Pharmacology: Renal

Drugs and the Kidney .............................................................................................................................................................. 2

Diuretics .................................................................................................................................................................................. 5
Drug Treatment of Essential Hypertension............................................................................................................................. 9

1
 Drugs and the Kidney
The kidney’s effect on drugs
Elimination, Metabolism, Distribution, and Absorption

Elimination
Filtration (glomerular)
 Aminoglycosides (big issue: toxin hits from tubular size)
 Digoxin (high toxicity potential)
 most β-lactam antibiotics: not a big problem usually (high therapeutic index)
 fluoroquinolones, vancomycin (rarely an issue)

Remember: Plasma creatinine has a non-linear relationship to GFR

Cockcroft-Gault Formula: MEMORIZE THIS

140 − age × lean body weight (in kg)
𝐶𝐶𝑟 = × (0.85 𝑓𝑜𝑟 𝑤𝑜𝑚𝑒𝑛)
𝑃𝐶𝑟 × 72

Aminoglycoside dosing: need to be careful if diminished renal function

1. Loading dose : get up there quick
a. Hit target concentration immediately
b. Depends on Vd, NOT clearance (not renal function)
c. “Once daily dosing”: 5-7 mg/kg for loading dose
i. “Traditional” q8h dosing: 2mg/kg (3-4 mg/kg in ICU for sepsis)
2. Maintenance dosing
a. “Once daily” 5-7 mg/kg, “traditional”q8h 5-7 mg/kg
b. GFR-adjusted based on serum creatinine & calculated creatinine clearance
c. Use CCr from formula above to calculate clearance, adjust
d. (if 50% renal function, give 50% dose – because it’s almost all renally cleared)
3. Target concentration
a. Peak “once daily” not established
b. Peak “traditional” 7-10 μg / mL or peak / MIC ratio
4. All this applies to gent & tobra, amikacin doses/targets are 4x higher

Meperidine (Demerol): morphine-like agent

 If you’re renally impaired, you can’t excrete nor-meperidine
o neuro-toxic metabolite formed after oral / high-dose parenteral
administration
 Accumulates more rapidly if renal glomerular impairment

Secretion (tubular)

Probenecid: blocks renal secretion of all penicillins and cephalosporins

 also zidovudine & cidofovir (reduces toxicity of cidofovir)
 Not used with penicillin anymore (originally used to conserve penicillin during war: could use less PCN)
 Uricosuric agent:
o uric acid filtered & then reabsorbed
o reabsorption blocked by probenecid, makes you pee out uric acid (good for gout)

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Reabsorption (tubular)

Aspirin (acetyl-salicylic acid)  rapidly de-acetylated to salicylic acid (SA)

 SA is both metabolized by liver & eliminated by kidney in a pH-dependent fashion
 In overdose setting: hepatic SA metabolism is CAPPED (zero-order kinetics)
o Renal elimination is therefore key to get rid of that SA
o Eliminated by NON-IONIC DIFFUSION

Non-ionic diffusion
 Remember henerson hasselbach
 SA is a weak acid (pKa = 3.4), acids ionize above their pKa
 Only uncharged particles cross lipid barrier
o Alkalinize the urine, you can trap ionized SA in the urine &
excrete it
o Top picture = normal urine pH, bottom = after Urine pH↑
 Give bicarb to treat aspirin overdose
o Rise of 1 in urine pH  10x decrease in reabsorption (or 10x
increase in excretion) of SA

Metabolism
Vitamin D
 In renal impairment: can’t generate Vitamin D active metabolite
 2-step process: Vitamin D hydroxylation
o Hepatic: 25-hydroxylation
o Renal: 1-hydroxylation (active 1-25OH Vit D generated)
 Vitamin D deficiency is key component of renal osteodystrophy (bone problems)

Imipenem
 Filtered & secreted from blood to renal cells
 Hydrolyzed to inactive / toxic metabolite by dehydropeptidase (DHP)
 Give with cilastin to block DHP
o ↑ imipenem *urine+, no renal toxicity

