renal3 Flashcards
Regulation of Blood Pressure
Blood pressure is the product of cardiac output (C.O.) and peripheral vascular resistance (P.V.R.). Factors affecting C.O.: inotropic state of cardiac muscle; heart rate; filling pressure. These factors are influenced by sympathetic and parasympathetic activity, circulating hormones, intrinsic cardiac muscle function, volume regulatory hormones, renal function, volume intake, posture. Factors affecting P.V.R: sympathetic and parasympathetic activity; vasoconstrictor and vasodilator hormones, blood viscosity, blood volume, cardiac function.
ACE Inhibitors Mechanism of Action
Inhibits converting enzyme activity; blocks the conversion of angiotensin I to angiotensin II, preventing angiotensin II-mediated vasoconstriction and stimulation of aldosterone release. Blocks degradation of bradykinin. Bradykinin (along with Substance P) cause bronchoconstriction and stimulate irritant receptors.
Adverse Effect of ACEI
Cough (approx. 20%) -hyperkalemia - Contraindicated in pregnancy. mild increase in serum creatinine (contraindicated with bilateral renal artery stenosis), angioedema (rare) –anemia (rare)
Uses of ACEI
HTN -heart failure -chronic kidney disease -diabetic nephropathy
Angiotensin II Receptor Blockers (ARBs)
Losartan, irbesartan, candesartan, valsartan
Mechanism of Action of ARBS (Losartan, irbesartan, candesartan, valsartan)
Irreversibly blocks the actions of angiotensin II at AT1 receptor. Prevents angiotensin II-mediated vasoconstriction, aldosterone release
Adverse Effect of ARBS
Similar to ACE inhibitors except cough not seen - may be associated with lower hyperkalemia · HTN -heart failure -chronic kidney disease -diabetic nephropathy
Calcium Channel Blockers
Dihydropyridines (DHP): amlodipine, nislodipine, nifedipine, felodipine
Non-dihydropyridines (NDHP): diltiazem, verapamil
Mechanism of Action of Calcium channel blockers
Cause arterial vasodilation and lower peripheral vascular resistance by blocking L-type calcium channels. Dihydropyridines (DHP) are more selective to blocking L-type Ca channels in blood vessels while verapamil
binds equally to cardiac and vascular L-type Ca channels. Non-dihydropyridines, decrease conduction through AV node and have moderate negative chronotropic and
inotropic actions.
Pharmacokinetics of Calcium channel blockers
Readily absorbed, extensively protein bound, metabolized by the liver to inactive metabolites. Drug interactions NDHP»_space;>DHP
NDHP – inhibit and are metabolized by Cytochrome P450 3A4 system
Examples: atorvastatins (and other statins), amiodarone, cyclosporine, carbamazepine, warfarin,
grapefruit juice, St. Johns wort, phenytoin, ritonavir (and other protease inhibitors), erythromycin (and other macrolides).
DHP – metabolized and mild inhibitor of cytochrome P450 3A4 system. Prolonged half-life allows for once daily dosing (diltiazem, and verapamil have long acting formulations)
Adverse Effect of Calcium channel blockers
Non-DHP: nausea -headache -constipation -gingival hyperplasia -conduction defects (contraindicated in 2° or 3° heart block).
DHP:
- peripheral edema -reflex tachycardia -flushing, headache -gingival hyperplasia.
