Pharmacotherapy ch. 39

Pancreatitis Complications
Majority of acute
pancreatitis patients 20% of adults will
resolve without have a severe course
complications

Progressing to
Organ failure or
chronic pancreatitis
necrosis increases
depends on acute
mortality ~30%
etiology

Bolesta. Pharmacotherapy ch. 39

Pancreatitis Clinical Manifestations

Epigastric Pain Nausea and Vomiting Hypotension, Elevated amylase and

tachycardia, low-grade lipase
fever (often observed)

Images courtesy of: https://www.medgadget.com/2017/06/now-patients-can-report-drug-side-effects-with-emojis.html

Bolesta. Pharmacotherapy ch. 39

 Check Point #1
What structure contains the Which enzyme breaks down What are potential causes of
cells that secrete insulin? starch? acute pancreatitis?

A. Acini A. Carbohase 1)

B. Islet of Langerhans B. Protease 2)

C. Ductules C. Lipase 3)

D. Gamma Cells D. Amylase 4)

Drug-Induced Mechanisms

Structural Toxins

Vascular-
Metabolic
Immune
Hung WY et al. 2014; 5(4).
 Structural Mechanism

Sphincter of Oddi Dysfunction

Gallstones block bile duct
• Meds cause stenosis (edema or
• Meds cause stone formation
hypertrophy)
• Meds increase cholesterol in bile
• Meds cause dyskinesia
• Meds excreted in bile
(tachyoddia, induced spasms)

Pancreatic Duct
• Meds that cause constriction

https://simple.wikipedia.org/wiki/Gallstone

Hung WY et al. 2014; 5(4).

 Structural Mechanism
Pancreatitis resulting from:
Organ injury, duct obstruction/constriction, or sphincter problem

Potential medications causing pancreatic structural adverse effects (Hung et al)

Cholestatic Liver Spasm of Sphincter of Obstruction Duct constriction Reported cases:
Injury Oddi  Octreotide
• Azathioprine • Opioids • Enalapril • Sulindac  Opium
• Cytarabine • Erythromycin  Rofecoxib
 Macrolides
 Ace-inhibitors
 Ceftriaxone
 Dipyridamole

Hung WY et al. 2014; 5(4).

 Structural Mechanism
◦ Theory (drugs that may cause “stones”):

◦ Ceftriaxone (3rd generation cephalosporin) is excreted from the bile duct and
may develop sludge or stones to cause obstruction

◦ Statins: Secrete cholesterol in bile which increases risk of forming stones

https://simple.wikipedia.org/wiki/Gallstone
◦ Octreotide + dypyridamole can precipitate in gallbladder which are excreted
in bile and may cause occlusion

Hung WY et al. 2014; 5(4).

 Check Point #2
What class of medication may
What drug increases risk of cause dysfunction of the Where is the sphincter of
gall stones? sphincter of Oddi? Oddi?

A. Ceftriaxone A. Class III Anti-arrhythmics A.

B. Acetaminophen B. Tricyclic antidepressant B.

C. Codeine C. Alpha blocker C.

D. Vitamin D D. Opioids D.
Drug-Induced Mechanisms

Structural Toxins

Vascular-
Metabolic
Immune
Toxins Mechanisms Overview

Think “free radicals”

Taniguchi CM et al. Drug Toxicity. Canadian Medical Association journal, 1964: 91(20); 1082.
Toxins Mechanisms
Hypothesized cumulative dose-dependent effect (Latency >30 days)
Nucleoside reverse transcriptase inhibitor: Inhibit mitochondrial DNA
polymerase-gamma, cannot make ATP

Metronidazole: May yield hydrogen peroxide, superoxide, free radicals under

aerobic conditions, toxic to pancreatic beta cells

Pentamidine: Direct cytotoxic effect on beta cells and acinar pancreatic cells

L-asparaginase: May disrupt acinar cell protein synthesis which inhibits exocytosis

Tetracycline: May cause fatty liver changes and/or produce toxic metabolite
and/or lead to high drug bile content

Hung WY et al. 2014; 5(4).

Toxins Mechanisms
Medications potentially toxic to pancreas (Hung et al)
Definite relationship (Class I/II) Probable Reported cases
• Acetaminophen • Metformin • Minocycline
• Didanosine • Tigecycline
• Isoniazid • Doxycycline
• Metronidazole • Statins
• Valproic Acid
• Mesalamine
• Pentamidine
• Asparaginase
• Sitagliptin
• Exenatide
• Tetracycline
• Pravastatin

Hung WY et al. 2014; 5(4).

