Drugs used to treat peptic ulcer. Antiemetic drugs Flashcards
How is acid secretion regulated in the stomach?
– Endogenous secretagogues: Gastrin (a hormone) Acetylcholine (a neurotransmitter) Histamine (a local hormone)
– Endogenous mucosa-protecting mechanisms: PGE and PGI2 inhibit acid and stimulate mucus and bicarbonate secretion
What is the pathogenesis of PUD?
Pathogenesis of PUD – Imbalance between aggressive factors (H. pylori, acid, pepsin) and protective factors (mucus, bicarbonate, local production of PGE and PGI2)
Which are the drugs used to treat peptic ulcers?
Drugs inhibiting gastric acid secretion (antisecretory drugs) – H2 antagonists – Proton pump inhibitors (PPIs) – Antimuscarinic drugs
Mucosal protective agents
– Colloidal bismuth compounds
– Sucralfate
– Misoprostol
Drugs used to treat H. pylori
infection
– Antibacterials
– Others: PPIs, colloidal bismuth
Antacids
What are examples of H2 antagonists?
Drugs Ranitidine Famotidine Nizatidine Cimetidine - Developed in 1971 and came into commercial use in 1977
What is the mechanism of action of H2 antagonists?
Mechanism of action – Inhibit H2 -receptors in the parietal cells
What are the side effects of H2 antagonists?
– Diarrhea, dizziness, muscle pain, transient rashes, hypergastrinemia – Cimetidine: Endocrine disturbances (antiandrogen effects) – gynecomastia, galactorrhea, reduced sperm count Drug interactions (through CYP inhibition)
What are the therapeutic uses of H2 antagonists?
Therapeutic use
– In peptic ulcer desease
– In reflux esophagitis
What are examples of PPIs?
Drugs Omeprazole Lanzoprazole Pantoprazole Rabeprazole Esomeprazole
What is the PK of PPIs?
Chemistry and PK – Pro-drugs (inactive) – Weak bases (pK 4-5) – Acid sensitive (given as enteric coated tablets) – Absorbed in the small intestine – Given 1 h before meals – Variable bioavailability according to the first pass metabolism by CYP isoforms – Accumulate in the acidic content of the parietal cells canaliculi (concentrated more than 1000-fold)
What is the mechanism of action of PPIs?
Mechanism of action and PD – Molecular conversion to reactive thiophilic sulfonamide cation in the acid – The activated molecules bind covalently to and irreversibly inhibit up to 80% of the active H+ /K+ ATPase (proton pump) – The inhibition lasts until the enzyme recovers and the effect is longer (12- 18 h) than the expected according to the plasma half-life (1.5 h) – PPIs have antibacterial action against H. pylori
What are the adverse reactions of PPIs?
Adverse effects
– Few adverse effects: headache, abdominal pain, nausea and
diarrhea
– Caution in patients with severe hepatic impairment, dosage
adjustment may be necessary
– In pregnancy – no teratogenic effect in animal studies but
their safety in people is not established
– Hypergastrinemia
What are the clinical uses of PPIs?
Clinical use
– In the treatment of peptic ulcer disease (including as a
component of the H. pylori eradication therapy)
– In the treatment of GERD
– In the prevention and treatment of NSAID-induced gastric
ulcers
– For other hypersecretory conditions (e.g. Zollinger-Ellison
syndrome )
What are examples of Mucosal protective agents
Colloidal bismuth subcitrate
Sucralfate
What is Colloidal bismuth subcitrate?
PK – Small amount is absorbed and excreted in the urine – Accumulation (and toxic effects) possible in renal failure
PD – Mucosal protection by Precipitating in acid and coating the ulcer base Absorbing pepsin – Activity against H. pylori
Adverse effects
– Constipation
– Blackening of the
tongue and feces
Clinical use
– In combination
regiments to treat H.
pylori infection
What is sucralfate?
– A salt of sucrose complexed to
sulfated aluminium hydroxide
PK – Given orally and frequently (4 times daily) – Minimal absorption of Al (accumulation possible in renal failure)
PD
– In the presence of acid sucralfate
dissociates into negatively charged
sucrose sulfate that binds to the positively
charged groups of proteins at the ulcer
base. As a result a viscous, tenacious
paste is formed that tightly adheres to the
ulcer and limits the back diffusion of H+
.
– Stimulates the local synthesis of PGs and
the production of mucus and bicarbonate
Unwanted
effects
– Constipation
Drug interactions – Reduces the absorption of many drugs – Antacids interfere with the activation of sucralfate
What is misoprostol?
