COMBINED
SEMINAR
ON THE USE OF DRUGS
IN RENAL FAILURE
maneuvers should be performed; namely, leaving the light on in the room, having a clock at the bedside, providing sensory input through music or television, repeated orienting contacts through a nurse, and so on. In the presence of significant depression with psychomotor retardation or of severe anxiety or aggressive behavior, antidepressants or major tranquilizers should be used. Initial doses should be small. Because these drugs are central nervous system depressants, they may decrease orientation and precipitate a paradoxical reaction with increased confusion and disorientation. Under these circumstances, dosages should be reduced or administration of the drug should be discontinued. Barbiturates are the worst offenders in this group and generally should not be used in the treatment of organic brain syndromes. Cortisone Psychoses. The consistent use of substantial doses of prednisone in post-transplant patients and its frequent use in other patients being treated with hemodialysis (namely, patients suffering from lupus erythematosus) make cortisone psychoses a not infrequent phenomenon in renal units. The predominant manifestations are increasing states of euphoria; paranoia; less frequently, depression; and depersonalization and derealization. These latter symptoms involve an altered state of the sense of the reality and proportions of the patient’s body or a feeling that the world about him is not real. Often the patient is able to describe these feeling states as abnormal. Generally, the patient remains oriented with intact cognitive functioning. The recommended treatment, if possible, is a diminution of the dose of prednisone. Major tranquilizers and antidepressants can be of help. The principles underlying the proper use of psychotropic drugs in patients with renal disease have been elaborated. These drugs have a useful place as an adjunct to the treatment of patients with behavioral disturbances, but they must never substitute for an integrated and coherent approach to the patient.
of treatment. Drowsiness is usually an early effect and disappear as tolerance develops within the first seven to 10 days. A lowered seizure threshold may present a problem in patients with hypertension and uremic encephalopathy. The extrapyramidal side effects include (1) akathisia or motor restlessness, which is the most common symptom and often is mistaken for anxiety; (2) pseudoparkinsonism; (3) acute dystonias and dyskinesias (especially in young men); and (4) tardive dyskinesias which appear late in contrast to the other symptoms and only with the prolonged use of large doses. The extrapyramidal side effects are, in themselves, not an indication for discontinuing therapy and patients can be successfully treated with antiparkinsonian agents; namely, trihexyphenidyl (ArtaneW), 2 to 5 mg, one to four times daily, or benztropine mesylate (Cogentin@), 0.5 to 2 mg, one to four times daily. A patient with an acute reaction may be treated with intramuscular or intravenous dosages of these agents or Benadryl, 25 to 50 mg intravenously or intramuscularly. This should afford rapid relief. The antiparkinsonian drugs should not be used prophylactically, and the dose often may be reduced or discontinued after one to three months. Organic Brain Syndromes. The incidence of organic brain syndromes in patients with terminal renal failure is very high. These syndromes are, of course, more frequent when the uremia is poorly controlled, but they occur at times even when the metabolic state appears to be in reasonable order. Moreover, progressive dementias seem to occur in some patients after they have undergone dialysis over long periods of time. The predominant manifestations are impairment of orientation, memory, intellectual functioning, affective and emotional response. Judgment is impaired, and hallucinations and delusions may occur, although they appear more fragmented, diffuse and incoherent than in patients with functional psychoses. Frequently, confused and aggressive behavior occurs. In the presence of significant disorientation, a whole array of orienting will
Pharmacokinetics of Propranolol, Quinidine, Procainamide and Lidocaine in Chronic Renal Disease DAVID
T. LOWENTHAL,
M.D., Hahnemann
Medical
College
People differ in their drug requirements and tolerances; factors influencing this variability include the person’s age, body habitus, preexisting disease states, nutritional status, gastrointestinal,absorption, drug volume distribution, hepatic metabolism and elimination kinetics. The biotransformation of drugs in end-stage renal
532
April 1977
The American Journal of Medicine
Volume 62
and Hospital,
Philadelphia.
