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DIURETICS, COMPLICATIONS of HCD/thiazides, INTERACTIONS, RESISTANCE, Mild…

- - - - Long acting. T½=40-50hrs
      - Exclusively antihypertensive
    - - Marked additive effect with frusemide
      - Addtnl PT action
      - Excr. unchanged in urine
      - Use- 1. Edema(5-10mg/d)
        
        HTN(2.5-5mg/d occasionally
    - - More action
      - Severe hypokalemia with ventricular arrhythmias reported
      - Use: Edema(40mg/d. Max- 80mg/d)
    - - Little diuretic action due to high lipid solubility & ext. metabolism
      - Retains anti HTN action. So favored by NICE guidelines for HTN
- - - - A/c changes in renal/systemic hemodynamics. GFR unaltered
      - Intrarenal hemodynamic chages: ↑ local PG synthesis
      - Compensatory mechanisms- actvn of RAAS& reflex symp. stimulation
    - - Oral:2-3hrs, BA:60%
      - High PPB
      - Conjugated with glcUA→excrn by GF&TS
      - Minimal excr. via bile and intestine
      - severe CHF- parenteral admn
      - Plasma T1/2: 1-2hrs. Prolonged in Pul edema/renal/ hepatic insufficiency
  - - - 40x more potent
      - More lipid soluble.
        More PPB, partially metabolized, partially excr unchanged in urine
      - T½:1hr.
        ↑in renal/hep insuff.
  - - - Oral abs. more rapid and more complete (even in patients with edema of bowels due to CHF
      - Longer duration of action
      - 2-3x more potent
      - Only HCD Not eliminated by kidney
- - - - ↑ Excrn of Na+, K+, HCO3-, H2O
        
        Alk. Urine bt continued action depletes body HCO3- →→less bicarb filtered at glomerulus→↓diuresis (Self limiting diuretic action)
    - - Eye :↓IOT d/t ↓ pdn of aq. humor
        
        GIT :↓ gastric HCl & pancr. NaHCO3 secr.(only @ very high doses-not clinical doses)
        
        Brain : ↑ CO2 in brain & pH lowering→ sedation & elevation of seizure threshold
        
        Resp. sys : Alter CO2 conc in lungs&tissues (bt compensatory action masks it)
    - - Good oral abs. & Excr. unchanged in urine
      - Action: 8-12 hrs
    - - 1. Glaucoma : Acetazolamide/ methazolamide(oral). Binzolamide/ dorzolamide(eye dops-better tolerated)
      - 2. Alkalinise urine : for UTI or to promote excr. of certain acidic drugs
      - 3. Epilepsy : Adjuvant in absence seizures bt tolerance develops to antiepi. action
      - 4. Mountain sickness : Pul/cerebral edema may occur after initial symptoms of headache/giddiness/ nausea. Prophylaxis/ symptomatic relief
      - 5. Perodic paralysis
    - - Acidosis/ hypo K+ / drowsiness/ paraesthesia / fatigue/ abd. discomfort
      - BMD- rare, bt serious
      - C/I in Liver disease→ ppt hepatic coma(interfere with urinary elmn of NH3)
      - COPD patients→ likely acidosis
      - HS: fever/ rashes
  - - - Spironolactone
        
        MOA: Acts from interstitial side.
        
        Inhibits the formation of AIPs
        
        Competitve antagonist
        
        ↑Na+ and ↓ K+ excr. also ↑Ca2+ excr.
        
        Mild saluretic(maj Na+ absorbed already proximal to its SOA)
        
        Antagonise K+ loss by other diuretics
        
        PK
        
        Oral BA: 75%
        
        Highly PPB
        
        Completely metabolised in liver
        
        Active metabolite Canrenone
        
        Responsible for 60% in vivo action
        
        T½ (spirololactone)=1-2 hrs
        
        T½ (canrenone)= 18hrs
        
        Some enterohep circulation occurs
        
        Dose:25-50mg BD-QID
        
        Max 400mg/d
        
        Uses
        
        1. Combination with other diuretics: counteract K+loss due to LD and Tz
        
        2. Edema :
        
        Cirrhotic/nephrotic edema(ald levels generally very high)
        