 Check Point #3
How do you know when a
medication is causing
pancreatitis?
A. Patient is taking medication from
Class I/II relationship list
B. Discontinue all medications
C. Rule out common causes, then
discontinue possible agent
D. You can’t help this patient
What is one hypothesized
mechanism of a drug-induced
toxicity to the pancreas?
A. Creation of free radicals
B. Disrupts normal gut flora
C. Inhibits first-pass metabolism
D. Pancreas makes too much
insulin
Despite specific drug toxicity
mechanism, what is the end
result to the pancreas?
A. Inflammation
B. Pancreas is injured from own
enzymes
C. Pancreatic cells can’t function
properly
D. All of the above
Drug-Induced Mechanisms

Structural Toxins

Vascular-
Metabolic
Immune
 Metabolic Mechanism
Hyper- Hyper-
triglyceridemia calcemia

Calcium responsible for Recall:

TG > 1000 mg/dL acinar cell secretory
process Trypsinogen is
a precursor to
the proteolytic
enzyme,
Lipase turns TG into
Too much Ca++ causes trypsin
toxic free fatty acids and
vacuole formation and
injures pancreatic blood
trypsinogen activation
vessels

Images courtesy of http://biology4alevel.blogspot.com/2014/08/10-lipids.html and https://www.medicalnewstoday.com/articles/322012.php

Hung WY et al. 2014; 5(4).

Metabolic Mechanism

Visual:
Pathogenesis of hypertriglyceridemia
induced acute pancreatitis

http://www.discoverymedicine.com/Yao-Yao-Guo/2019/02/hypertriglyceridemia-induced-acute-pancreatitis-disease-mechanisms-treatment-modalities/

Guo YY, et al. Discov Med. 2019; 27(147): 101-109.

Metabolic Mechanism

Visual:
Pathogenesis of hypercalcemia induced
acute pancreatitis

https://www.semanticscholar.org/paper/Research-Progress-on-the-Relationship-Between-Acute-Feng-Wei/0620e1afa94fb31dd8cb3f8ebf334cf380915086

Feng S et al. Digestive Diseases and Sciences. 2018; 64: 25-38.

 Metabolic Mechanism
Medications with metabolic mechanism to pancreatitis (Hung et al)
Definite relationship (Class I/II) Probable Reported cases
• Estrogens • Hydrochlorothiazide • Isotretinoin
• Corticosteroids • Interferon alfa • Retinoid derivatives
Potential to • Furosemide • Propofol • Protease inhibitors
elevate • Beta-blocker • Tamoxifen • Saw palmetto
triglycerides • Clomiphene • Ethacrynic acid
• Aripiprazole, clozapine,
olanzapine, quetiapine,
risperidone
Potential to • Hydrocholothiazide • IV calcium
elevate • Vitamin D
Calcium
 Check Point #3
What is elevated in metabolic
mechanism of drug-induced
pancreatitis?
A. Sodium and/or LDL
B. Triglycerides and/or Calcium
C. Sodium and/or Calcium
D. Potassium and/or Triglycerides
What medication has potential
to increase both triglycerides
Both mechanisms described
and/or calcium?
(↑Ca++ and/or TG), may form
reactive oxygen species in its
A. Furosemide
destructive pathway (aka “free
radicals).
B. Ethacrynic acid
A. True
C. Bumetanide
B. False
D. Hydrochlorothiazide
Drug-Induced Mechanisms

Structural Toxins

Vascular-
Metabolic
Immune
Vascular-Immune Mediated Mechanism
Vascular modality
◦ Ischemia (Rare)
◦ Cholesterol emboli (suspect after cardiac
catherization)
◦ Malignant hypertension
◦ Severe heart failure
◦ Potent vasoconstrictors
◦ Contrast-dye: High viscosity in vessels
Immune-mediated
◦ Observed within 1st month of initial drug
exposure, then within 1-3 days upon re-
initiation of drug
◦ Correlation with immune disorders (Crohn’s
disease and HIV infections)
Hung WY et al. 2014; 5(4).
Vascular-Immune Mediated Mechanism
Medications with Vascular-Immune mechanism to pancreatitis (Hung et al)
Definite relationship (Class I/II) Probable Reported cases
• Azathioprine • ACE inhibitors (local • Contrast media-iopamidol
• Mercaptopurine angioedema vs direct toxicity • Procainamide
speculated)

Hung WY et al. 2014; 5(4).

Drug-induced pancreatitis overview
Duct Obstruction (structural)
Leads to interstitial edema, impairs
blood flow, cause ischemia

Acute Pancreatitis:
(Enzymes back-
flow into pancreas)

Defective intracellular transport Acinar cell injury (Toxin/Vascular)

(Toxin/metabolic/immune)
Release intracellular proenzymes and
Cause intracellular enzyme activation lysosomal hydrolases, activates enzymes

Hung WY et al. 2014; 5(4).