Pennsylvania
disease is influenced by an impairment to the renal elimination of drugs, impaired hepatic metabolism, abnormal protein binding and altered tissue sensitivity, all of which can alter drug disposition in end-stage renal disease and can lead to adverse effects from the customary doses of drugs [ 111.
COMBINED
SEMINAR ON THE USE OF DRUGS IN RENAL FAILURE
I
.i I_f -
2
4
6
8
10
TIME
12
I4
I6
I8
20
22
24
(HRS) I
Figure 1. Propranolol levels in normal subjects (broken line) and in patients with end-stage renal failure (solid line) after the administration of a single dose of 80 mg. From Lowenthal et al. [ 171. Reprinted with permission.
Because atherogenesis and coronary artery disease occur in high frequency in end-stage renal disease [ 121, the complications of which may be irregularities in rate and rhythm conduction, it has been necessary to devise studies and to obtain information regarding the biotransformation of commonly used antiarrhythmic drugs. Propranolol. Propranolol, a beta-adrenergic blocking agent, is used primarily in the adjunctive treatment of patients with hypertension, angina pectoris and cardiac arrhythmias. When administered orally, propranolol undergoes a first-pass hepatic extraction and is metabolized by the hepatic oxidative pathway, specifically by hydroxylation to 4-hydroxypropranolol. In subjects with normal renal function, propranolol is well absorbed when taken orally; due to the avid hepatic binding, oral doses result in lower plasma concentrations than equivalent intravenous doses. In addition, long-term administration of propranolol results in hepatic saturation, which results in higher plasma concentrations and a prolongation of the biologic half-life [ 131. There
is significant interindividual variability in the plasma concentration dose relationship, as well as significant intraindividual variability in plasma concentrations, depending upon the relationship between the administration of the dose and the meal consumed [ 14,151. In addition, there is variability in the plasma propranolol concentration due to technical interference with vacutainer-type tubes [ 161. This results in low plasma concentrations of propranolol and possibly erroneous interpretation of results. Previous studies [ 171 in our laboratory have demonstrated no impairment to absorption in patients with chronic renal disease when compared with that in normal subjects ano, of great interest, have demonstrated significantly higher plasma concentrations of propranolol within lx hours after the administration of 80 mg. Following the administration of the same dosage to normal volunteer subjects, the peak plasma concentration was approximately one-third that obtained in the patients, and it occurred at approximately 2’/2 hours after the dose was given (Figure 1). In the patient
April 1977
The American Journal of Medicine
Volume 62
533
COMBINED SEMINAR ON THE USE OF DRUGS IN RENAL FAILURE
TABLE
Acute
III
Pharmacokinetics
Normal 4.4
T l/2 (hr)” Elimination fhr-‘)
Subjects
3.5 0.198
0.157
(hr)*
Elimination fhr-‘)
with Chronic
3.2
12.8 (N) 19.3 (A)
0.216
0.054 0.036 Yes
No
NOTE:
T l/2
*These
measurements
Comparison Chronic
= half-life;
of Mean Renal
“Metabolic
(hr)
51.6 r 1 .O
4.4*
155 * 40 p < 0.05
3.2 + 0.67 N.S. p > 0.3
tfs=
Clearance
Q
Elimination Constant (hr-‘1
1.0
0.270
? 0.08
0.533
Undetermined; probably no
Undetermined; probably no
of a single dose.
