1st lec Pharmacology notes
Chronic Kidney Disease
❑ (CKD) is progressive, irreversible kidney damage
characterized by decreased estimated glomerular filtration
rate (eGFR) or evidence of kidney damage for at least 3
months.
❑ The loss of renal function may be due to:
• Previous episodes of acute renal failure with subsequent long
term kidney damage.
• Diseases which cause progressive deterioration of the
kidney:
✓ Primary kidney diseases (glomerulonephritis).
✓ Secondary disorders such as diabetes, hypertension, or
auto-immune disorders.
consequence of loss of kidney functions:
▪ Anemia:
✓ Erythropoietin deficiency
▪ Toxic wastes products will accumulate in the body:
✓ Creatinine
✓ Urea, and
✓ Drug metabolites
▪ Electrolyte disturbances:
✓ High potassium Arrhythmias.
✓ Low calcium Osteoporosis and myopathies.
✓ High phosphates.
▪ In the early stages of chronic kidney disease, there may be
few signs or symptoms.
▪ Chronic kidney disease may not become apparent until
kidney function is significantly impaired.
▪ Chronic kidney disease can progress to end-stage renal
failure, which is fatal without artificial filtration (dialysis) or a
kidney transplant.
▪ Treatment for chronic kidney disease focuses on slowing the
progression of the kidney damage, usually by controlling the
underlying cause.
Chronic kidney disease management
Delaying the Progression of Chronic Kidney Disease
Treating the Pathologic Manifestations of Chronic Kidney
Disease
Renal replacement therapy (RRT)
A. Delaying progression of chronic kidney disease (CKD)
➢ Treatment of the underlying conditions if possible.
➢ Blood pressure control.
➢ Hyperlipidemia control by antihyperlipidemic drugs.
➢ Glycemic control by antidiabetic drugs.
➢ Avoidance of nephrotoxins, including intravenous (IV) radio
contrast media, nonsteroidal anti-inflammatory agents
(NSAIDs), and aminoglycoside antibiotics.
➢ Use of renin-angiotensin system (RAS) blockers among
patients with diabetic kidney disease (DKD) and proteinuria.
B. Treating the underlying Pathologic Manifestations
➢ Anemia: Erythropoiesis-stimulating agent (ESA) such as
epoetin alfa and epoetin beta.
➢ Hyperphosphatemia: Dietary phosphate binders and dietary
phosphate restriction.
➢ Hypocalcemia: Calcium supplements with or without
calcitriol.
➢ Hyperparathyroidism: vitamin D & its analogues, or
calcimimetics.
➢ Metabolic acidosis: Oral alkali supplementation.
Medications Commonly used for (CKD) Patients
➢ Vitamins: water soluble.
➢ Phosphate binders: Calcium, Aluminum hydroxide, given
with meals.
➢ Iron Supplements: don’t give with phosphate binder or
calcium.
➢ Antihypertensives: Atenolol, Metoprolol, Amlodipine and
ACE inhibitors.
➢ Erythropoietin (EPO): to increase formation of RBCs.
➢ Calcium Supplements: Between meals, not with iron.
➢ Activated Vitamin D3: aids in calcium absorption.
➢ Antithrombotic drugs- Tinzaparin.
➢ Sodium bicarbonate: to maintain acid base balance.
➢ Quinine sulphate: It is used to minimize muscle cramp
because some patients on dialysis may experience muscle
cramp on or between the session.
➢ Pain-killers: Paracetamol but Ibuprofen and Diclofenac only
after discussion with the physicians.
➢ Blood thinners: Aspirin, Clopidogrel and Dipyridamole (to
reduce the consistency of the blood may help dialysis line).
➢ Antibiotics: to prevent infection that may result due to
dialysis.
Hematopoietic growth factors
➢ they are glycoprotein hormones that regulate the
proliferation and differentiation of hematopoietic progenitor
cells in the bone marrow.
➢ Tissue hypoxia induces the production of endogenous
erythropoietin (EPO) by the kidney.
➢ In anemic state, more EPO is produced, signaling the bone
marrow to produce more red blood cells.
➢ In patients with chronic renal failure, kidney is unable to
produce EPO and thus external supplementation of EPO
supplementation is needed.