Uses DHP of Calcium channel blockers
HTN, migraine prophylaxis NDHP: HTN, migraine prophylaxis, angina, rate control for atrial fibrillation
Beta Blockers
Selective beta 1 (cardio) receptor blockers: atenolol, metoprolol
Non-selective beta 1 and beta 2 (located in bronchial and vascular system) blockers: propranolol, timolol Beta and alpha blocker: carvedilol, labetalol
Mechanism of Action of beta blockers
Beta-1 selective beta-adrenergic receptor blocking agents compete with catecholamines at peripheral adrenergic neuron sites, block cardiac receptors to decreased cardiac output, and suppression of renin activity. Bind to receptors in cardiac nodal tissue, the conducting system, and contracting myocytes
Agents with intrinsic sympathomimetic activity (ISA) have a lower propensity to negatively influence cardiac output or heart rate at rest. ISA or partial agonist activity is mediated directly at adrenergic receptor sites and is manifested by a smaller reduction in resting cardiac output and resting heart rate. examples: Labetolol and Acebutolol
Adverse Effect of beta blockers
fatigue, elevate lipids, mask symptoms of hypoglycemia, sexual dysfunction, and respiratory abnormalities
Uses of beta blockers
post MI/CAD (1st line), angina, glaucoma (ophthalmic), heart failure (metoprolol, carvedilol), rate control in atrial fibrillation, migraine prophylaxis, HTN
Direct Vasodilators
(hydralazine, minoxidil)
Mechanism of Action of direct vasodilators (hydralazine, minoxidil)
peripheral, vasodilating effect through a direct relaxation of vascular smooth muscle. The peripheral, vasodilating effect causes decreased peripheral vascular resistance; and an increased heart rate, stroke volume, and cardiac output. The preferential dilatation of arterioles, as compared to veins, minimizes postural hypotension and promotes the increase in cardiac output. Increase in renin activity in plasma, presumably as a result of increased secretion of renin by the renal juxtaglomerular cells in response to reflex sympathetic discharge. This increase in renin activity leads to the production of angiotensin II, which then causes stimulation of aldosterone and consequent sodium reabsorption.
Hydralazin mechanism of action
alter cellular calcium metabolism, interferes with the calcium movements within the vascular smooth muscle that are responsible for initiating or maintaining the contractile state. Release of nitric oxide from drug or endothelium
Minoxidil mechanism of action
a potassium channel opener, causing hyperpolarization of cell membranes
Pharmacokinetics of Hydralazine
peak plasma levels are reached at 1 to 2 hours. Half-life of 3 to 7 hours. Extensive hepatic metabolism
Pharmacokinetics of Minoxidil
extent and time course of blood pressure reduction do not correspond closely to its plasma concentration. half life = 4.2 hours
Adverse Effect of hydralazine, minoxidil
Headache, anorexia, nausea, vomiting, diarrhea, palpitations, tachycardia Hydralazine: SLE –like symptoms
Minoxidil: reflex tachycardia and salt/H20 retention (3 drug drug), hair growth
Uses and dosing of hydralazine, minoxidil
3 or 4th line agents Hydralazine: HTN, heart failure Minoxidil: HTN, hair growth (topical)
Alpha-1 blockers
(prazosin, terazosin, doxazosin)
Mechanism of Action of Alpha-1 blockers (prazosin, terazosin, doxazosin)
Selectively block alpha-1 adrenergic receptors. This blockade causes a reduction in systemic vascular resistance, thus causing an antihypertensive effect. Blockade of the alpha-1 adrenergic receptor (which is present in high density in the prostatic stroma, prostatic capsule, and bladder neck) decreases urethral resistance and may relieve the obstruction and improve urine flow and BPH symptoms
Adverse Effect of Alpha-1 blockers (prazosin, terazosin, doxazosin)
Orthostatic hypotension - headache -peripheral edema. Positive or no effect on serum TG/LDL/HDL
Uses of Alpha-1 blockers (prazosin, terazosin, doxazosin)
Benign prostatic hypertrophy (BPH). HTN: 3 or 4th line agent or sooner for patients with BPH
Mechanism of Action of Clonidine
Stimulation of alpha-2 adrenergic receptors in CNS and periphery. reducing sympathetic nerve impulses resulting in a decrease in peripheral vascular resistance. increase parasympathetic outflow from vasopressor center (dec HR). presynaptic inhibition of peripheral norepinephrine release
Adverse Effect of Clonindine
Orthostatic hypotension, dry mouth, sedation, rebound HTN if high dose discontinued abruptly (reduce dose over 2-4 days)
Uses of Clonidine
HTN (3 or 4th line ), ADHD, smoking cessation, ETOH withdrawal
Methyldopa
transformed to alpha methylnorepinephrine (false transmitter) – alpha 2 adrenergic agonist. Older agent with safety data in pregnancy
- Rarely used due to adverse effects (hepatotoxicity, mental status changes, sedation), Produces positive direct Coomb’s test and hemolytic anemia (1%).