Between
Normal
Volunteer
Subjects
Metabolic Clearance* (liters/minj
and
Patients with
fst
with Chronic
Renal
0.817
r 0.039
0.254
T = 30 mg, threshold
AUC SF = fs (D-T) __. D
Journal
cl Medicine
Volume
62
* 0.04
0.158
+ 0.02
Disease
716 t 149 p < 0.05
0.637 r 0.04 p < 0.05
0.440 * 0.05 p < 0.05
= F X D
The Atnerlcan
FS
Group 274 k 49
0.366 + 0.07 N.S. p > 0.3
AUC where Q = hepatic blood flow of 1 .l liter/min,
April 1977
0.105
AUC (ng/ml.hr)
Q + D-T
534
1.8 (77 min)
chronic renal disease [ 17,181. These observations, in addition to the greater dosage per unit weight (mg/kg), may explain the early, higher plasma levels and AUC observed in the patients with renal disease. Because of the first-pass phenomenon, less drug normally reaches the systemic circulation, and the calculation of the volume of distribution would he theoretically inaccurate. A decrease in red blood cell mass, the decrease or absence of anatomic renal tissue and loss of muscle mass (and, therefore, body weight) from chronic renal disease all contribute to a decrease in the volume of distribution in patients with end-stage renal disease. These facts, too, may explain the high AUC in the patient group. Recent studies from our laboratory in patients with chronic renal insufficiency have shown that when
Parameters
Patients 1.44 f 0.2 p
SEMINAR
ON THE USE OF DRUGS
IN RENAL FAILURE
maneuvers should be performed; namely, leaving the light on in the room, having a clock at the bedside, providing sensory input through music or television, repeated orienting contacts through a nurse, and so on. In the presence of significant depression with psychomotor retardation or of severe anxiety or aggressive behavior, antidepressants or major tranquilizers should be used. Initial doses should be small. Because these drugs are central nervous system depressants, they may decrease orientation and precipitate a paradoxical reaction with increased confusion and disorientation. Under these circumstances, dosages should be reduced or administration of the drug should be discontinued. Barbiturates are the worst offenders in this group and generally should not be used in the treatment of organic brain syndromes. Cortisone Psychoses. The consistent use of substantial doses of prednisone in post-transplant patients and its frequent use in other patients being treated with hemodialysis (namely, patients suffering from lupus erythematosus) make cortisone psychoses a not infrequent phenomenon in renal units. The predominant manifestations are increasing states of euphoria; paranoia; less frequently, depression; and depersonalization and derealization. These latter symptoms involve an altered state of the sense of the reality and proportions of the patient’s body or a feeling that the world about him is not real. Often the patient is able to describe these feeling states as abnormal. Generally, the patient remains oriented with intact cognitive functioning. The recommended treatment, if possible, is a diminution of the dose of prednisone. Major tranquilizers and antidepressants can be of help. The principles underlying the proper use of psychotropic drugs in patients with renal disease have been elaborated. These drugs have a useful place as an adjunct to the treatment of patients with behavioral disturbances, but they must never substitute for an integrated and coherent approach to the patient.
of treatment. Drowsiness is usually an early effect and disappear as tolerance develops within the first seven to 10 days. A lowered seizure threshold may present a problem in patients with hypertension and uremic encephalopathy. The extrapyramidal side effects include (1) akathisia or motor restlessness, which is the most common symptom and often is mistaken for anxiety; (2) pseudoparkinsonism; (3) acute dystonias and dyskinesias (especially in young men); and (4) tardive dyskinesias which appear late in contrast to the other symptoms and only with the prolonged use of large doses. The extrapyramidal side effects are, in themselves, not an indication for discontinuing therapy and patients can be successfully treated with antiparkinsonian agents; namely, trihexyphenidyl (ArtaneW), 2 to 5 mg, one to four times daily, or benztropine mesylate (Cogentin@), 0.5 to 2 mg, one to four times daily. A patient with an acute reaction may be treated with intramuscular or intravenous dosages of these agents or Benadryl, 25 to 50 mg intravenously or intramuscularly. This should afford rapid relief. The antiparkinsonian drugs should not be used prophylactically, and the dose often may be reduced or discontinued after one to three months. Organic Brain Syndromes. The incidence of organic brain syndromes in patients with terminal renal failure is very high. These syndromes are, of course, more frequent when the uremia is poorly controlled, but they occur at times even when the metabolic state appears to be in reasonable order. Moreover, progressive dementias seem to occur in some patients after they have undergone dialysis over long periods of time. The predominant manifestations are impairment of orientation, memory, intellectual functioning, affective and emotional response. Judgment is impaired, and hallucinations and delusions may occur, although they appear more fragmented, diffuse and incoherent than in patients with functional psychoses. Frequently, confused and aggressive behavior occurs. In the presence of significant disorientation, a whole array of orienting will
Pharmacokinetics of Propranolol, Quinidine, Procainamide and Lidocaine in Chronic Renal Disease DAVID
T. LOWENTHAL,
M.D., Hahnemann
Medical
College
People differ in their drug requirements and tolerances; factors influencing this variability include the person’s age, body habitus, preexisting disease states, nutritional status, gastrointestinal,absorption, drug volume distribution, hepatic metabolism and elimination kinetics. The biotransformation of drugs in end-stage renal
532
April 1977
The American Journal of Medicine
Volume 62
and Hospital,
Philadelphia.