➢ Erythropoietin (EPO) is a glycoprotein produced in
juxtatubular cells in the kidney and also in macrophages, it
stimulates committed erythroid progenitor cells to proliferate
and generate erythrocytes.
➢ Epoietin (recombinant human erythropoietin) exists in
several forms (alpha, beta, theta and zeta).
➢ Methoxy polyethylene glycolepoetin beta is another
preparation with long half-life.
➢ Darbepoetin, a hyperglycosylated form, has a longer half-
life and can be administered less frequently.
1. Hemopoietic Growth Factors
➢ EPO alpha: Epoetin alpha is an isoform of recombinant
DNA-derived erythropoietin (rEPO), synthesized in Chinese
hamster ovary (CHO) cells.
➢ EPO beta: Epoetin beta is also synthesized by CHO cell lines
and differs from epoetin alpha in containing:
I. a greater proportion of more basic isoforms,
II. a greater proportion of EPO binding to Erythrina cristagalli
lectin or agglutinin (ECL/ECA), and
III. isoforms with higher in vivo: In vitro bioactivity.
➢ Note: ECL/ECA binds to carbohydrate structure in
membrane and serum glycoproteins of mammalian cells.❑
EPO is the first human hematopoietic growth factor to be
isolated.
❑ It is a glycoprotein hormone that regulate the proliferation
and differentiation of hematopoietic progenitor cells.
Site of action:
❑ EP receptors (EPO-R) on red cell progenitors.
Mechanism of action (MoA):
❑ It binds to EPO receptor and brings about the
phosphorylation of protein (JAK/STAT) and activation of
transcription factor to regulate cellular function such as
stimulation of erythroid proliferation and differentiation.
Darbepoetin alfa:
➢ Darbepoetin alfa is a modified EPO that is more heavily
glycosylated as a result of changes in amino acids.
➢ Darbepoetin alfa has a 2-3-fold longer half-life than Epoetin
alfa.
➢ Methoxypolyethyleneglycol Epoetin beta is an EPO isoform
covalently attached to a long polyethylene glycol polymer.
➢ This long-lived recombinant product is administered as a
single intravenous or subcutaneous dose at 2-week or monthly
intervals.
Adverse effects
o Transient influenza-like symptoms are common.
o Hypertension is also common and can cause encephalopathy
with headache, disorientation and sometimes convulsions.
o Iron deficiency can be induced because more iron is required
for the enhanced erythropoiesis.
o Blood viscosity increases as the haematocrit (i.e. the fraction
of the blood that is occupied by red blood cells) rises,
increasing the risk of thrombosis, especially during dialysis.
2. Iron Products
▪ Oral preparations:
e.g. Ferrous sulphate, succinate, gluconate or fumarate.
➢ Ferrous sulfate is used as a building block for hemoglobin
synthesis in patients of CKD with anemia.
▪ Parenteral preparations: e.g. Iron sucrose, Iron-dextran
➢ Iron sucrose is used to treat iron deficiency anemia (in
conjunction with erythropoietin) in patients.
▪ Dialysis also leads to iron deficiency due to:
✓ Blood loss during the dialysis procedure,
✓ Increased erythropoiesis, and
✓ Reduced absorption of iron.
Adverse effects (Iron products)
➢ Oral iron adverse effects are dose-related and include
nausea, abdominal cramps and constipation.
➢ Parenteral iron can cause anaphylactic reactions.
➢ Iron is an important nutrient for several pathogens and
there is concern that excessive iron could worsen the clinical
course of infection.
➢ Iron treatment is usually avoided during infection for this
reason.
3. Phosphate binders
▪ Excess of phosphate in blood is removed by normal kidney.
▪ In CKD, kidneys fail to remove phosphorus from the blood
resulting in hyperphosphatemia.
▪ High phosphorus levels can cause damage to the body and
pulls calcium from bones and thus bone becomes weak.
▪ Phosphate Scavengers are used to reduce phosphate level
and they act only in the gut to reduce phosphate absorption
from the gut.
Sevelamer hydrochloride
▪ It is a polymeric phosphate binder for oral administration,
does not contain aluminum (i.e., non-aluminum). and thus,
aluminum intoxication not a concern.
