Week 5 - Dyspepsia & Altered Bowel Habit Flashcards
Name 3 examples of drugs that undergoes substantial first pass metabolism in the liver?
Aspirin, Isosorbide dinitrate, Glyceryl trinitrate, Levodopa, Lidocaine, Morphine, Propranolol, Salbutamol
How can liver disease alter the response of drugs in the body?
o Impaired drug metabolism
o Hypoproteinemia → especially drugs that bind to albumin to get around the body
o Reduced clotting
o Hepatic encephalopathy
o Fluid overload → worsens liver function itself.
o Hepatotoxic drugs
Name 3 common hepatotoxic drugs…
Paracetamol, Isoniazid, statins, methotrexate, phenytoin, aspirin, alcohol, oral contraceptives, antibiotics
Name some antibiotics to be avoided in liver disease?
Chloramphenicol, Erythromycin, Tetracycline, pyrazinamide, Griseofulvin, Nalidixic acid, Nitrofurantoin
Antibiotics to be avoided in liver disease
Why is Erythromycin avoided in liver disease?
Erythromycin estolate - causes cholestasis
Antibiotics to be avoided in liver disease
Why is Tetracycline avoided in liver disease?
Tetracycline - dose related hepatotoxicity
Antibiotics to be avoided in liver disease
Why is pyrazinamide avoided in liver disease?
Antituberculous therapy in combinations, pyrazinamide → hepatotoxic
Antibiotics to be avoided in liver disease
Why is nalidixic acid avoided in liver disease?
Nalidixic acid – increase incidence of adverse effects
Antibiotics to be avoided in liver disease
Why is Nitrofuratonin avoided in liver disease?
Nitrofurantoin - prolonged use can cause liver problems e.g. jaundice
Antibiotics to be avoided in liver disease
Why is Chloramphenicol avoided in liver disease?
Chloramphenicol - higher risk of bone marrow suppression (markedly increased half life)
What is the effect of Hepatic Disease on Pharmacokinetics?
•
Hepatic disease may lead to:
Drug accumulation → Its not being metabolized properly and active metabolites are circulating in the system
Failure to form an active or inactive metabolite
Increased bioavailability after oral administration
Alteration in drug protein binding, and kidney function (low albumin)
What is the definition of hepatic drug clearance?
Hepatic drug clearance can be defined as the volume of blood perfusing the liver that is cleared of the drug per unit of time.
What are the 3 major parameters that determine drug elimination by the liver?
- Blood flow (Q) through the liver -> reflects drug delivery to liver
- The fraction of drug (f) in the blood that is free or unbound to plasma proteins and capable of interacting with hepatic enzymes
- Intrinsic clearance (Clint) is the intrinsic ability of the liver to metabolize drug in the absence of flow limitations and binding to cells or proteins in the blood.
What is the formula for hepatic clearance?
Hepatic clearance = Cl(hep) = Q X E = Q X (Ci – Co) Q = blood flow E = extraction Clhep = hepatic clearance Ci = conc. of drug in portal circulation Co = conc. of drug in hepatic outflow
What is the extraction ratio (ER)?
The fraction or percentage of the drug removed from the perfusing blood during its passage through the organ
How do we class extraction ratio (ER)?
- High (>0.7),
- Intermediate (0.3-0.7) or
- Low (<0.3),
How does ER relate to bioavailability? How does this effect cirrhotic patients?
Drugs with high hepatic ER have a large first-pass effect, therefore low oral bioavailability.
In cirrhotic patients, therefore the initial and maintenance doses of oral drugs have to be reduced.
How do you alter drug doses of drugs metabolised in the liver in patients with hepatic impairment?
Reduced dose = (Normal dose X bioavailability) / 100
Normal dose = starting dose in patient without liver dysfunction
Bioavailability = drug’s bioavailability in a healthy person (1-ER)
How should you prescribe high extraction drugs in liver impairment?
High extraction drugs given ORALLY, initial and maintenance dose should be reduced in patients with impaired blood flow
High extraction drug given IV, normal initial dose but maintenance dose should be reduced according to hepatic blood flow
How should you prescribe low extraction drugs, with low albumin binding in liver impairment?