Distribution
Think: pH partitioning (salicylate toxicity) - ↑ pH in urine to hasten elimination (See above)

Absorption
Dialysis Dementia: stuttering speech, altered mental status/cognition, seizures, death
 ↑ serum aluminum (high Al in dialysis water sources, Al hyperabsorption in phosphate-binding oral Al salts)
+3 +3

 No longer a problem (don’t use phosphate-binding Al salts, treat water to remove Al)

Renal Toxicity
Even with rational drug design, “toxicity is always a crapshoot” – see table to right for partial list of nephrotoxic drugs

Factitious Toxicity: ↑ SCr or BUN but not really causing toxicity

 Assay interference (ketone bodies, flucytosine, cefoxitin)
 ↓ creatinine secretion (cimetidine, pentamidine)
 ↑ creatinine release (rhabdomyolysis)
 ↑ BUN (corticosteroids, tetracycline)

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Aminoglycoside nephrotoxicity
 Onset: late in 1st week (5-7 days), can last up to 1 week after d/c drug
 Proximal tubule death & release of enzymes detectable in all patients

 Non-oliguric, no proteinuria (not damaging glomerulus)

 Usually mild (as measured by GFR), rarely severe
o “always” reversible – if you can get them through the ARF
o PT cells can regenerate if you haven’t damaged BM, and AGs don’t – but ototoxicity not reversible

 Gent > tobra > amikacin for toxicity at equimolar doses (so you can give 4x dose ami)
 ↑ risk: total dose, females, elderly, liver disease

How does AG nephrotoxicity happen?

 Bound, incorporated by proximal tubular epithelium (pinocytosis) from lumen (reabsorption)
 Accumulation, long retention by proximal renal tubules
o Labeling studies in mice: accumulates in kidney, esp kidney, only PT!
 ALWAYS proximal tubular damage
 NO damage to basement membrane  tubules can regenerate
Other nephrotoxic drugs
Aspirin / NSAIDs
 Both non-specific & specific cox-2 inhibitors Cisplatin
 Nephrotoxicity: in situations that depend on prostacyclin to  Nephrotoxicity depends on a renal glutathione S-transferase
maintain intraglomerular pressure o (normally a “detoxifying enzyme” but here forms a
o Blocking prostacyclin’s dilation of afferent arteriole toxic metabolite!)
o Block synthesis  can’t maintain IGP
Cidofovir
ACE inhibitors  Transported into renal tubular cell by organic anion
 Same kind of deal: block constriction of efferent arteriole  transporter (HOAT-1)
can’t maintain IGP o Probenecid blocks this transporter  ↓
nephrotoxicity
Amphotericin B
 Nearly inevitable nephrotoxicity (every patient!) Bevcizumab
 Vascular, glomerular, tubular damage  Anti-angiogenesis agent
but mechanisms unclear (anti-VEGF mAb for cancer chemo)
 Lipid formulations  less severe damage (but still not great) o Causes proteinuria in 21-64% treated, HTN in 3-36%
o Renal thrombotic microangiopathy seen in pts
Radiocontrast affected
 Peaks 2 /3 day after exposure
nd rd

 Recovery in 2 wks is the rule, occasionally permanent loss of
function
o Animal models: osmotically-induced endothelin-1 mediated
renal vasoconstriction involved
Radiocontrast: Gadolinium
 New syndrome: nephrogenic systemic fibrosis
o ESRD on dialysis
o Odds ratio (exposed vs unexposed): 20/1 – 46/1
Cyclosporin
 Haven’t been able to separate mechanism of
immunosuppressant activity from nephrotoxic activity
 Seems to be “on target” nephrotoxin (rapamycin may not
share nephrotoxicity?)
 Is nephrotoxicity related to VEGF target?
In other words, can we fix this or not?
o Looks like it’s direct reduction of VEGF target (↓
glomerular VEGF production) that’s at fault –VEGF-A
production needed to maintain integrity of vascular
bed, bevcizumab interferes with cross-talk between
podocytes & glomerulus
Fangchi:
 Chinese herbal nephropathy: progressive interstitial
fibrosis with glomerular sparing, often with urothelial
cancers in Belgian women taking fangchi for weight
reduction
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 Diuretics
Background
 Some of most commonly prescribed drugs in US
 Increase urine flow (“diuresis”) by inhibiting reabsorption of NaCl (different sites of nephron for different classes)
o Loss of urinary NaCl (“saliuresis”)  water loss
 Treat: HTN (thiazides are #1), edematous states (CHF, cirrhosis, nephrotic syndrome: loop diuretics are #1)