Chronic kidney disease (CKD)
defined as a permanent reduction in glomerular filtration rate (GFR). The National Kidney Foundation has now divided CKD into 5 stages. The purpose of this classification is to foster recognition of chronic kidney disease early in it course and to give clinicians guidelines for effective interventions at various stages of kidney disease. Biochemical and physiologic derangements are detectable at varying stages of CKD and therapeutic interventions need to be directed accordingly. Symptoms directly related to CKD typically do not occur until chronic kidney disease is advanced, often not until the GFR falls below 15 ml/min/1.73m2. End stage renal disease (ESRD) is the term often used when chronic kidney disease has deteriorated to the point where renal replacement therapy (dialysis or transplantation) is needed. Any process that permanently damages the kidneys can result in CKD. There are estimated to be about 7.4 million people with stage 3 CKD and there are over 400,000 patients with end stage kidney disease on dialysis. A list of the most common causes of CKD follows. The cost to care for each patient with ESRD on dialysis is $50-100,000 per year.
Most Common Causes of CKD
Diabetic nephropathy- most common, Hypertensive nephrosclerosis & Renal vascular disease, Glomerulonephritis, Polycystic kidney disease, Interstitial nephritis, Obstruction
Pathophysiology of chronic kidney failure
Perhaps the most intriguing aspect of CKD is that compensatory mechanisms exist that allow the loss of 90% of GFR before many manifestations of the uremic syndrome are evident. It should be noted that there is essentially no evolutionary pressure to adapt to chronic kidney disease as people with CKD have decreased fertility. Therefore, the adaptive mechanisms are essentially the chronic stimulation of the mechanisms we use to respond to acute environmental stresses. Such mechanisms include intact nephron hypothesis, magnification phenomenon, individual solute control systems, trade-off hypothesis.
Intact Nephron Hypothesis with CKD
Nephrons functioning in diseased kidneys maintain glomerulotubular balance comparable to all other nephrons. That is, filtration and net excretion are coordinated.
The Magnification Phenomenon with CKD
Although nephrons in diseased kidneys function homogeneously, they alter their handling of given solutes as needed to maintain external balance of that solute if possible. That is, they magnify their excretion of a given solute.
Individual Solute Control Systems with CKD
Each solute appears to have a specific control system that is geared to maintain external balance in CKD. Each solute system has individual tubular handling and hormonal influences.
Trade-off Hypothesis with CKD
The mechanisms that are magnified to maintain individual solute control may have deleterious effects on other systems. This trade-off is seen in the increased parathyroid hormone (PTH) secretion seen in CKD that helps to maintain normal serum calcium and enhances renal phosphorus excretion. PTH has been implicated in the pathogenesis of many disturbances of uremia (sleep, sex, bone disease, anemia, lipidemia, vascular disease). The corollary of the trade-off hypothesis is the concept of proportional reduction of solute, that is, reduction of solute intake (e.g. phosphorus) in proportion to decrements in GFR could prevent the compensatory changes (e.g. increased PTH) that themselves may contribute to the development of uremia.
Creatinine and Urea Balance handling with CKD
For the most part, balance of nitrogenous wastes such as creatinine and urea depends on their rates of filtration (i.e., GFR). Balance (rate of filtration) is maintained for creatinine and urea at the expense of elevated plasma concentrations of these waste products in other words, the excretion rates for urea and creatinine remain constant in the face of diminished clearance.
Water Balance handling with CKD
In order to maintain balance, the fraction of water reabsorbed by the kidney must decrease. Thus, an increased flow per nephron ensues. With progressive CKD, the ability to excrete a water load is compromised and the patient may develop hypoosmolality. Urine concentrating ability is fixed around 300 mOsm/kg H2O and thus the patient is also susceptible to dehydration if water intake is lowered. Thus, a CKD patient is prone to both water excess (hyponatremia) and water deficiency (hypernatremia). Nocturia is common in CKD due to the inability of the kidneys to concentrate the urine at night.
Sodium Balance handling with CKD
In order to maintain balance the fraction of sodium reabsorbed must be decreased and the fraction excreted increased. A humoral natriuretic peptide has been described that helps to increase sodium excretion in CKD along with other adaptive mechanisms. In CKD, the kidneys are unable to rapidly adjust sodium excretion in response to sudden changes in sodium intake or extrarenal losses. Thus, major increases in sodium intake result in edema and major decreases in intake or increases in extrarenal losses result in volume depletion. The hallmark of CKD is the loss of flexibility in responding to changes in the external balance of solutes and water.