For drugs with a low extraction ratio (first pass metabolism ≤30%) and low binding to albumin…
Reduce maintenance dose or increase dosing interval.
How should you prescribe low extraction drugs, with high albumin binding in liver impairment?
For drugs with a low extraction ratio with high binding to albumin (≥90%)
o Reduce initial dose if low albumin
o Adjust maintenance dose based on clinical effect or drug level
What is the best practise for prescribing to patients with liver disease?
Use drugs eliminated by routes other than liver
Avoid hepatotoxic drugs
Avoid sedatives, diuretics, drugs which cause constipation –> precipitate encephalopathy
Avoid drugs that interfere with haemostasis e.g. aspirin, warfarin
Drugs that cause Na retention e.g. NSAID’s or steroids exacerbate fluid overload and ascites
In summary, what are the main pharmacokinetic alterations in liver disease?
Drug accumulation & ↑ oral bioavailability (Absorption)
Formation of active & inactive metabolites (Metabolism) Reduced protein binding (Distribution & Excretion)
How does dyspepsia present?
Spectrum of usually intermittent upper GI symptoms including :
• Epigastric pain
• Heartburn
• May include bloating, nausea, vomiting
What is a Peptic ulcer?
Acid related ulcer in the lining of the stomach or duodenum
Ulceration can be seen in mucosa
What is the pathophysiology of peptic ulcers?
Layer of mucus in our stomachs to protect our cells from the stomach acid (HCL) → a disruption in the mucous layer is what leads to problems like ulceration.
Parietal Cells that secrete HCl into the stomach are targets for pharmacological therapy. PPIs target the pump that actively exchanges potassium ions for hydrogen ions and lowers the pH in the stomach.
Inhibiting the pump will increase the pH
What are the factors that increase risk of ulceration?
Increased acid production • Gastrin • Parasympathetic stimulation • Pepsin • H. Pylori • Histamine Decreased Mucosal protection • Mucin / HCO3- secretion • H. Pylori • Prostaglandin inhibition (Cox)
What are the common causes of PUD?
Helicobacter pylori infection – 60 - 95% (most common)
NSAIDS use 5% ical
o Reduced mucin/HCO3 production – COX I inhibitory effect
Long term steroid use
Alcohol & Smoking
Severe physiological stress → Major burns / CNS trauma / surgery, medillness - ITU
Hypersecretory states – Zollinger Ellison syndrome
What is the most common cause of PUD?
Helicobacter pylori infection – 60 - 95% (most common)
o Common childhood infection
o Inflammation / Increased acid production
What is the difference in the pain associated with duodenal and peptic ulcers?
Both cause epigastric pain
Gastric Ulcer – worse with / shortly after meals
Duodenum U – relieved during meals, worse 2-3h after meals or at night
What are the common pharmacological causes of Dyspepsia?
o NSAIDs – gastritis and peptic ulcers o Steroids – gastritis and peptic ulcers o Calcium antagonists - gastritis o Nitrates - Reflux o Theophyllines - gastritis o Bisphosphonates – oesphageal erosion and ulceration.
What are the Emergency Presentations related to PUD and dyspepsia?
UGI bleeding o Haematemesis o Melaena o Haemodynamic compromise o Severity scoring → BLATCHFORD score & Rockall score
Acute abdomen
o Perforation – gastric / duodenal
What are the differentials for dyspepsia?
Ulcer, Gastric cancer, Reflux disease, Gallstones, Chronic pancreatitis, Myocardial infarction
What are the common investigations in patients with dyspepsia? (apart from FBC, etc.)
H. pylori tests o Faecal antigen test o Carbon 13 urea breath test o Serum H.pylori antibody test o Endoscopic biopsy samples – rapid urease test - CLO
Endoscopy
What are the different ways of testing for H. Pylori?
o Faecal antigen test
o Carbon 13 urea breath test
o Serum H.pylori antibody test
o Endoscopic biopsy samples – rapid urease test
What is the general advise given to patients with dyspepsia?