The Four Major Classes

In order of potency (most  least)
Class Acts at
Loop diuretics TALH
Thiazide diuretics Distal tubule & connecting segment
Potassium-sparing diuretics Cortical collecting tubule
(aldosterone-sensitive principal cells)
Carbonic anhydrase inhibitors Proximal tubule

Sodium reabsorption: things to keep in mind

 Huge amount of sodium filtered & reabsorbed every day
o Affecting even ~ 3% of reabsorption (collecting tubule) can have a
significant effect on sodium excretion
 PT is #1 for absorption (microvilli, mitochondria, tons of SA)
 TALH is #2
 Site of action of diuretic affects the “ceiling” – what % of Na
reabsorption can potentially be blocked?

How to measure sodium intake? 24hr sodium excretion!

Step increase or decrease in Na intake  increase or decrease in excretion (after lag) to match
 ↑ Na+ intake  ↑ ECF (levels off when excretion↑ to equal new higher intake)
+
o So steady state volume depends on Na balance (esp. intake)
 ↑ ECF  ↑ Na+ excretion
 Mechanisms involved (see other lectures)
o hemodynamics (arterial pressure  carotid / cardiopulmonary / afferent arteriole sensors  RAAS, symps)
o hormones responsive to ECF (ADH, aldosterone, ANP, etc)
o direct kidney involvement (tubuloglomerular feedback)

Edema
 ↑ ECF volume b/c reduced ability to EXCRETE SODIUM for a given ECF volume
o CHF, renal failure, cirrhosis, nephrotic syndrome
 See graph: ↑ threshold ECF for Na+ excretion
o (takes more ECF to get Na+ excretion > 0)
o Edema at lower sodium intake

Best initial treatment: DIETARY SALT & FLUID RESTRICTION

 Go to diuretics when this doesn’t work

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 Chronic Adaptation to Diuretics
1) ↑ NaCl excretion initially with diuretic use
+
a. Negative sodium & chloride balance  net Na excretion 
net water loss
b. ↓ECF, edema lessens, etc.
2) Na / H2O loss declines with time: “braking phenomenon”
a. Go back to baseline levels
b. Adaptive processes: ECF is dropping!
c. RAAS, sympathetic, aldosterone, etc. (see above) kick in
d. Good: if you always had a negative balance, ECF would keep
dropping and pt would be dehydrated
3) So what good are diuretics?
a. Reach new steady state with a lower ECF!
b. Diuretic resistance: if adaptation happens
before desired ECF reached (↑ dose if
possible)

Too much diuretic?

 Hypovolemia results (↓ ECV)
 Symptoms: thirst, weaknes, lethargy, lightheadedness
 Signs: postural hypotension, ↑Hct, azotemia (↑BUN)
 Note: can have intravascular volume depletion (↓ ECV) at the same time as ECF overload (edema)!

