Carbonic anhydrase inhibitors

Clinical pharmacology: carbonic anhydrase inhibitors and their use in clinical practice, adenosine receptor antagonists

1. Domina Petric, MD
Carbonicanhydraseinhibitors

2. Carbonicanhydraseis presentinmanynephronsites.
Predominantlocationis theepithelialcellsofthe
proximalconvolutedtubule(PCT).
InthePCT carbonicanhydrasecatalyzes:
dehydrationofH
2CO
3to CO
2at theluminal
membrane
rehydrationofCO
2to H
2CO
3inthe
cytoplasm
Introduction

3. By blocking carbonic anhydrase,
inhibitors blunt NaHCO
3reabsorption
and cause diuresis.
Theprototypicalcarbonicanhydrase
inhibitoris ACETAZOLAMIDE.
Introduction

4. Thecarbonicanhydraseinhibitorsare well
absorbedafteroraladministration.
Anincreaseinurine pH fromtheHCO
3
-
diuresisis:
apparentwithin30 minutes
maximalat 2 hours
persistsfor 12 hoursaftera singledose
Excretionofthedrug is bysecretionintheproximal
tubuleS2 segment: dosingmust bereducedin
renalinsufficiency.
Pharmacokinetics

5. Inhibition of carbonic anhydrase activity profoundly
depresses HCO
3
-
reabsorption in the PCT.
At its maximal safe dosage, 85% of the HCO
3
-
reabsorptive
capacity of the superficial PCT is inhibited.
Some HCO
3
-
canstillbeabsorbedat othernephronsitesso
theoveralleffectis about45% inhibitionofwholekidney
HCO
3
-
reabsorption.
Pharmacodynamics

6. Carbonicanhydraseinhibitioncauses
significantHCO
3
-
lossesandmayleadto
hyperchloremicmetabolicacidosis.
Thediureticefficacyofacetazolamide
decreasessignificantlywithuse overseveral
daysbecauseHCO
3
-
depletionleadsto
enhancedNaClreabsorptionbythe
remainderofthenephron.
Pharmacodynamics

7. Group
Urinaryelectrolytes
NaCl NaHCO
3K
+
BodypH
Carbonicanhydrase
inhibitors
+ +++ + ↓
Loopagents ++++ 0 + ↑
Thiazides ++ + + ↑
Loopagentsplus thiazides++++++ ++ ↑
K
+
sparingagents + + - ↓
Changesinurinaryelectrolytepatternsand
bodypH inresponseto diureticdrugs

8. Themajor clinicalapplicationsof
acetazolamideinvolvecarbonicanhydrase-
dependentHCO
3
-
andfluid transport at sites
otherthanthekidney.
TheciliarybodyoftheeyesecretesHCO
3
-
fromthebloodintotheaqueoushumor.
Formationofcerebrospinalfluid bythe
choroidplexusinvolvesHCO
3
-
secretion.
Pharmacodynamics

9. CLINICALINDICATIONSANDDOSAGE

10. Thereductionofaqueoushumor formationby
carbonicanhydraseinhibitorsdecreasesthe
intraocularpressure.
Topicallyactiveagentsreduceintraocularpressure
withoutproducingrenalor systemiceffects:
dorzolamide, brinzolamide.
Peroralagents:
Glaucoma
Drug Usualoraldosage
Dichlorphenamide 50 mg 1-3 timesdaily
Methazolamide 50-100 mg 2-3 timesdaily

11. Uricacidandcystineare relativelyinsoluble:
formationofstonesinacidicurine.
Cystinuriais a disorderofcystinereabsorption.
Solubilityofcystinecanbeenhancedby
increasingurinarypH from7,0-7,5 with
carbonicanhydraseinhibitors.
Inthecaseofuricacid, pH needsto beraised
onlyto6,0-6,5.
Urinaryalkalinization

12. IntheabsenceofHCO
3
-
administration, these
effectsofacetazolamidelastonly2-3 days.
ProlongedtherapyrequiresoralHCO
3
-
administration.
Excessiveurinaryalkalinizationcanleadto
stoneformationfromcalciumsalts.
Urine pH shouldbefollowedduringtreatment
withacetazolamide.
Urinaryalkalinization