Potassium Balance handling with CKD
excretion in the cortical collecting duct is regulated by flow, sodium delivery and aldosterone. Increased tubular secretion of potassium helps maintain potassium balance until kidney disease is severe. Around this time fecal excretion of potassium increases to assume perhaps 50% of the load for potassium excretion. Thus, plasma potassium and total body potassium are maintained on normal dietary intake, but the patient is susceptible to hyperkalemia from sudden potassium loads.
Hydrogen ion handling with CKD
In CKD functioning nephrons produce more NH4+ to compensate for the loss of nephron mass This increase in NH4+ production (about a 4-fold increase) keeps acid balance normal until the GFR falls below 20-25 ml/min. At that time there is a continuous positive balance (retention) of hydrogen ion that titrate down the serum bicarbonate and result in a non-anion gap metabolic acidosis.
Uremia
Literally, uremia means urine in blood- by implication, it is the clinical syndrome resulting from retention of certain substances that are normally excreted into the urine and thus accumulate causing toxicity.
Pathogenesis of Uremia
Since the uremic syndrome resembles a systemic intoxication, the search for a putative uremic toxin has been the subject of intensive investigation. However, multiple factors may contribute to the pathogenesis of this syndrome.
Retained Metabolic Products with uremia
Many chemical compounds have been suspected to be responsible for the uremic syndrome. Urea and other nitrogenous products of metabolism have been suggested to play a role in causing uremic symptoms, and their plasma concentrations are useful in assessing adequacy of dialysis therapy. However, a distinct relationship between one or a combination of these substances and the entire syndrome has not been established.
Overproduction of Counter-regulatory Hormones with uremia
overproduction of parathyroid hormone in response to hypocalcemia and natriuretic hormone in response to volume overload could contribute to many aspects of the uremic state.
Underproduction of Renal Hormones with uremia
Decreased erythropoietin production causes anemia. Decreased 1-hydroxylation of vitamin D contributes to bone disease and secondary hyperparathyroidism. Clearly, these and other such deficiencies could play a role in the uremic state.
Clinical features of uremia
Neurological Disorders: encephalopathy, peripheral neuropathy. Hematological Disorders: anemia, bleeding tendency- due in part to
platelet dysfunction. Cardiovascular Disorders: pericarditis, hypertension, congestive heart
failure, coronary artery disease, vascular calcification. Pulmonary Disorders: pleuritis, pulmonary edema. Gastrointestinal Disorders: anorexia, nausea, vomiting, gastroenteritis,
gastrointestinal bleeding. Metabolic-Endocrine Disorders: glucose intolerance, hyperlipidemia,
hyperuricemia, malnutrition, sexual dysfunction and infertility. Bone, Calcium, Phosphorus Disorders: hyperphosphatemia,
hypocalcemia, dystrophic calcification, secondary hyperparathyroidism,
1,25-dihydroxy vitamin D3 deficiency, osteomalacia, osteitis fibrosa. Skin Disorders: pruritus, hyperpigmentation, easy bruising. Psychological Disorders: depression, anxiety. Fluid and Electrolyte Disorders: edema, hyponatremia, hyperkalemia,
hypermagnesemia, metabolic acidosis, volume expansion or depletion.
Anemia with Uremia
Anemia is almost universal as GFR falls below 25 ml/min; it may occur with mild CKD. Several factors may contribute: Erythropoiesis is markedly depressed, probably due to reduced erythropoietin production, also, there may be reduced end-organ response to erythropoietin with reduced heme synthesis. Red cell survival is shortened with a mild to moderate decrease in red cell life span, possibly due to a “uremic” toxin. Blood loss is common in uremic patients, possibly secondary to abnormal coagulation due, in large part, to decreased platelet function. Marrow space fibrosis occurs with the osteitis fibrosa of secondary hyperparathyroidism and can contribute to decreased erythropoiesis, especially in patients with longstanding ESRD.
Hypertension with Uremia
Hypertension occurs in 80%-90% of patients with chronic kidney disease. Several factors contribute: Expansion of extracellular fluid volume; this may arise because of reduced ability of the kidneys to excrete ingested sodium. Increased activity of the renin-angiotensin system is common; many patients with advanced CKD have renin levels that are not completely suppressed by the elevated blood pressure; this renin may contribute to the increased blood pressure. Dysfunction of the autonomic nervous system; frequently, the baroreceptors are insensitive, with increased sympathetic tone. Possible diminished presence of vasodilators; there may be decreased renal generation of prostaglandins or of factors in the kallikrein-kinin system.