Where diuretics work

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 Loop diuretics
Furosemide (Lasix), bumetanide, torsemide, ethacrynic acid
 #1 diuretics for ↓ volume (edema) – high potency
 “High ceiling” diuretics (potent: 25% Na reabsorbed @ TALH)
 Short half life with steep dose-response curve: sometimes hard to hit the sweet spot
o “Lasix” “lasts six” hours (t1/2 = 6h)
 Rebound sodium retention can ↓ efficacy, so give twice daily
o Delivering more Na distally, can ↑ Na reabsorption in DT (↑ aldo)
 Keep in mind that these are working on urine side  drug is secreted in PT

How they work: Block Na/K/2Cl transporter in TALH (apical side) – 25%

Other effects:
+
 ↑ Ca excretion (mainstay Rx for hypercalcemia )
 ↑ venous capacitance
(post-IV administration: Rx for acute pulmonary edema)

Side effects / Toxicity:

 ↑ K+/ H+ loss  HYPOKALEMIC METABOLIC ALKALOSIS
(CONTRACTION ALKALOSIS)
o #1, most important side effect – can be really bad!
+
o ↑ K loss (blocking Na/K/2Cl transporter)
+ +
o ↑ Na delivery ↑ Na absorption distally  ↑ K . H secretion
+ +
o ↑ renin (low volume)  ↑ AT II  ↑ aldo K , H loss
 Hyperuricemia (↓ uric acid clearance)  gout sometimes
 Ototoxicity (inhibits cotransporter isoform in inner ear)
o Especially ethacrynic acid + aminoglycoside (now don’t use EA that much)

Thiazide Diuretics
Hydrochlorothiazide (HCTZ), chlorthalidone, indapamide, metolazone
 #1 diuretics for hypertension (1st line for essential HTN)
 Moderate/low efficacy after 1 dose (“low ceiling”)
 Daily dose: Longer half life than loops, no rebound sodium retention

How they work: block Na / Cl cotransporter in DCT (apical side) – 5-10%

Other effects:
 Anti-HTN independent of diuretic effect!
 ↓ Ca+ excretion with long-term use (opposite of loops!)
+
o Rx for nephrolithiasis (reduce urine Ca ), may help in osteoporosis

Side effects / Toxicity:

 ↑ K+/ H+ loss  HYPOKALEMIC METABOLIC ALKALOSIS (CONTRACTION ALKALOSIS) – same reasons as loops
 Hypokalemia is more common than with “loops” (counterintuitive: loops blocking Na/K/2Cl transporter)
+ +
o Give K supplementation or K -sparing diuretic
 Hyperuricemia (↑ with ↑ dose)  gout
 Hyponatremia
 Hyperglycemia, hyperlipidemia (except indapamide)

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 K+-sparing Diuretics
Sprinonolactone (aldosterone antagonist)
Amiloride, triamterene (sodium channel blockers)
 All have low efficacy (only 3% filtered at this part of nephron)

How they work: work on principal cell of collecting duct

 Aldosterone antagonists: inhibit aldosterone-sensitive Na/K exchange
(natriuresis & K retention result)
 Sodium channel blockers: block sodium channels (yep)  natriuresis
+ +
o Less negative lumen  less K secretion  K sparing
Other effects:
 Spironolactone: ↓ mortality in CHF pts (with ACEi ± ARB)
o 30% improvement @ 3 years!
 Amiloride: helps in lithium toxicity (Li enters cells via Na channel that amiloride blocks)
 All useful in potassium wasting disorders

Side effects / Toxicity

 HYPERKALEMIA (esp in pts with renal failure)  can be FATAL
o With acidosis (K+ and H+ retention) too
 Spironolactone: gynecomastia, impotence (↓ in newer, more expensive drugs)

Carbonic Anhydrase Inhibitors

Mild potency (distal nephron compensates, and you’re only blocking one of many ways for Na to get into PT)

How they work: inhibit CA, which normally produces H+, which is exchanged for Na+ as part of bicarb system
 Loss of Na+/H+ exchange  Na+ loss (with ↓ reabsorption of bicarb)

Other effects:
 Acute mountain sickness (brain effects, probably a more common use)
 Useful in open-angle glaucoma, Meniere’s disease too
 Used in patients with metabolic alkalosis occasionally (if saline can’t be given)

Side effects / Toxicity

 Hypokalemia
 Acidosis (bicarb loss)
 TERATOGENIC
Other Diuretics
Osmotic diuretics: don’t usually use as diuretics but for other things
 Freely filtered, not reabsorbed so drag water out too
 Use: treatment of cerebral edema (intravascular osmotic agent)

