Drug altered urinary pH

and stone formation

Dep. Farmakologi & Terapeutik,

Fakultas Kedokteran
Universitas Sumatera Utara

16 September 2011, KBK FK-USU, Medan

Urinary System
 Urine pH
Normal pH
The average is about 6 (range from 5~9; depends on diet)
Higher pH---alkaline urine (greater than 8.0)
1. Alkaline urine may indicate hyperkalaemia or vegetarian diet for
example
2. drugs: sodium bicarbonate (NaHCO3)
3. classic renal tubular acidosis
4. alkalosis (metabolic or respiratory)
5. urease (+) bacteria
6. delayed processing (bacteria/CO2 loss)
Lower pH---acid urine (less than 4.5)
1. Acidic urine may be due to acute starvation,
2. diabetic ketoacidosis or
3. hypokalemia/furosemide therapy
4. drugs: ammonium chloride
5. high-protein diet
6. acidosis (metabolic or respiratory)
 Crystalluria
Formation dependent on
pH,
temperature,
solubility, and
concentration of the crystalloid.
Types of kidney/ureter stones
Oxalate (Calcium Oxalate)

Phosphate

Uric Acid & Urate

Cystine
 Ammonium
Urate Uric Acid Cystine
Solubility

Phosphate

5 6 7 8 pH

Effect of pH on Urinary Solubility of Lithogenic Substances

 Sediment Evaluation
(crystalluria)
Type of Crystal Acidic Neutral Alkaline
Ammonium urate + + +
Amorphous urate + +/- -
Bilirubin + - -
Ca carbonate - +/- +
Ca ox dihydrate + + +/-
Ca ox monohyd. + + +/-
Cystine + + +/-
Mg ammonium phosphate +/- + +
Sulfa metabolites + +/- -
 Acidic Urine Crystals

Sulfa

Ca oxalate dihydrate
 Alkaline Urine Crystals

calcium carbonate

Mg ammonium phosphate
Calcium oxalate monohydrate Ammonium biurate

Cystine
Radioopaque Stones
- Calcium stones.
- Struvite.
- Cystine.
- Triamterene (faint).
Radiolucent Stones
- Uric Acid.
- Indinavir stones.
 Uric Acid Stones
Defect in uric acid
stone formers is an
excessively acid
urine.
Usually are not
hyperuricosuric.
Rx is urinary
alkalinization.
alkalinization
 Uric Acid Stones
Only form in acidic urine (pH < 5.8)
Low urine pH = Uric acid stone
High urine pH = Urate stone
Treatment:
1.Urinary Alkalinization
Aim pH of 7 - 7.2 (Patient monitored with pH strips)
Potassium Citrate / Sodium Bicarbonate
Citrus juices / High bicarbonate mineral water
2.Decrease Uric acid excretion
Low purine diet
Allopurinol
Adenine Hypoxanthine Xanthine Uric acid
Instead Xanthine oxidase converts alloprurinol to oxypurinol
3.Increase urine dilution (3 lts / day)
Sodium urate is 15 times more soluble than uric acid.
At a urine pH level of 6.8, 10 times as much sodium urate as uric
acid is present.
At a urine pH level of 7.8, 100 times as much sodium urate as uric
acid is present
 Calcium Oxalate
Aim is urinary alkalinisation:
Potassium Citrate (9-12g/d)
Citrate binds Calcium and enhances excretion
Care in Renal failure, Hypertension,
Hyperkalaemia
Sodium Bicarbonate (4.5g/d)
Sodium can cause hypercalciuria !
Magnesium (200-400mg/d)
Can be given if pH is normal or alkaline
Care in renal failure
 Struvite
Triple phosphate or infection stones
Alkaline urine promotes struvite calculi
formation
Urea-splitting organisms break down urea
Carbon dioxide and ammonia are produced
Urine pH increases
Carbonate levels rise
Treatment
Long term antibiotic prophylaxis
Acidify urine: pH < 6.2
L-methionine or Ammonium Chloride
Dilution of urine (reduce bacterial concentration)
Well balanced diet
 Cystine
Treatment
Urine dilution
Urine volume > 3.5 lts / day (1.5 lts of urine at night)
Urine Alkalinisation
pH > 7.5. Use Alkaline citrate or Sodium Bicarb.
Measure pH regularly throughout the day.
Medications to reduce Urinary Cystine
Ascorbic acid.
Thiola (-mercaptopropionylglycine)
Diet
Low sodium. Low protein (avoid methionine). Drink juice.
 Acidification & Alkalinization
of Urine
Acidification of urine------> increases
ionization of weak bases--->increases
renal elimination
Salicylates lead to acidic urine,
urine then if
combined: Uricosuric action of sulfinpyrazone
may be reduced.
Alkalinization of urine------> increases
ionization of weak acids--->increases
renal elimination
 Antidotes
Antidotes now considered obsolete include
universal antidote for ingested poisons,
acetazolamide for modification of urinary pH,
ascorbic acid for methemoglobinemia.
In the case of drugs which are weak
organic acids and bases, a much greater
effect on clearance can be obtained by
manipulation of the urine pH.
Urine pH is therefore much more important
than urine flow rate
 Antidotes
FORCED ALKALINE DIURESIS
Raise the urinary pH to 7.5 for weak acids e.g.,
barbiturates,
salicylates
sulfonamide
jengkolic acid
with 1.4 % NaHCO3.
FORCED ACIDIC DIURESIS
Maintain urinary pH to 5.5-6.5 in poisoning with weak bases
e.g.,
amphetamine
tricyclic antidepressant and
phenytoin,
with ammonium chloride 4 g administered every two hourly
through Ryles tube
 Salcylates poisoning
Symptoms
Mild or early poisoning (1 to 12 hours after acute
ingestion): nausea , vomiting , abdominal pain ,
headache, tinnitus, dizziness , fatique
Moderate or intermediate poisoning (12 to 24
hours after ingestion ): fever, sweating ,
deafness, lethargy, confusion , hallucinations,
breathlessness
Severe or late poisoning ( greater than 24 hours
after acute ingestion or unrecognized, untreated
chronic ingestion ): coma, seizures, fever
 Salcylates poisoning
Sign
Mild or early: lethargy , ataxia , mild agitation ,
hyperpnea, mild abdominal tenderness
Moderate or intermediate: fever, asterixis,
diaphoresis, deafness, pallor, confusion , slurred
speech, disorientation .agitation , hallucinations,
tachycardia, tachypnea, orthostatic hypotension
Sever or late : dehydration , coma , seizures,
hypothermia or hyperthermia , tachycardia,
hypotension, respiratory depression, pulmonary
edema, arrhythmias , papilledema
 Treatment of Salcylates poisoning