Stable analog of PGE1
PK – Given orally – Rapidly metabolized – Plasma half-life < 30 minutes frequent administration (3-4 times daily)
PD
– Inhibits gastric acid secretion
– Stimulates the secretion of mucus and bicarbonate
– Maintains the mucosal blood flow
Adverse effects: frequent (10-20%)
– Diarrhea and abdominal cramps
– Uterine contractions (contraindicated in pregnancy)
Clinical use
– To prevent the gastric damage that can occur with chronic use of
NSAIDs
What is H.pylori?
H. pylori is considered a leading factor in the pathogenesis of peptic ulcer disease and, more particularly, of duodenal ulcer. It acts through increasing acid secretion and producing toxins and enzymes. Elimination of the bacillus can produce: – Rapid healing of the active ulcer – Long-term remission (low rate of relapse)
What is the treatment of H.Pylori?
Antimicrobial drugs effective in inhibiting H.
pylori:
– Amoxicillin, clarithromycin, metronidazole, tetracyclinе,
levofloxacin
Other drugs: PPI, Bismuth subcitrate
Eradication programs differ in the drugs included,
duration of therapy (7-14 days), tolerability and price:
– Triple therapy regimens, based on two antimicrobials and
a PPI, e.g:
Amoxicillin, metronidazole, omeрrazole
Amoxicillin, clarithromycin, omeрrazole
– Quadruple therapy regimens, e.g.
Clarithromycin, metronidazole, omeрrazole, bismuth
subcitrate
What are antacids?
Sodium bicarbonate Magnesium oxyde Hydrotalcite Combinations: – Almagel – Almalox – Stop-acid, etc.
Act by neutralizing gastric
acid and thus raising
gastric pH.
Unwanted effects and drug interactions – Interference with bowel function – Alkalosis and milk alkali syndrome (Sodium bicarbonate) – Inhibit absorption of other drugs
Clinical use: limited
– For symptomatic relief in
peptic ulcer
– In non-ulcer dyspepsia
What is the pathophysiology of vomiting?
Vomiting centre (М and NK1 receptors)
5 sources of afferent impulses to the
vomiting centre:
– Chemoreceptor trigger zone
(without BBB): D2
, 5-HT3 and NK1
receptors
– Labyrinth – vestibular nuclei: Мand Н1
-receptors (in motion
sickness)
– Irritation of the pharynx, innervated
by the vagus nerve
– Vagal afferents and afferents from intestinal mucosa: 5-HT3 receptors. Chemotherapy, radiation therapy, stretching, acute gastroenteritis lead to release of serotonin and stimulate vagal afferent fiber to the center of vomiting.
– CNS – sensor signals, stress,
memory
What are dopamine antagonists?
Drugs – Metoclopramide – Haloperidol – Domperidone – Itopride
What are the PD, ADRs, and clinical uses of dopamine antagonists?
PD
– Blockade of D2
receptors in the chemoreceptor trigger zone (metoclopramide,
haloperidol, domperidone)
– Blockade of D2
receptors and anticholinestrase activity (itopride)
– Metoclopramide, domperidone and itopride have additional prokinetic actions
Adverse effects
– Restlessness, drowsiness, insomnia, agitation
– Extrapyramidal symptoms (dystonias, akathisia, Parkinson-like), especially in
younger people
– Endocrine (elevated prolactin)
– Domperidone has no central side effects (acts peripherally)
Clinical use: Metoclopramide is the main drug
– Widely used for antiemetic therapy
– In the treatment of GERD
Which anticholinergics are used as antiemetic drugs?
Scopolamine (transdermal patch) Side effects – Confusion, dry mouth, cycloplegia, urinary retention Clinical use – For prevention of motion sickness
Which antihistamines (H1-blockers are used as antiemetics)?
Drugs
Dimenhydrinate
Diphenhydramine
Side effects
– Sedation, dizziness
Clinical use
– For prevention of motion sickness
– In severe nausea and vomiting during pregnancy
What are 5-HT3 antagonists? (setrons)
Drugs
– Ondansetron
– Granisetron
– Tropisetron
Mechanism of action: inhibit 5-HT3 receptors on the vagal afferents and in the chemoreceptor trigger zone
PK
– Given orally or IV
– Long plasma half-lives
(4-9 h)
Adverse effects
- Headache, constipation
- Expensive
Clinical use - In emetogenic therapy (chemotherapy, radiation, surgery) to prevent and treat vomiting
What are NK1 receptor antagonists?
Substance P causes vomiting when injected
intravenously and is released by gastrointestinal
vagal afferent nerves as well as in the vomiting
centre itself.
Aprepitant
– Blocks substance P (NK1) receptors in the chemoreceptor
trigger zone and vomiting center.
– Given orally
– Effective in controlling the late phase of emesis caused by
cytotoxic drugs
Fosaprepitant
– A prodrug of aprepitant
– Given intravenously