13. Metabolicalkalosisis generallytreatedby
correctionofabnormalitiesintotal bodyK
+
,
intravascularvolumeor mineralocorticoid
levels.
Whenthealkalosisis dueto excessiveuse of
diureticsinpatientswithsevereheart
failure,replacementofintravascularvolume
maybecontraindicated.
Metabolicalkalosis

14. Acetazolamidecanbeusefulincorrectingthe
alkalosisas wellasproducinga smalladditional
diuresisfor correctionofvolumeoverload.
Acetazolamidecanalsobeusedto rapidlycorrect
themetabolicalkalosisthatfollowsthecorrection
ofrespiratoryacidosis.
Metabolicalkalosis

15. Mountaintravelerswhorapidlyascend
above3000 m mayexperienceweakness,
dizziness, insomnia, headacheandnausea.
Symptomsare usuallymildandlastfor a
fewdays.
Inmore seriouscases, rapidlyprogressing
pulmonaryor cerebraledema canbelife-
threatening.
Acutemountainsickness

16. Acetazolamidedecreasescerebrospinalfluid
formationandcerebrospinalfluidpH, which
increasesventilation.
Acetazolamidediminishessymptomsof
mountainsickness.
Thismildmetaboliccentraland
cerebrospinalfluid acidosisis alsousefulin
thetreatmentofsleepapnea.
Acutemountainsickness

17. Carbonicanhydrase
inhibitorshavebeenused
as adjuvantsinthe
treatmentofepilepsyandin
some formsofhypokalemic
periodicparalysis.
Otheruses

18. Thesedrugsare alsousefulintreating
patientswithcerebrospinalfluid (CSF)
leakage(tumor, headtrauma, idiopathic).
Byreducingtherate ofCSF formationand
intracranialpressure, carbonicanhydrase
inhibitorscansignificantlyslowtherate of
CSF leakage.
Otheruses

19. Thesedrugsincrease
urinaryphosphate
excretionduringsevere
hyperphosphatemia.
Otheruses

20. TOXICITY

21. Acidosis results from chronic reduction of body
HCO
3
-
stores by carbonic anhydrase inhibitors.
Acidosislimitsthediureticefficacyofthese
drugsto 2 or 3 days.
Itpersistsas longasthedrug is continued.
Hyperchloremicmetabolicacidosis

22. Phosphaturiaandhypercalciuriaoccurduringthe
bicarbonicresponseto inhibitorsofcarbonic
anhydrase.
Renalexcretionofsolubilizingfactors(citrate)
mayalsodeclinewithchronicuse.
Calciumsaltsare relativelyinsolubleat alkalinepH.
Thepotentialfor renalstoneformationfrom
calciumsaltsis enhanced.
Renalstones

23. Potassiumwastingcanoccurbecausetheincreased
sodium, presentedto thecollectingtubule
(togetherwithHCO
3
-
), is partiallyreabsorbed.
Thatincreasesthelumen-negative electrical
potentialinthatsegment andenhancespotassium
secretion.
Treatment/prevention: simultaneous
administrationofpotassiumchlorideor a
potassium-sparingdiuretic.
Renalpotassiumwasting

24. Drowsinessandparesthesias:following
largedosesofacetazolamide.
Carbonicanhydraseinhibitorsmay
accumulateinpatientswithrenalfailure:
nervoussystemtoxicity.
Hypersensitivityreactions: fever, rashes,
bone marrowsuppressionandinterstitial
nephritis.
Othertoxicities

25. Carbonicanhydraseinhibitor-inducedalkalinization
oftheurine decreasesurinaryexcretionofNH
4
+
by
convertingitto rapidlyreabsorbedNH
3.
Thismaycontributeto thedevelopmentof
hyperammonemiaandhepaticencephalopathyin
patientswithcirrhosis.
Contraindications

26. ADENOSINEA1 RECEPTOR
ANTAGONISTS

27. ThesedrugsinterferewiththeactivationofNHE3 inthePCT and
theadenosine-mediatedenhancementofcollectingtubuleK
+
secretion.
Caffeine and theophylline are weak diuretics because of their
modest and nonspecific inhibition of adenosine receptors.
Adenosinereceptor antagonistsare understudy.
Adenosinereceptor antagonists

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