H2 receptor antagonists

Clinical pharmacology

1. H
2-receptor antagonists
Domina Petric, MD

2. Pharmacokinetics
Cimetidine, ranitidine, famotidine and nizatidine.
All four agents are rapidly absorbed from the intestine.
Cimetidine, ranitidineandfamotidineundergofirst-pass
hepaticmetabolismresultingina bioavailabilityof
approximately50%.
Nazitidinehaslittlefirst-passmetabolism.

3. Pharmacokinetics
•Theserum half-livesrangefrom1,1 to 4 hours.
•Durationofactiondependson thedosegiven
to thepatient.
•H2 antagonistsare clearedbya combinationof
hepaticmetabolism, glomerularfiltrationand
renaltubularsecretion.
•Dosereductionis requiredinpatientswith
moderateto severerenalandhepatic
insufficiency.
•Intheelderly, thereis a declineofupto 50% in
drug clearanceas wellasa significant
reductioninvolumeofdistribution.

4. Drug Relative
potency
Doseto achieve
>50% acidinhibition
for 10 hours
Usualdose
for acute
duodenalor
gastriculcer
Usualdose
for GERD
Usualdose
for prevention
ofstress
related
bleeding
Cimetidine1 400-800mg 800 mg HS or
400 mg bid
800 mg bid 50 mg/h
continuous
infusion
Ranitidine4-10 150 mg 300 mg HS or
150 mg bid
150 mg bid 6,25 mg/h
continuous
infusionor
50 mg iv.
every6-8 h
Nizatidine4-10 150 mg 300 mgHS or
150 mg bid
150 mg bid Notavailable
Famotidine20-50 20 mg 40 mg HS or
20 mgbid
20 mg bid 20 mg iv.
every12 h

5. Pharmacodynamics
Thesedrugsexhibit
competitiveinhibitionat the
parietalcellH
2receptor and
suppressbasalandmeal-
stimulatedacidsecretionina
linear, dose-dependent
manner.

6. Pharmacodynamics
•Theyare highlyselectiveand
do notaffectH
1or H
3
receptors.
•Thevolumeofgastricsecretion
andtheconcentrationofpepsin
are alsoreduced.

7. Mechanismsofaction
•Histamine releasedfromECL cellsby
gastrinor vagalstimulationis blocked
frombindingto theparietalcellH
2
receptor.
•Directstimulationoftheparietalcellby
gastrinor acetylcholinehasa
diminishedeffecton acidsecretionin
thepresenceofH
2-receptor blockade.

8. Pharmacodynamics
•Whengiveninusualprescription
dosesall inhibit60-70% oftotal
24-houracidsecretion.
•H
2antagonistsare veryeffective
at inhibitingnocturnalacid
secretionwhichdependslargely
on histamine.

9. Pharmacodynamics
•H2 antagonistshavea
modestimpacton meal-
stimulatedacidsecretion
whichis stimulatedby
gastrinandacetylcholine,
as wellas histamine.

10. Pharmacodynamics
•NocturnalandfastingintragastricpH
is raisedto 4-5, but theimpacton the
daytime, meal-stimulatedpH profile
is less.
•Recommendedprescriptiondoses
maintaingreaterthan50% acid
inhibitionfor 10 hours.

11. Pharmacodynamics
Thesedrugsare
giventwicedaily.

12. CLINICALUSE

13. GERD (gastroesophageal
refluxdisease)
•Patientswithinfrequentheartburnor
dyspepsia(<3 timesperweek) may
takeeitherantacidsor intermittentH
2
antagonists.
•Antacidsprovide fastersymptom
relief, but withshort-livedeffect(1-2
hours) incomparissonto H
2
antagonists(6-10 hours).

14. GERD
•H
2antagonistsmaybetaken
prophylacticallybeforemeals.
•Frequentheartburnis bettertreated
withtwice-dailyH
2antagonistsor
proton pumpinhibitors.
•Proton pumpinhibitorsare preferred
inpatientswitherosiveesophagitis.

15. Pepticulcerdisease
•Proton pumpinhibitorsare
prefferedinthisindication.
•NocturnalacidsuppressionbyH
2
antagonistsaffordseffective
ulcerhealinginmost patients
withuncomplicatedgastricand
duodenalulcers.

16. Pepticulcerdisease
H
2antagonist,
administeredoncedailyat
bedtime, resultsinulcer
healingratesofmore than
80-90% after6-8 weeksof
therapy.

17. Pepticulcerdisease
•Incasesofpatientsthathaveto take
NSAID, proton pumpinhibitorsare
preferred, as wellas inthecaseof
Helicobacterpyloriinfection.
•H
2antagonistsmaybegivendailyat
bedtimeinhalf oftheusualulcer
therapeuticdoseto preventulcer
recurrence.

18. Nonulcerdyspepsia
•H2 antagonistsare commonly
usedas over-the-counter
agentsandprescription
agentsfor treatmentof
intermittentdyspepsianot
causedbypepticulcer.

19. Preventionofbleedingfrom
stress-relatedgastritis
•Clinicallyimportantbleedingfrom
uppergastrointestinalerosionsor
ulcersoccursin1-5% ofcritically
illpatientsas a resultofimpaired
mucosaldefensemechanisms
causedbypoorperfusion.

20. Preventionofbleedingfrom
stress-relatedgastritis
•AgentsthatincreaseintragastricpH
reducetheincidenceofclinically
significantbleeding.
•For patientswithouta nasoenteric
tube or withsignificantileus, H
2
antagonistsincontinuousinfusion
are preferred.

21. Adverseeffects
•Diarrhea, headache, fatigue,
myalgiasandconstipationin<3% of
thepatients.
•Iv. H
2antagonistsmayincreasethe
riskofnosocomialpneumoniain
criticallyillpatients, as wellas mental
status changes: confusion,
hallucinations, agitation.

22. Adverseeffects
Cimetidineinhibitsbindingof
dihydrotestosteroneto androgen receptors,
inhibitsmetabolismofestradioland
increasesserum prolactinlevels.
Inthecaseoflong-termuse or inhigh
doses, itmaycausegynecomastiaor
impotenceinmenandgalactorrheain
women.

23. Adverseeffects
•H
2antagonistscrosstheplacenta
sotheyshouldnotbe
administeredto pregnantwomen,
unlessabsolutelynecessary.
•Theseagentsare alsosecreted
intobreastmilkandmayaffect
nursinginfants.

24. Adverseeffects
•H
2antagonistsmayrarelycause
blooddyscrasias.
•BlockadeofcardiacH
2receptorsmay
causebradycardiaandhypotension,
especiallyifgiveninrapidiv.
infusion.
•Iv. injectionsshouldbegivenover30
minutes.

25. Drug interactions
•CimetidineinterfereswithP450
drug metabolismpathways:
CYP1A2, CYP2C9, CYP2D6 and
CYP3A4.
•Thehalf-livesofdrugs
metabolizedbythesepathways
maybeprolonged.

26. Drug interactions
•Ranitidinebinds4-10 timesless
avidlythancimetidineto
cytochromeP450.
•H
2antagonistscompetewith
creatinineandcertaindrugs
(procainamide) for renaltubular
secretion.

27. Drug interactions
Allofthese
agents, except
famotidine, inhibit
gastricfirst-pass
metabolismof
ethanol, especially
inwomen.

28. Literature
•Katzung, Masters, Trevor.
Basicandclinical
pharmacology.