GENERAL PRINCIPLES
It is important to understand how to appropriately prescribe medications to patients with various levels of acute or chronic kidney disease(CKD), particularly those undergoing some form of renal replacement therapy. Drug effects and their handling by the body also are influenced by underlying comorbidities, age, liver function,
nutritional status, critical illness, and other concurrently prescribed medications. This is best achieved by developing a firmgrasp of the following concepts.
Definitions
Pharmacokinetics
● Defined as process by which a drug is absorbed, bound to protein (or not), distributed to various tissue compartments, and ultimately metabolized (biotransformation) or excreted intact
Clinical pharmacokinetics.
Refers to application of pharmacokinetic methods to drug therapy in humans
Utilizes a multidisciplinary approach to individually optimize drug dosing strategies based on such patient characteristics as age, sex, disease state(s), genetics, and ethnic differences
Pharmacodynamics
● Refers to how medications affect the patient
● Represents interaction of a drug with its target site (receptor) and the pharmacologic response that results
● Reflects relationship between achieved drug concentrations at receptor and associated
pharmacologic response
Pharmacogenetics
● Refers to how genetic differences in patients influence their respective responses to drugs; these genetic differences give rise to interpatient variation in drug absorption, distribution, biotransformation, and elimination.
PHARMACOKINETICS
Absorption and bioavailability refer to theprocess of drug uptake into the body and ultimate level achieved within systemic circulation.
Absorption
● Drug must pass from absorption site through or around layers of cells, unless it
is administered parenterally, before it gains access into the circulation
● Gastrointestinal absorption may be decreased in patients with advanced kidney
disease for various reasons:
Absorption is dependent on physicochemical properties of drugs, nature of drug
product, and anatomy and physiologic functions at site of drug absorption.
Parenteral, enteral, inhalation, transdermal, or intranasal routes for systemic
absorption are available
There are 2 major factors to consider regarding drug absorption:
E Extent of drug absorption
E Rate of drug absorption
Bioavailability
● Bioavailability of drugs is percentage or fraction of administered drug that reaches
systemic circulation
● Drugs that are administered by intravenous(IV) route have complete bioavailability (F= 1.0); bioavailability is <=1.0 for all other administration routes because of incomplete absorption and “first-pass” hepatic metabolism
● Absorption from gastrointestinal tract can
be reduced for several reasons:
Removal of drug:
- Nasogastric suction and vomiting
Gastric pH change (1pH):
- Salivary urea converted to ammonia in patients with kidney disease
- Acid inhibition, ie, with H2-blockers and proton pump inhibitors
Altered gastrointestinal peristalsis:
- Gastroparesis (diabetic and uremic)
- Ileus
Reduced gut function:
- Pancreatitis
- Complete or partial bowel obstruction
- Uremia (decreased small-bowel absorptive function)
Diminished absorptive surface area:
- Small-intestine resection of 100 cm of ileum
Decreased splanchnic blood flow:
- Intravascular volume depletion
- Heart failure
Concomitant drug administration:
- Phosphate binders, etc
● Presystemic metabolism or first-pass metabolism reduces drug levels in those that
undergo significant intestinal mucosal cell or hepatic metabolism:
IV/oral dose ratio is low ( 1:4) due to
first-pass metabolism of drugs with 100% absorption
It is important to understand how to appropriately prescribe medications to patients with various levels of acute or chronic kidney disease(CKD), particularly those undergoing some form of renal replacement therapy. Drug effects and their handling by the body also are influenced by underlying comorbidities, age, liver function,
nutritional status, critical illness, and other concurrently prescribed medications. This is best achieved by developing a firmgrasp of the following concepts.
Definitions
Pharmacokinetics
● Defined as process by which a drug is absorbed, bound to protein (or not), distributed to various tissue compartments, and ultimately metabolized (biotransformation) or excreted intact
Clinical pharmacokinetics.
Refers to application of pharmacokinetic methods to drug therapy in humans
Utilizes a multidisciplinary approach to individually optimize drug dosing strategies based on such patient characteristics as age, sex, disease state(s), genetics, and ethnic differences
Pharmacodynamics
● Refers to how medications affect the patient
● Represents interaction of a drug with its target site (receptor) and the pharmacologic response that results
● Reflects relationship between achieved drug concentrations at receptor and associated
pharmacologic response
Pharmacogenetics
● Refers to how genetic differences in patients influence their respective responses to drugs; these genetic differences give rise to interpatient variation in drug absorption, distribution, biotransformation, and elimination.
PHARMACOKINETICS
Absorption and bioavailability refer to theprocess of drug uptake into the body and ultimate level achieved within systemic circulation.
Absorption
● Drug must pass from absorption site through or around layers of cells, unless it
is administered parenterally, before it gains access into the circulation
● Gastrointestinal absorption may be decreased in patients with advanced kidney
disease for various reasons:
Absorption is dependent on physicochemical properties of drugs, nature of drug
product, and anatomy and physiologic functions at site of drug absorption.
Parenteral, enteral, inhalation, transdermal, or intranasal routes for systemic
absorption are available
There are 2 major factors to consider regarding drug absorption:
E Extent of drug absorption
E Rate of drug absorption
Bioavailability
● Bioavailability of drugs is percentage or fraction of administered drug that reaches
systemic circulation
● Drugs that are administered by intravenous(IV) route have complete bioavailability (F= 1.0); bioavailability is <=1.0 for all other administration routes because of incomplete absorption and “first-pass” hepatic metabolism
● Absorption from gastrointestinal tract can
be reduced for several reasons:
Removal of drug:
- Nasogastric suction and vomiting
Gastric pH change (1pH):
- Salivary urea converted to ammonia in patients with kidney disease
- Acid inhibition, ie, with H2-blockers and proton pump inhibitors
Altered gastrointestinal peristalsis:
- Gastroparesis (diabetic and uremic)
- Ileus
Reduced gut function:
- Pancreatitis
- Complete or partial bowel obstruction
- Uremia (decreased small-bowel absorptive function)
Diminished absorptive surface area:
- Small-intestine resection of 100 cm of ileum
Decreased splanchnic blood flow:
- Intravascular volume depletion
- Heart failure
Concomitant drug administration:
- Phosphate binders, etc
● Presystemic metabolism or first-pass metabolism reduces drug levels in those that
undergo significant intestinal mucosal cell or hepatic metabolism:
IV/oral dose ratio is low ( 1:4) due to
first-pass metabolism of drugs with 100% absorption
Table 2. Pharmacokinetic Changes Associated With Various Comorbidities
| Kinetic Factor | Pathophysiologic Change | Drug Effect |
| Absorption | ↓GI acidity and pill interactions* ↓Small-bowel surface area | ↓Absorption of certain drugs ↓Absorption of certain sustained-release medications |
| Distribution | ↑Adipose tissue ↓Lean body mass* ↓Albumin* | ↑Half-life of lipid-soluble drugs ↓Drug dose ↑Active (unbound) drug |
| Metabolism | Phase I (↑or↓) Phase II (↑or↓) | ↑or↓Half-life of drugs metabolized by this route ↑or↓Half-life of drugs metabolized by this route |
| Excretion | ↓RPF,↓GFR* | ↑Half-life of drugs that are excreted by kidneys |
Abbreviations: GI, gastrointestinal; RPF, renal plasma flow.
*Changes present in patients with CKD.
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