Digestive Pharmacology

Pharmacology of the GI tract

 H2-receptor antagonists: the drug that competes with histamine for the binding site of the H2 receptors on the parietal cell. They are made based on the structure of the histamine but without functional signal transduction.
 Benefits of H2-receptor antagonists:
- rapid action within 30 mins
- long term maintenance for peptic ulcer and acid reflex
- effective at reducing nocturnal acid secretion (sterilization purposes) but not as good for food-stimulated secretion
 Disadvantages of H2-receptor antagonists:
- the drug will not achieve full acid inhibition effect as histamine only occupy some sites and other pathways of stimulation such as gastrin and acetylcholine are obviously unaffected
- The drug can be overcome by strong agonist effect
- Body can develop tolerance with gradual decrease in effect
- Amount not proportional to effect (less additive effect)
 Clinical problems:
- not effective for patients with heartburn and unable to heal above moderate oesophagitis, i.e. only 50% decrease in acid
- need multiple doses for severe symptoms
- required as a lifelong treatment
 Proton pump inhibitor: irreversible blocker of activated proton pumps. The drug is required to be absorbed into the blood first and then passage into the parietal cell and canaliculi space.
- omeprazole: a type of proton-pump inhibitor that works by binding to the sulphdryl group on the extra-cellular domain
- required for prophylaxis if ulcers is caused by anti-inflammatory drugs
- used to aid healing of ulcers and acute bleeding as it prevent an acidic environment and hence loss of pepsin activity
 Benefits of Proton pump inhibitor:
- long duration of action (approx 24 hours) hence only require one dose per day
- cannot be overcome by agonist effects such as stimulation of histamine, acethylcholine and gastrin.
- 90% or more suppression of acid in most people
 Disadvantages of Proton Pump Inhibitor
- several days for a maximum effect
- degraded by gastric acid (enteric coated)
- need food to stimulate proton pump
 Long term problems with acid inhibition:
- bacterial overgrowth in the stomach which predispose development of carcinogenic compound formed from foods (shown with pernicious anaemia experiments)
- loss of sterilization of food which is a risk factor for enteric infection
- a minute loss of ability to absorption of B12 and Fe
- mild hyperplasia of ECL as the lack of feedback mechanism, (i.e. no acid) leads to increased gastrin levels and increase in ECL tumour growth
 Disadvantages of Proton pump inhibitors:
- Irreversible binding of drug to the receptor means effect of drug can only be overcome if new pumps are produced. Consequent, the body’s supply of proton pump can be easily depleted through daily dosing
 Effect of drug delivery on gut:
- acid degradation of drug, so use enteric coating to protect the substance inside
- acid enhanced absorption such as the drug itraconazole
- rate of gastric emptying can affect how fast a drug ingested enters the duodenum to be absorbed
- When taken with food, absorption of drug is slowed in a similar to alcohol uptake
- Hepatic enzyme function might modify drugs to activate/inactivate it
- Enterohepatic circulation possibly govern the time for distribution of drug to the liver
 Replacing pancreatic enzymes in chronic pancreatitis: large quantity of enzyme is required to be delivered to duodenum and compensate for lost function due to pancreatic inflammation
- problems: degradation by acid, need for neutral pH in the duodenum and release in the proximal bowel
- solution: enteric capsule that resist low pH but breaks down with high pH, but have challenges of size and time of release; administrate non-enteric coated drug along with a proton pump inhibitor
 5-aminosalicylic acid: requires to be delivered in the highest concentration to areas of inflammation mostly terminal ileum and colon (for cases of Crohn’s disease).
- Problem: 5-ASA alone is degraded by acid
- sulphasalazine therapy: delivered as sulphasalazine which contains an active site that is cleaved by colonic bacteria to form 5-ASA and sulphapyridine. However sulphur group of the sulphapyridine component produce adverse hypersensitive effect in certain patients despite effectiveness of drug
- pH dependant slow release: slow release in neutral or alkali pH
- enteric coated slow release: capsulated to resist acid but degraded by enzymes to release the drug
- colonic bacteria: joining of two 5-ASA molecules together with a diazo bond
 Anti-inflammatory drugs: drugs such as aspirin etc. Common treatment for arthritis and musculoskeletal pains
- problems: NSAID causes gastrointestinal bleeding from gastric ulcers by inhibition of prostaglandin (an important lipid compound for mucus HCO3- production and mucosal proliferation). Also produce microvascular injury with increased adhesion molecules and exudation of neutrophils along with stasis of blood flow leading to microvascular anemia.
- Solutions: alternatives to NSAID, use lowest possible dose, considering prescribing protective drugs such as proton pump inhibitors and prostaglandin analogues (i.e. act as decoy). Recently discovered new NSAID called COX2 inhibitors that reduce bleeding by 50% but expensive and have risk of myocardial infarction.

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