Clinical use
 Loop diuretics for severe edema (CHF, nephrotic syndrome, cirrhosis, renal failure)
o Thiazides added in combo if edema loop diuretic resistant
o (as part of compensation, ↑ % reabsorption in DT after loop diuretic taken: so bigger thiazide effect!)
 Thiazides for mild edema and #1 for HTN
Drug combos
 Loop + thiazide: potent & useful

+
Thiazide + K -sparing: for HTN, help with K-lowering effects of thiazide

+
ACEi + thiazide: ACEi reduces K loss (inhibits RAAS), thiazide synergistic for anti-HTN effects (lisinopril + HCTZ)

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 Drug Treatment of Essential Hypertension
Epidemiology:
 Prevalence of HTN is high (50% in older age groups)
o Treatment really reduces morbidity/mortality
o Only 30-40% are well controlled
 AA > caucasian (midlife, evens out later in life) Classification of BP for adults 18yo or older
 Females > Males BP classification SBP (mm Hg) DBP (mm Hg)
Normal <120 and <80
Classification: see table (from another lecture) Prehypertension 120-139 or 80-89
Stage 1 hypertension 140-159 or 90-99
Stage2 hypertension ≥160 or ≥100
Complications start at 110/75 (seems low!)
 BP is major risk factor for:
o CVD, CHF, LVH, ischemic stroke, intracerebral hemorrhage, chronic renal insufficiency & ESRD

White coat hypertension: higher with doctors! Some patients have ↑↑ BP when a doctor takes it!

General Points
General efficacy: In essential HTN, aggressive lowering is better!
 AMOUNT BP LOWERED but not drug used is KEY DETERMINANT OF OUTCOME
o (don’t get suckered by big bad pharma)

Monotherapy: if no specific indication, can choose from:

1. Thiazide diuretics
2. Long-acting calcium channel blockers (usually a dihydropyridine)
3. ACEi / ARB

 (NOT β-blocker: ↑ stroke, ↑ risk heart disease)

Combination therapy:
 Start on combo if > 20/10 mm Hg above goal (e.g. 140/100)
 Many patients initially controlled with monotherapy will eventually need combo (30% @ 1yr, 40% @ 5yr)

Blood Pressure goals:

Condition Goal
Uncomplicated combined systolic & diastolic HTN 140/90 mm Hg
Special Circumstances
 Diabetes mellitus
130/80 mm Hg
 Proteinuric chronic kidney disease
 Atherosclerotic CVD
Older individuals with isolated systolic HTN Treat systolic as much as
 Wide pulse pressure! possible but maintain
 SBP > 140 but DBP < 65 = isolated systolic HTN DBP > 65 mm Hg

LOWER BP GRADUALLY if patient doesn’t have end-organ damage / urgency

 Patient needs time for homeostatic mechanisms to adapt to new, lower BP
 Lower too fast  stroke, other cerebrovascular / coronary events
 STROKE, ACUTE MI, other signs of acute end organ damage: do lower emergently!

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 Resistant Hypertension
Definition: DBP > 95-100 despite 3+ antiHTN meds

Why does it happen?

 Suboptimal therapy  Secondary HTN
 ECV expansion  Office / “white coat” HTN
 Poor compliance (medical ± dietary therapy)  Pseudohypertension

Discontinuing Therapy
Some patients with mild HTN are well controlled on single medication – can consider stopping the meds gradually

If you chose to discontinue therapy: TAPER (discontinue gradually!)

 5-55% pts remain normotensive for 1-2 yrs on no meds
 More do well with less meds or lower doses
 Best success if can use nonpharm techniques (wt loss, sodium restriction)

Abrupt cessation of short-acting β-blocker (e.g. propranolol) or short-acting α-2-agonist (clonidine) CAN BE FATAL
 Withdrawal syndrome! Need to gradually taper, consider switching temporarily to longer-lasting agents

Chronic Kidney Disease

 Aggressive treatment is better (down to 130/80 or less!)