Trade-off hypothesis related to Altered Calcium and Phosphorus Metabolism (Mineral Bone Disease of CKD) with Uremia
This classic hypothesis states that as the kidney fail phosphorus is retained which through a physio-chemical relationship drives down the ionized calcium. The fall in ionized calcium stimulates PTH release. The PTH in turn increases excretion of phosphate and helps restore calcium levels to normal. However, this occurs only at the expense of elevated serum PTH levels. This cycle repeats itself with continued declines in GFR and PTH levels increase progressively. Ultimately, the renal tubules can no longer respond to higher levels of PTH with a further decrease in phosphorus reabsorption. When this occurs, hyperphosphatemia develops, hypocalcemia may become prominent and PTH levels can increase to very high levels. High PTH levels cause bone disease with severe osteitis fibrosa and may have systemic toxicity.
As our understanding has increased we realize that this theory is a significant oversimplification. It is now clear that there are two and probably three independent regulators of PTH. The primary regulator is calcium which is sensed via a transmembrane calcium sensing receptor. When calcium is bound to this receptor it inhibits PTH secretion and downregulates PTH production. 1,25 vitamin D downregulates PTH gene transcription by binder to its cytoplasmic sterol receptor that migrates to its site of action in the nucleus. Phosphorus may also have a direct action to increase PTH secretion although the mechanism is unclear.
Calcium sensing receptor with regards to Altered Calcium and Phosphorus Metabolism (Mineral Bone Disease of CKD) with Uremia
The calcium sensing receptor is a transmembrane receptor that senses extracellular free calcium. When calcium is bound to the receptor it results in a decrease in PTH release and a downregulation of PTH production. Both activating mutation and inactivating mutations of this receptor have been discovered. Medications targeted at this receptor are being studied and used to decrease PTH in patients with both primary and secondary hyperparathyroidism.
Decreased production of 1,25 vitamin D with regards to Altered Calcium and Phosphorus Metabolism (Mineral Bone Disease of CKD) with Uremia
As the GFR falls renal production of 1,25 vitamin D falls. While this may in part be due to the reduction in kidney mass there is now strong evidence that FGF-23 (see below) down regulates 1,25 vitamin D production in a compensatory manor to decrease serum phosphorus by decreasing gut phosphorus absorption. 1,25 vitamin D has several actions that include: stimulating the absorption of calcium and phosphorus from the intestine; and at the level of the parathyroid gland down-regulates PTH gene transcription. Therefore, a lack of this hormone would: decrease calcium absorption from the diet thereby stimulating PTH and directly increasing PTH production by releasing the PTH gene from inhibition.
Increase FGF-23 with regards to Altered Calcium and Phosphorus Metabolism (Mineral Bone Disease of CKD) with Uremia
Recently, a new class of hormones called phosphotonins were discovered. These are phosphorus regulatory hormones and the best studied is FGF-23. It is predominately produced by osteocytes in bone and causes phosphaturia (increased phosphorus excretion) and decreases the kidneys production of 1,25 vitamin D, presumably as a compensatory mechanism to prevent phosphorus overload. The relative role and importance of each of these factors for parathyroid gland proliferation and PTH secretion remains somewhat controversial. However, the central role that phosphorus plays early in the disease process suggests that early attention to phosphorus balance may be important in CKD. Dialysis patients have difficulty eliminating aluminum (usually excreted by the kidney), and are also subjected to aluminum loads (e.g., aluminum from poorly treated dialysate or aluminum binding antacids). Aluminum toxicity may ensue that in addition to causing osteomalacia may also result in brain disease (aluminum encephalopathy) and anemia.
Pathophysiology of the progressive nature of kidney disease
It is suggested that compensatory events secondary to the loss of nephrons may accelerate the rate of destruction of the remaining nephrons in a diseased kidney. The evidence for this is considerable, although the exact pathophysiologic mechanisms involved are still debated. At a clinical level, it has been appreciated for some time that patients tend to lose kidney function at a relatively constant rate during the slowly progressive phase of the disease. In other words, the 1/Scr vs. time plot for a given patient with progressive chronic kidney disease tends to follow a straight line. This observation can be used clinically to ascertain when a patient is likely to require dialysis therapy (e.g. when their kidney function will fall to less than 1/10th of normal) or whether an experimental maneuver is actually successful in slowing the rate of progression (i.e. changes the slope of this line). Regarding the mechanisms operant in the progression of CKD, the most well studied phenomenon is that of glomerular hyperfiltration and hypertension in surviving nephrons.