Rapid cool patient

Alkalinize urine with D5W with 3 ampules of
sodium bicarbonate begin drip at 150ml/hr
and target urine pH of 7.5
Monitor serum electrolytes
Consider dialysis for renal failure if persistent
acidemia, pulmonary edema , deterioration
despite supportive care, or severe mental status
changes or coma , in the aged with co-morbid
disease.
 Drugs acidifying urine
Ascorbic acid
NH4Cl

Clinical implication
Cinoxacin against some common urinary tract
pathogens was pH dependent.
A four- to eightfold reduction in cinoxacin activity was
generally observed at pH 8 compared with lower pH values.
Mecamylamine (potent ganglionic blocking agent),
slowly excreted in urine unchanged.
alkalinization of urine reduces renal excretion, and
acidification promotes renal excretion.
 Drugs alkalinizing urine
NaHCO3
Citrate
Acetazolamide (carbonic anhydrase inhibitor)
Contraindicated Drug Combination:
POTASSIUM WASTING DIURETICS/CISAPRIDE - Adverse reaction
with both drugs
SULFONAMIDES/METHENAMINE - Adverse reaction of the former drug
Severe Interaction:
Action is required to reduce the risk of severe adverse interaction.
CARBONIC ANHYDRASE INHIBITORS/TOPIRAMATE
Moderate Interaction:
Assess the risk to the patient and take action as needed.
SALICYLATES - Adverse reaction with both drugs
LITHIUM - Decreased effect of the latter drug
URINARY ALKALINIZERS/SYMPATHOMIMETICS - Increased effect of
the latter drug

Clinical implication
Dissolve uric stones, sulfonamide crystals
Reducing pain in interstitial cystitis
Ma kaseeeh
Kidney
Stones
 Calcium Oxalate Monohydrate
or Dihydrate
Pathogenesis/risk factors
Idiopathic
Metabolic defects
Alkaline urine pH
Hypercalciuria
Hyperoxaluria
Hyperuricosuria
Family history
Dehydration
Diet or medications
Vitamins A,D,C
Acetazolamide
Antacid abuse
 Calcium Phosphate
Pathogenesis/risk
factors
Hypercalciuria
Vitamin D intoxication
Hyperparathyroidism
Sarcoid
Alkaline urine
Urinary acidification
defect
Distal, Type I RTA
Acetazolamide
Milk-alkali syndrome
Uric Acid Calculi
Pathogenesis
Hyperuricosuria
gout
psoriasis
Lesch Nyhan syndrome
obesity
Status post chemotx
Persistently acid, concentrated
urine (pH < 5.5)
chronic diarrheal disease, esp. via
ileostomy
Uric acid solubility decreases 10-20x
when urine pH falls 7 to 5
 Uric Acid Calculi Cont
Treatment
Very susceptible to solubility conditions
Alkalinization to reach urinary pH 6.5-7.0
Fluids, Rx underlying condition, education
 Struvite Stones
Pathogenesis/risk factors
Urinary tract infection with urea-splitting organism
Proteus - most common
Kliebsiella
Serratia
Enterobacter
Markedly alkaline urine (pH 7.5-8.0)
Supersaturation with magnesium-ammonium
phosphate
Struvite Dx & Rx
Diagnosis
stone analysis
struvite crystals diagnostic of
UTI with urea splitting organism
NOT struvite stone
urinary pH 8 suspect struvite
stones
Treatment
antibiotics
percutaneous
surgery/lithotripsy
fluids, Rx underlying disease,
education
 Cystine Dx
Diagnosis
Stone analysis
Cystine crystalluria
Hexagonal crystals
Cyanide-nitroprusside
test
Qualitative
24 hour urine studies
Quantitative
Homozygous vs
heterozygous
 Cystine Rx

Treatment
High fluid intake (4L/d)
Patient education- compliance
Resistant to ESWL
Alkali therapy
Increase in cystine solubility at urine pH > 7.5
Penicillamine
Covalently bonds to cystine, making a soluble complex
Toxic -- glomerulonephritis, SLE syndrome, marrow depression
-MPGsimilar action to penicillamine but better
tolerated
 Inhibitors
Deficient in urine of stone-former
Citrate
Forms a soluble Ca+2-citrate complex
Increases urinary pH
Hypocitraturia occurs in states of chronic
metabolic acidosis (distal RTA, chronic real
failure, acetazolamide therapy), K+ depletion
and idiopathic cases
Presumably raises the formation product
of all types of calcium stones
 Chronic Management: Rx
Fluid intake 24 hours/day > 2-3 L/day

Dietary modification

Regulate urinary pH

Alkalinization: uric acid and cystine stones

Acidification almost never indicated

Cranberry juice NOT indicated