TREATMENT IN CKD:
FIRST THERAPY (↓ progression renal dz via ATII block)
ACEi
 ARB if contraindicated, bad cough, etc.
Should add too! Most patients not controlled on monotherapy
DIURETIC  LOOP if GFR < 20 mL/min (↓ thiazide efficacy)
 can use thiazide + loop if refractory edema

If HTN not resolved with ACEi + diuretic, add another one of these:
Ca channel blockers More effective if pt volume expanded (better result with ↑ salt diet)
(potent vasodilator) – use if refractory HTN
Minoxidil
 Side effects: Na retention, worsening edema, hirsutism

ACEi/ARB: potential complications in CKD pts

↓ GFR (from ↓ glomerular capillary pressure) Hyperkalemia
 Can’t dilate afferent > efferent arteriole to maintain
 Already have ↓ ability to excrete K (kidney messed up)
GFR
 Now, ↓ AT-II  ↓ aldosterone release  ↓ Na/K
 Remember: worse with NSAID (↓prostacyclin)
exchange
 Common to have acute ↑ SCr
 If needed: use loop diuretic (excrete more K!),
 Recommendation: as long as SCr doesn’t increase more
institute low K diet
than 30-35%, keep them on ACEi

Subgroups: AA patients
AA patient: generally respond less well to ACEi than whites for HTN treatment
 In CHRONIC KIDNEY DISEASE the RECOMMENDATIONS ABOVE are THE SAME

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 Uncomplicated Essential HTN
FIRST LINE: Really doesn’t matter which you use – all work the same (keep it cheap)
 Thiazide-type diuretics
 ACEi/ARB
 Ca-channel blockers

Thiazide diuretics: Β-blockers NOT used for initial therapy

 HCTZ used more commonly & more widely
available, but
 chlorthalidone might be better in trials (longer-
acting) & both really cheap (use it if you can)
except for in specific populations:
 POST-MI PATIENTS
 SYSTOLIC HEART FAILURE (+ ACEi)
 Other patients that are on β-blockers for
another problem (e.g. migraine)

Subgroups with Selective Responses

Subgroup Response:
Younger patients & Caucasians Better ACEi response
Older patients & African Americans Better Ca-channel blocker response

This shouldn’t change initial selection –

 Each agent will normalize BP in 30-50% of pts with mild HTN
 If you switch unresponsive pt to a different class, 50% will respond

Take home: if drug from class #1 doesn’t work, SWITCH to class 2, and then 3, before adding!
 Can often (60-80%) find a monotherapy that works! (or use a combo if it’s still one pill/day, etc.)

Specific antiHTN drugs

DRUGS SPECIAL INSTRUCTIONS

Cardioprotective beyond BP lowering effect! Use if:
 HF, asymptomatic LV dysfunction, systolic dysfunction,
ACEi (& ARB)
 Post-STEMI, post-non-STEMI with anterior infarct
 diabetes, proteinuric CKD
Chlorthalidone is preferred (HCTZ less potent, shorter acting).
Thiazide diuretics
Loop diuretics for volume control if HF or CKD ± nephrotic syndrome
No absolute indications; usually use long-acting dihydropyridines (verapamil, diltiazem)
Ca channel blockers
 Can use for other effects: A-fib or angina control
NOT initial antiHTN therapy, esp in pts > 60yo
 ↑ risk stroke, coronary dz, CV events, maybe mortality!
 Also ↓ glucose tolerance, ↑ risk new onset diabetes
β-blockers Use if:
 Post-acute-MI
 HF or asymptomatic LV dysfunction (start with low doses!)
 Rate control for A-fib, angina control, others
ALLHAT: doxazosin terminated prematurely (↑ risk HF compared to chlorthalidone)
α-blockers
 Can use in older men with prostatism symptoms (esp if not high CV risk)
Pregnant women (just from clinical safely experience)
α-methyl-dopa

nd
β-blocker is acceptable as 2 choice

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