▪ Sevelamer is not absorbed from the gut and has an additional
effect in lowering low-density-lipoprotein cholesterol.
▪ Mechanism of action: it prevents the absorption of
phosphate by forming an ionic and hydrogen bond with
phosphates and bile acids to promote fecal excretion.
▪ Adverse effects: gastrointestinal (GI)
disturbances.Lanthanum carbonate
▪ Non-calcium, non-aluminum phosphate binder
Mechanism of action:
▪ It directly binds to dietary phosphorus in the upper
gastrointestinal tract forming insoluble lanthanum phosphate
complexes, thereby inhibiting its absorption.
Sucroferric oxyhydroxide
▪ Iron-based, calcium-free phosphate binder.
Mechanism of action:
▪ Dietary phosphate is adsorbed in the gastrointestinal tract
and eliminated in the feces.
4. Vitamin D & its analogues 5. Calcimimetics
▪ Vitamin D (Vit D) & its analogues are recommended in ▪ They mimic calcium at the parathyroid hormone (PTH)
patients with CKD stages 3-5 with elevated serum parathyroid receptor and reduces PTH levels.
hormone (PTH) levels. ▪ Calcimimetics enhance the sensitivity of the parathyroid Ca 2+-
▪ Vit D increases the serum calcium level by promoting the sensing receptor to the concentration of blood Ca2+
absorption of calcium from the intestines and thus decreases , with a consequent decrease in secretion of PTH and reduction
PTH levels. in serum Ca2+ concentration. (See figure 6)
▪ Calcitriol or 1,25-dihydroxycholecalciferol (abbreviated 1,25- Etelcalcetide
(OH)2- ▪ MoA: Calcimimetic agent, allosterically modulates the
D3) is the active form of Vit D found in the body (vitamin D3). calcium-sensing receptor (CaSR) and enhances activation of
▪ Vit D and/or Calcitriol is used in patients with kidney disease, the receptor by extracellular calcium. Activation of the CaSR on
who are unable to synthesize active Vit D.▪ In humans, there parathyroid chief cells decreases PTH secretion.
are two important forms of Vit D, termed D2 and D3: Cinacalcet
1. Dietary ergocalciferol (D2), derived from ergosterol in plants ▪ MoA: Cinacalcet directly lowers intact PTH levels by
and foods. increasing the sensitivity to extracellular calcium of calcium-
2. Cholecalciferol (D3), generated in the skin from 7- sensing receptors on chief cells of the parathyroid glands. It
dehydrocholesterol by the action of ultraviolet irradiation also results in a concomitant decrease in serum calcium.
during sun exposure, or formed from cholesterol in the wall of
the intestine.
▪ Cholecalciferol is converted to calcifediol (25-hydroxy-Vit D3)
in the liver, and this is converted to a series of other
metabolites of varying activity in the kidney, the most potent
of which is calcitriol (1,25-dihydroxy-Vit D3) (see figure 5).
Alphacalcidol
▪ Alphacalcidol is a Vit D analogue (1-alpha-hydroxy
cholecalciferol)
▪ It does not require activation by the kidneys.
▪ Alphacalcidol is indicated for the treatment of secondary
hyperparathyroidism in patients with CKD.
Paricalcitol
▪ Paricalcitol is a synthetic Vit D analogue that binds and
activates Vit D receptors in the kidneys, parathyroid glands,
intestines, and bones.
Mechanism of action (Vitamin D)
▪ Vit D and its active form (calcitriol) increases the synthesis of
Calbindin (Ca2+ carrier protein) and thus enhances the
absorption of calcium and phosphate from intestine.
▪ Vit D /Calcitriol → binds to cytoplasmic
receptor → translocates into the nucleus → increase synthesis
of specific mRNA →regulation of protein synthesis.
Adverse effects (Vitamin D)▪ Vit D at normal doses usually has
no side effects.
▪ Too much Vit D can cause harmful high calcium levels and
can be manifested as: nausea/vomiting, constipation, loss of
appetite, increased thirst, increased urination, mental/mood
changes, unusual tiredness.
▪ A very serious allergic reaction to this drug is rare. symptoms
of a serious allergic reaction, including: rash, itching/swelling
(Especially of the face/tongue/throat), severe dizziness,
trouble breathing.