- Stop smoking
- Reduce alcohol intake
- Lose weight
- Increase exercise
- Reduce fatty/spicy foods
- Eat small regular meals
- Raising head of the bed
What is the mechanism of acid suppression therapy– PPI?
- PPI becomes activated by acid in the canaliculus and irreversibly binds to the proton pump, blocking its action.
- Receptors are still active, but cannot stimulate acid production as the pump is blocked.
- Inactive PPI diffuses out of blood vessels and across the parietal cell to the canaliculus.
Name 2 antacids…
Aluminium hydroxide
Magnesium carbonate
Magnesium trisilicate
What is the mechanism of action of antacids?
o Antacids are made of alkaline Al3+ and Mg2+ salts
o Raise the pH of the stomach
o Neutralising stomach acid
o Bind to and inactivate pepsin
What are the adverse effects of antacids?
o Constipation
o Diarrhoea
What are the contraindications of antacids?
Aluminium hydroxide and Magnesium hydroxide should not be given to patients with hypophosphataemia
H2-receptor antagonist
Name 2 H2-receptor antagonists…
Cimetidine and Ranitidine (better tolerated)
What is the mechanism of action of H2-receptor antagonists?
H2 receptor antagonists competitively block the action of histamine on the parietal cell by antagonising the H2 receptor
name 2 PPIs
Omeprazole and Lansoprazole
What is the mechanism of action of PPIs?
PPIs cause irreversible inhibition of H+/K+ ATPase responsible for H+ secretion from parietal cells
What are the problems with PPIs?
o C. difficile diarrhoea risk with PPIs + Antibiotics
o Electrolyte disturbance with PPIs
o Drug – drug interactions →PPI vs. Clopidogrel
When should the H2-receptor antagonist cimetidine be avoided?
Cimetidine should be avoided in patients on warfarin, phenytoin, theophylline (inhibits the P450 enzyme system hepatic metabolism)
What are the H. pylori eradication therapies?
Triple therapy
o PPI, amoxicillin and clarithromycin
o PPI, amoxicillin and metronidazole
Quadruple therapy
o Eradication failure:
• Omeprazole, 2 antibiotics (tetracycline and metronidazole) and bismuth chelate
What is the treatment of PUD?
Heal the ulcer
o Antisecretory medications
o Post treatment repeat endoscopy
H. pylori eradication
o Antibiotics and PPI – triple therapy
Stop NSAID use if applicable
Surgery
o If failed medical / endoscopic management in UGI bleed or if there are complications
What are the 4 types of laxatives?
Bulk forming, Osmotic, Stimulant and Faecal softeners
Name some examples of osmotic laxatives…
- Lactulose – semi synthetic disaccharide (not absorbed from the GI Tract),
- Macrogol
Name some examples of bulk forming laxatives…
Bran, Methylcellulose, Ispaghula husk
Name some examples of stimulant laxatives…
Senna, Danthron, Bisacodyl and Sodium picosulphate
Name some examples of faecal softeners…
Liquid paraffin and Docusate sodium
What is the mechanism of action of bulk forming laxatives?
Increase volume of non- absorbable material in the gut
Distend the colon and stimulate peristaltic movement
What is the mechanism of action of osmotic laxatives?
Increase water content in the bowl via osmosis
Distend the colon and stimulate peristaltic movement
What is the mechanism of action of stimulant laxatives?
Increase gastrointestinal peristalsis
Increase water and electrolyte secretion by the mucosa
What is the mechanism of action of faecal softeners?
Promote defecation by softening the stool (Docusate sodium)
Promote defecation by lubricating the stool (Liquid paraffin)
What are the contraindications of bulk forming laxatives?
Dysphagia, intestinal obstruction, colonic atony, faecal impaction
What are the contraindications of osmotic laxatives?
Intestinal obstruction
What are the contraindications of stimulant laxatives?
Intestinal obstruction
What are the contraindications of faecal softeners?
Should not be administered to children under 3 years old
What are the adverse effects of bulk forming laxatives?
