Drugs used to treat peptic ulcer. Antiemetic drugs

Question 1

How is acid secretion regulated in the stomach?

Answer 1

– 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

Question 2

What is the pathogenesis of PUD?

Answer 2

Pathogenesis of PUD
– Imbalance between aggressive
factors (H. pylori, acid, pepsin)
and protective factors (mucus,
bicarbonate, local production of
PGE and PGI2)

Question 3

Which are the drugs used to treat peptic ulcers?

Answer 3

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

Question 4

What are examples of H2 antagonists?

Answer 4

Drugs
Ranitidine
Famotidine
Nizatidine
Cimetidine - Developed
in 1971 and came into
commercial use in 1977

Question 5

What is the mechanism of action of H2 antagonists?

Answer 5

Mechanism of
action
– Inhibit H2
-receptors in
the parietal cells

Question 6

What are the side effects of H2 antagonists?

Answer 6

– Diarrhea, dizziness, muscle pain,
transient rashes, hypergastrinemia
– Cimetidine:
Endocrine disturbances
(antiandrogen effects) –
gynecomastia, galactorrhea,
reduced sperm count
Drug interactions (through CYP
inhibition)

Question 7

What are the therapeutic uses of H2 antagonists?

Answer 7

Therapeutic use
– In peptic ulcer desease
– In reflux esophagitis

Question 8

What are examples of PPIs?

Answer 8

Drugs
Omeprazole
Lanzoprazole
Pantoprazole
Rabeprazole
Esomeprazole

Question 9

What is the PK of PPIs?

Answer 9

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)

Question 10

What is the mechanism of action of PPIs?

Answer 10

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

Question 11

What are the adverse reactions of PPIs?

Answer 11

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

Question 12

What are the clinical uses of PPIs?

Answer 12

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 )

Question 13

What are examples of Mucosal protective agents

Answer 13

Colloidal bismuth subcitrate

Sucralfate

Question 14

What is Colloidal bismuth subcitrate?

Answer 14

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

Question 15

What is sucralfate?

Answer 15

– 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

Question 16

What is misoprostol?

Answer 16

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

Question 17

What is H.pylori?

Answer 17

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)

Question 18

What is the treatment of H.Pylori?

Answer 18

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

Question 19

What are antacids?

Answer 19

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

Question 20

What is the pathophysiology of vomiting?

Answer 20

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

Question 21

What are dopamine antagonists?

Answer 21

Drugs
– Metoclopramide
– Haloperidol
– Domperidone
– Itopride

Question 22

What are the PD, ADRs, and clinical uses of dopamine antagonists?

Answer 22

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

Question 23

Which anticholinergics are used as antiemetic drugs?

Answer 23

Scopolamine (transdermal patch)
Side effects
– Confusion, dry mouth, cycloplegia, urinary
retention
Clinical use
– For prevention of motion sickness

Question 24

Which antihistamines (H1-blockers are used as antiemetics)?

Answer 24

Drugs
Dimenhydrinate
Diphenhydramine

Side effects
– Sedation, dizziness

Clinical use
– For prevention of motion sickness
– In severe nausea and vomiting during pregnancy

Question 25

What are 5-HT3 antagonists? (setrons)

Answer 25

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

Question 26

What are NK1 receptor antagonists?

Answer 26

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