        R/x of ascites d/t cirrhosis: Potentiates Tx & LD
        
        Breaks resistance to LD/Tz d/t 2° hyperaldosteronism → used in refractory edema
        
        3. HTN : Augment Tz in Rx of resistant HTN
        
        Prevent Tz-ind hypoK+
        
        ↓ HTN related renal fibrosis & ventr/vascular hypertrophy
        
        4. HF : Added to conventional CHF therapy to retard disease progression & ↓ mortality
        
        5. 1° hyperaldosteronism (Conn's syndrome)
        
        Interactions
        
        Spironolactone + K+ supplements : dangerous hypoK+
        
        Aspirin inhibits tub. secr. of Canrenone
        
        ↑ hypoK+ in patients taking ACEI/ARBs
        
        ↑digoxin conc.
        
        ADR
        
        Drowsiness/ Ataxia/ Mental conf. / epigastric distress/ loose stools
        
        Interacts with progestin/ androgen recceptors
        
        Gynecomastia/ erectile dysfunction/ loss of libido in men, breast tenderness/ menstrual irregularities in women
        
        Hasten testosterone clearance/ peripheral conversion to estradiol
        
        HyperK+ in renal failure
        
        Acidosis in cirrhotics
        
        C/I in peptic ulcer patients
      - Eplerenone
        
        Newer & more selective aldosterone antagonist
        Much lower affinity for androgen/progesterone R
        (hormonal S/E none)
        
        PK
        
        Good oral abs.
        
        Inactivated in liver by CYP3A4
        
        Enz Inhibitors ↑ blood levels
        (Clarithromycin, Itraconazole, etc)
        
        Enz Inducers ↓ its efficacy
        (Carbamezepine, rifampin, etc)
        
        Excr. in urine(maj.) and feces
        
        Indications
        
        Mod-severe CHF
        
        Post infarction LV dysfn & HTN
    - - Triamterene
        
        PK
        
        Incomplt. oral abs.
        
        Partly PPB
        
        Met. in liver→ active metabolite
        
        Excr in urine
        
        T½=4 hrs
        effect of single dose=6hrs
        
        S/E
        Nausea/ dizziness/ muscle cramps/ ↑ blood urea, IGT, photosensitivity.
        Urate levels not increased
        
        Dose = 50-100mg/d
      - Amiloride
        
        PK
        
        10x more potent
        
        Only 25% oral abs. Not PPB.
        Not metabolized
        
        T½= 20hrs, DOA > triamterene
        
        Actions
        
        ↓ Ca & ↓ Mg excr. but ↑ urate excr.
        
        High dose- inhibit Na+ reabs in PT (clinically no significance)
        
        Mild anti HTN action reported
        
        Blocks entry of Li+ thru Na+ channels in CD cells → used in Diabetes insipidus induced by Li+
        
        Other Use
        
        DI induced by lithium
        
        Aerosol- symptomatic Rx in cystic fibrosis
        
        Dose : 5-10mg OD-BD
      - MOA: ENaC/ amiloride sensitive Na+ channels present on luminal membrane of late DT & CD cells.
        
        Na+ enters cell via EC grad. produced by Na-K+ ATPase on basolat, membrane
        
        -15mV p.d. is produced→ promotes K+ secr. via K+ channels
        
        ↑ delivery of Na+ to distal nephron→↑ entry thru Na+ channel→ ↑ luminal membrane depolarisation → ↑ driving force for K+ secr. to lumen
        
        Amiloride/triamterene block luminal Na+ channels →inhibit K+ excr indirectly with minor net excess loss of Na+
        
        CD intercalated cells have ATP driven H+ pump(secretes H+ into lumen) facilitated by lumen -ve potential.
        
        Amiloride ↓ lumen -ve pot. → ↓ H+ secr. → predisposes to acidosis
        
        Amiloride conserve K+ & H+ & ↑ Na+ excr.
        
        Ca, Mg excr. also ↓
        
        Excess Na+ loss is matched by Cl-, HCO3- →slightly alkalinised urine
      - Indications
        
        Used with Tz/LD to prevent hypoK+ and slightly augment natriuretic response. AntiHTN action of Tz also supplemented
      - ADR
        
        R/o dang. hyperkalemia
        
        C/I in RF/ patients on K+ supplements
        
        HyperK+ likely with ACEI/ARBs/ ß blockers/ NSAIDs
        
        Digoxin plasma levels↑