The pathophysiology of glomerular hyperfiltration and hypertension with CKD
The compensatory event to increase SNGFR that is mediated via the dilatation of the afferent arteriole, allows increased flow and pressure to be transmitted to the glomerular tuft. It has been suggested that this glomerular hypertension leads to the destruction of the glomerulus. Although glomerular hypertension is associated with progressive kidney failure in some animal models, tubular factors may also be important, but are less well characterized. In particular, increases in the oxygen consumption of remaining nephron units that is out of proportion to the amount of sodium that they transport has been demonstrated in animal models of progressive chronic kidney disease.
Progression of chronic kidney disease
is prevented by the administration of converting enzyme inhibitors or angiotensin receptor blockers. Hypertension has also been shown to be especially injurious to a diseased kidney. The injury, again, is felt to be mediated by the increased pressure being transmitted to the remaining nephrons. Studies show that treatment of hypertension with converting enzyme inhibitors or angiotensin receptor blockers is more effective than using other antihypertensive medications. The decrease in efferent arteriolar tone reduces elevated glomerular capillary pressure and thereby may reduce glomerular injury. The implications of this observation to clinical medicine has been demonstrated in controlled clinical trials.
Therapy of chronic kidney disease
Although no clinical approach can completely stop the progression of CKD, there is now excellent data to support aggressive therapy of hypertension with angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARBs). In addition, it is standard of care to maintain serum phosphorus in a near normal range with dietary counseling and phosphate binders. Advanced chronic kidney disease will eventually be accompanied by the uremic syndrome. This can be treated by several approaches including hemodialysis, peritoneal dialysis and renal transplantation. The advantages and disadvantages of these approaches will be discussed during your third year clerkship and fourth year elective in renal diseases.
Effect of CKD on Absorption of drugs
[Bioavailability (F) or fraction of dose administered that reaches systemic circulation from non-IV (primarily oral) route of administration]. Limited clinical evidence regarding effect of CKD on drug absorption although it can be assumed
that factors seen in CKD such as altered gastrointestinal transit time, changes in gastric pH, nausea/vomiting, and diarrhea all have the potential to affect drug bioavailability. Drug-drug interactions are possible and even likely given the large number of drugs a typical CKD patient is taking, especially with cation-containing phosphate binders (for hyperphosphatemia) and bile acid sequestrants (for hyperlipidemia) that can bind concomitantly administered drugs and reduce their bioavailability.
Effect of CKD on Distribution of drugs
[Estimated by volume of distribution (Vd) that allows conversion of administered dose (MD: maintenance dose or LD: loading dose) to a plasma concentration (Cp) value.]
DOSE (mg)/ Vd (L) = Cp (mg/L).
Examples of Decreased Vd
A drug like the congestive heart failure agent digoxin has a relatively large Vd due to extensive tissue binding. In CKD patients, the Vd has been shown to decrease by as much as 50% in stage 5 as a result of decreased tissue binding (mechanism uncertain). Thus, any given dose of digoxin will result in a higher Cp due to the smaller Vd and as CKD progresses it will be necessary to gradually reduce the daily dose of digoxin to prevent toxic accumulations.
Example of Increased Vd
The anticonvulsant phenytoin (DilantinÒ) is highly protein bound in patients with normal kidney function. In CKD, organic acids are excreted less efficiently and accumulate in plasma competing with phenytoin for albumin binding sites (analogous to protein-binding displacement drug-drug interaction). Hypoalbuminemia may also occur in CKD and these changes result in less phenytoin binding to proteins, greater levels of free phenytoin and greater ability to distribute outside of the plasma and greater potential for toxicity. Generally, these effects would be of potential clinical significance only in the acute initialization of dose phase.
Effect of CKD on Elimination of drugs
At steady state, the MAINTENANCE DOSE (MD) represents the dose that is designed to equal the amount of drug that has been eliminated by the body in the preceding dosage interval (tau [τ]), thus maintaining the steady state plasma level [Cpss (avg)].