Check Point #4
How do you know when a The patient improves after
medication is causing possible medication is
pancreatitis? discontinued, what next?

A. Patient is taking medication A. Have a trial period; re-initiate

from Class I/II relationship list medication and assess tolerance

B. Discontinue all medications B. Never use the medication again

C. Rule out common causes, then C. Avoid all drugs in the same
discontinue possible agent class

D. You can’t help this patient D. You can’t help this patient
Pancreatitis Management
Relieve Therapy Goals:
• Supportive care pain
• Resolve underlying cause
• Monitor patient
Replace
fluids and
electrolytes
• Practitioner to determine acute
Minimize
pancreatitis severity systemic
• Mild, Moderate, Severe complications

Bolesta. Pharmacotherapy ch. 39

Pancreatitis Management
Nonpharmacologic: Pharmacological:

-Procedural (ERCP): -IV anti-emetics: (ondansetron,

Endoscopic retrograde cholangio promethazine)
pancreatography
-IV analgesics: (acetaminophen,
-Nutritional support NSAID, morphine, fentanyl,
-Nasogastric tube (suction): hydromorphone)
empties gastric contents to relieve
nausea and vomiting

Fluids:
-Crystalloids 5-10 mL/kg/h or 250-500 mL/h
-Goal: HR<120bpm, MAP 65-85 mmHg, UO >0.5 mL/mg/h

Bolesta. Pharmacotherapy ch. 39

 Pancreatitis Management Algorithm
MILD:
Start food when pain and lab
values improving
If infected, treat
MODERATE: with antibiotics
Screening and Treat systemic complications and
Acute pancreatitis
supportive care possible ICU. Advance diet
gradually Improvement?
Continue care
SEVERE:
ICU admission. Treat systemic
complications. Use enteral No improvement?
feeding tube R/O infected
pancreatic necrosis

Bolesta. Pharmacotherapy ch. 39

Drug-induced Pancreatitis Management
Important for clinicians to be
aware of potential drug-
related causes
If medication is a suspected
problem, discontinue
promptly
Prevention:
-Avoid similar medications
-Educate patient to report
pancreatitis symptoms
-Closely monitor patients with
risk factors
-Use lowest effective dose of
immunosuppressive agents
Kale-Pradhan PB. Pancreatitis. ch. 39
10 Minute
Break

Image courtesy of:

https://www.coolpun.com/topic/pancreas
In-Class Activity
1. Read and assess the patient case provided in class

2. Answer the questions provided regarding the patient case

3. Create your abbreviated CARE PLAN using the template provided (15 minutes total)

4. Discuss care plan as a class

Key Take Away
The pancreas is an organ with both exocrine and endocrine functions that aid digestion

Pancreatitis manifests as abdominal pain and nausea/vomiting, with elevated serum lipase and amylase

Pancreatitis has the potential to lead to severe complications and death

There are many possible drug-related etiologies for pancreatitis

One - minute paper (Write on notecard)

What was the most important concept

you learned in class today?
References
1. Bolesta S, Montgomery PA. Pancreatitis. In: DiPiro JT, Talbert RL, Yee GC, Matzke GR, Wells BG, Posey L. eds. Pharmacotherapy: A Pathophysiologic Approach,
10e New York, NY: McGraw-Hill; . http://accesspharmacy.mhmedical.com.maproxy.palni.edu/content.aspx?bookid=1861&sectionid=146059813. Accessed
December 31, 2019.
2. Hung W, Lanfranco OA. Contemporary review of drug-induced pancreatitis: A different perspective. World J Gastrointest Pathophysiol. 2014; 5(4): 405-415. doi:
10.4291/wjgp.v5.i4.405.
3. Taniguchi, C.M., Armstrong, S.R., Green, L.C., Golan, D.E., & Tashjian, A.H. (1964). Drug Toxicity. Canadian Medical Association journal, 91 20, 1082.
4. Guo YY, Hui-Xia Li, Zhan Y, Wne-Hua H. Hypertiglyceridemia-induced acute pancreatitis: Progress on disease mechanisms and treatment modalities. Discov Med.
2019; 27(147): 101-109.
5. Feng, S., Wei, Q., Hu, Q., Huang, X., Zhou, X., Luo, G., Deng, M., & Lü, M. Research Progress on the Relationship Between Acute Pancreatitis and Calcium
Overload in Acinar Cells. Digestive Diseases and Sciences, 2018; 64: 25-38. doi: 10.1007/s10620-018-5297-8.
6. Kale-Pradhan PB, Wilhelm SM. Pancreatitis Chapter 39. 877-904.
DRUG-INDUCED
PANCREATITIS
Christina Ford PharmD, PGY1
Lutheran Hospital
February 26, 2020
cford3@lutheran-hosp.com