Flatulence, abdominal distension and gastro intestinal obstruction
What are the adverse effects of osmotic laxatives?
Flatulence, cramps and abdominal discomfort
What are the adverse effects of stimulant laxatives?
- Short term: cramps and abdominal discomfort
- Long term use: damage to the nerve plexuses
- Can cause deterioration of normal intestinal function
What are the adverse effects of faecal softeners?
Long term use of liquid paraffin can impair absorption of fat soluble vitamins (Vitamin A and Vitamin D)
What type of ulcer is likely if epigastric pain is relieved by eating?
Duodenal ulcer
How does NICE recommend you to manage patients with persistent dyspepsia?
< 55 years “Test and Treat”
• Test for H. pylori – C13 Urea breath test or stool antigen (2 week washout post PPI)
• 4 weeks full dose PPI
> 55 years with unexplained, persistent symptoms – URGENT endoscopy referral
• Don’t prescribe PPI pre-endoscopy → as need to be off acid suppression medication for > 2 weeks prior to endoscopy
What test is used to test a biopsy sample for H. pylori?
CLO test
Endoscopic biopsy samples – rapid urease test
Why are duodenal ulcer relieved by eating?
Symptoms of duodenal ulcers would initially be relieved by a meal, as the pyloric sphincter closes to concentrate the stomach contents, therefore acid is not reaching the duodenum.
Duodenal ulcer pain would manifest mostly 2–3 hours after the meal, when the stomach begins to release digested food and acid into the duodenum
Why are gastric ulcers exacerbated by eating?
A gastric ulcer would give epigastric pain during the meal, as gastric acid production is increased as food enters the stomach.
How often are duodenal ulcers and gastric ulcer associated with H. pylori?
Duodenal - 90% association
Gastric - 60% association
How does H. pylori effect risk of cancer?
Increases carcinoma incidence by x3
What is the therapy for a H. pylori ulcer?
Triple therapy
Omeprazole, amoxicillin and clarithromycin
Then continue PPI for 8 weeks
How long do you continue PPI for after triple therapy?
8 weeks
What are the side effects of PPIs
Low magnesium
Increased risk of C difficile and infective diarrhoea
o Suspend PPI in patients receiving course of antibiotics
Acute interstitial nephritis
Microscopic colitis
What is the therapeutic pathway for non-ulcer dyspepsia?
- Test and treat for HP
- 4 weeks low dose PPI
- If symptoms recur step down PPI/H2RA to lowest dose to control symptoms.
What is the Blatchford score?
Gives an idea of how risky a GI bleed is
Low risk = 0, Anything higher is high risk
What is the Rockall score?
Measures risk of mortality and re-bleeding
What should you do when prescribing NSAIDS in those with past dyspepsia?
Give PPI cover
Which NSAIDS are better and why?
COX1 and COX2 both convert arachadonic acid into pGs and other mediators.
COX-2 are better than non-selective
COX-2 inhibits the proinflammatory pathways
Non-selective will also inhibit COX-1 which increases GI side effects.
If a patient has suspected c-diff, what is your first treatment?
Admit in isolation
Which pharmacological treatments increase risk of c-diff, what should you do to prevent this?
PPI + Abx
Suspend PPI when you prescribe Abx
What are the causes of constipation?
Primary • Hirschsprung’s disease • Rectocele/ prolapse • Impaired pelvic floor relaxation Secondary • Medication: Opiates/ CCB/ Iron • Neurological: PD/MS/MD/spinal lesions • Dietary: Low fibre diet and immobility • Mechanical: Ca/stricture/painful sphincter • Metabolic: High and low calcium, Low K+, Low Mg, uraemia • Endocrine: Hypothyroidism, diabetes • Psychiatric: depression, anxiety, somatization, eating disorders
When cant you use stimulant or bulk forming laxatives?
Intestinal obstruction
What non-pharmacological management is advised in constipated patients?
Well-balanced diet high in fibre
Cutting down on white bread, cakes and sugar.
Drinking at least 6 to 8 glasses of water a day.
Prunes and plum juice can also be beneficial.
Regular exercise