MD / tau [mg/hr] = Cpss (avg) [mg/L] x CL [L/hr]. Most dosing adjustment recommendations are based on arbitrary GFR values, often set by drug manufacturers from clinical trials. Dosing reductions are generally not recommended until GFR falls below 50 ml/min/1.73 m2 (stage 3 to stage 5), thus patients in stage 1 or 2 of CKD will generally not require any change in maintenance dose.
Effect of CKD on Metabolism of drugs
In combination with excretory processes, major contributor to drug clearance (CL) from plasma and a determinant of maintenance dose (MD). Although majority of drug metabolism occurs in the liver, up to 20% of phase I CYP450 reactions can occur in the kidney. The kidneys also contribute to phase II reactions such as conjugation with glucuronide, sulfate, or glutathione. In diabetic patients without CKD, renal metabolism is responsible for removal of 30% of an insulin dose. Insulin metabolism decreases markedly in CKD and requires a 25% insulin dose reduction in stage 3 / 4 and as much as a 50% reduction in stage 5. Hepatic metabolism can result in active metabolites that are renally excreted and can accumulate in CKD resulting in drug toxicity. Examples include the excitatory metabolite of meperidine (normeperidine) and the hepatotoxic metabolite of acetaminophen (N-acetyl- p-benzoquinonimine).
Effect of CKD on Excretion of drugs
Renal excretion is the primary means of clearance (CL) for many drugs. As renal function deteriorates in CKD, renal drug clearance will decrease and drug half-life will increase necessitating dosage adjustments to prevent toxic accumulations. Estimating renal function (i.e., ability to excrete drugs or active metabolites) in CKD. NOTE: The kidney’s ability to excrete (clear) drugs is dependent on the combined processes of glomerular filtration, renal tubular secretion, and tubular reabsorption. Only glomerular filtration rate can be reliably measured clinically and it is recommended as the marker for quantifying renal function in adults for the purposes of both staging CKD and determining drug dosage.
Cockroft-Gault (C-G) equation
measures creatinine clearance [CLcr], which has been shown to correlate closely with GFR. Currently, the C-G equation is more widely used to assess kidney function and adjust drug dosage. CLcr (ml/min) = [(140 - Age) (ABW)] / Scr X 72. For females result is multiplied by 0.85 Age (in years) ABW (actual body weight in kg; use ideal body weight (IBW) in obese patients) Scr (serum creatinine, mg/dL)
Altered Response of Thiazide diuretics with CKD
are recommended first line treatment for hypertension. As the GFR falls in
CKD patients, less drug reaches the site of action in the nephron and diuretic efficacy decreases. At a GFR below 30, a more potent loop diuretic (e.g., furosemide) is necessary to maintain the anti- hypertensive effect.
Diuretic resistance with CKD
can occur in later stages of CKD. This can often be overcome by use of synergistic combinations of diuretics that act at different sites in the nephron (e.g., the loop diuretic furosemide with the thiazide diuretic metalozone). Clinical observations have noted that adverse effects of some drugs may occur in CKD patients at doses and plasma levels that are safe and effective in patients with normal renal function. Not well studied.
Altered Response of Oral hypoglycemic with CKD
Glyburide: Half-life prolonged. Glipizide: No adjustments necessary Thiazolidinediones: No adjustments necessary Metformin: Use NOT recommended if SCr > 1.5
Altered Response of insulin with CKD
Half-life prolonged
Altered Response of Diuretics with CKD
Thiazides may lose effectiveness as renal function declines; more potent loop diuretics (e.g., furosemide) are recommended Avoid potassium-sparing diuretics
Altered Response of ACE inhibitors ARBs with CKD
Used through all CKD stages; monitor for hyperkalemia and elevations in serum creatinine; may cause ARF in hypovolemic patients
Altered Response of Beta-blockers with CKD
Atenolol: Half-life prolonged. Metoprolol, Carvedilol: No adjustments necessary
Altered Response of Calcium channel blockers with CKD
No adjustments necessary
Altered Response of Alpha-blockers
with CKD
No adjustments necessary
Altered Response of Clonidine with CKD
No adjustments necessary; dry mouth side effect can increase thirst contributing to volume overload
Altered Response of Vasodilators with CKD
No adjustments necessary
Altered Response of HMG CoA reductase inhibitors with CKD
No adjustments necessary
Altered Response of Fibrates with CKD
Gemfibrozil recommended fibrate in CKD stage
Altered Response of Niacin with CKD
No adjustments necessary
Altered Response of Ezetimibe with CKD
No adjustments necessary
Complication of Anemia
with CKD Pathophysiology
Kidney synthesizes and secretes 90% of circulating erythropoietin, the red blood cell growth factor. As kidney function declines, the serum concentration is reduced and anemia results. Increase in prevalence at Stage 3 CKD, even more prevalent in Stages 4 and 5
Complication of Anemia
with CKD Pharmacotherapy
Epoetin Alfa (Epogen) and Darbepoetin Alfa (Aranesp) and iron supplements
MOA of Epoetin Alfa (Epogen) and Darbepoetin Alfa (Aranesp)
Glycoproteins prepared with recombinant DNA technology with biologic activity identical to erythropoietin
Pharmacokinetics Epoetin Alfa (Epogen) and Darbepoetin Alfa (Aranesp)
Given parenterally (SC) every week (epo) or every 1-2 weeks (darbepoetin)
Side effects Epoetin Alfa (Epogen) and Darbepoetin Alfa (Aranesp)
Generally well tolerated; hypertension most common event reported
Iron supplements (daily oral iron salts) or treatment (IV iron sucrose) MOA
Iron deficiency is most common cause of resistance to erythropoietic therapy. Supplements provide iron for production of hemoglobin and incorporation into red blood cells
Pharmacokinetics of Iron supplements
Oral route commonly used, but absorption is generally poor (bid-tid). IV administration often required, especially in Stage 5 CKD
Side effects of Iron supplements
Oral – constipation, nausea, abdominal cramping, often leading to reduced compliance. IV – allergic reactions, hypotension, headaches, anaphylactoid reactions (1.8% to iron dextran)
Drug-drug interactions of Iron supplements
Absorption decreased by calcium and by drugs that increase gastric pH (antacids, proton pump inhibitors, H2 antagonists)
Renal Osteodystrophy Pathophysiology with CKD
Declining kidney function results in decreased phosphate elimination and elevated serum phosphate levelsàlowers serum calciumàstimulates release of PTH. PTH initially normalizes serum calcium and phosphate concentrations by increasing renal calcium reabsorption and decreasing renal phosphate reabsorption BUT long term elevation of PTH leads to osteodystrophy (“trade-off hypothesis”). Problem is compounded by the failing kidney’s decreased ability to convert 25-hydroxy vitamin D to the most active 1,25-dihydroxy vitamin D resulting in a vitamin D deficiency and a further reduction in serum calcium levels and increased release of PTH
Pharmacotherapy for Renal Osteodystrophy with CKD
phosphate binding agent, vitamin D compounds, calcimimetics
Phosphate binding agents
Most commonly used are calcium compounds (calcium acetate [PhosLo]) or non-elemental agents (sevelamer HCl [Renagel], sevelamer bicarbonate [Renvela] àreduced incidence of metabolic acidosis)
MOA of Phosphate binding agents
Bind dietary phosphate in GI tract to form insoluble magnesium, calcium, or aluminum phosphate, which is excreted in the feces, thus decreasing phosphate absorption and serum levels.
Pharmacokinetics of Phosphate binding agents
Given orally, best taken with meals.
Side effects of Phosphate binding agents
Primarily GI side effects – constipation (Al+++ or Ca++), diarrhea (Mg++), nausea, vomiting, abdominal pain. Hypercalcemia possible with Ca++ salts; CNS toxicity with Al+++ salts limits use.
Vitamin D compounds
Best choice is agent that does not require renal conversion to the most biologically active form, i.e., 1, 25-dihydroxy vitamin D (calcitriol [RocaltrolÒ])
MOA of Vitamin D compounds
Suppresses PTH secretion indirectly by stimulating intestinal calcium absorption and directly by decreasing PTH synthesis in parathyroid gland.
Pharmacokinetics of Vitamin D compounds
Available in oral (Stage 1-4) and intravenous (Stage 5) dosage forms
Side effects of Vitamin D compounds
Hypercalcemia and hyperphosphatemia possible.
Drug-drug interactions of Vitamin D compounds
Absorption reduced by concomitant administration of cholestyramine.
Calcimimetics
Cinacalcet (SensiparÒ), alternative to vitamin D in patients developing hypercalcemia.