Pennsylvania
disease is influenced by an impairment to the renal elimination of drugs, impaired hepatic metabolism, abnormal protein binding and altered tissue sensitivity, all of which can alter drug disposition in end-stage renal disease and can lead to adverse effects from the customary doses of drugs [ 111.
COMBINED
SEMINAR ON THE USE OF DRUGS IN RENAL FAILURE
I
.i I_f -
2
4
6
8
10
TIME
12
I4
I6
I8
20
22
24
(HRS) I
Figure 1. Propranolol levels in normal subjects (broken line) and in patients with end-stage renal failure (solid line) after the administration of a single dose of 80 mg. From Lowenthal et al. [ 171. Reprinted with permission.
Because atherogenesis and coronary artery disease occur in high frequency in end-stage renal disease [ 121, the complications of which may be irregularities in rate and rhythm conduction, it has been necessary to devise studies and to obtain information regarding the biotransformation of commonly used antiarrhythmic drugs. Propranolol. Propranolol, a beta-adrenergic blocking agent, is used primarily in the adjunctive treatment of patients with hypertension, angina pectoris and cardiac arrhythmias. When administered orally, propranolol undergoes a first-pass hepatic extraction and is metabolized by the hepatic oxidative pathway, specifically by hydroxylation to 4-hydroxypropranolol. In subjects with normal renal function, propranolol is well absorbed when taken orally; due to the avid hepatic binding, oral doses result in lower plasma concentrations than equivalent intravenous doses. In addition, long-term administration of propranolol results in hepatic saturation, which results in higher plasma concentrations and a prolongation of the biologic half-life [ 131. There
is significant interindividual variability in the plasma concentration dose relationship, as well as significant intraindividual variability in plasma concentrations, depending upon the relationship between the administration of the dose and the meal consumed [ 14,151. In addition, there is variability in the plasma propranolol concentration due to technical interference with vacutainer-type tubes [ 161. This results in low plasma concentrations of propranolol and possibly erroneous interpretation of results. Previous studies [ 171 in our laboratory have demonstrated no impairment to absorption in patients with chronic renal disease when compared with that in normal subjects ano, of great interest, have demonstrated significantly higher plasma concentrations of propranolol within lx hours after the administration of 80 mg. Following the administration of the same dosage to normal volunteer subjects, the peak plasma concentration was approximately one-third that obtained in the patients, and it occurred at approximately 2’/2 hours after the dose was given (Figure 1). In the patient
April 1977
The American Journal of Medicine
Volume 62
533
COMBINED SEMINAR ON THE USE OF DRUGS IN RENAL FAILURE
TABLE
Acute
III
Pharmacokinetics
Normal 4.4
T l/2 (hr)” Elimination fhr-‘)
Subjects
3.5 0.198
0.157
(hr)*
Elimination fhr-‘)
with Chronic
3.2
12.8 (N) 19.3 (A)
0.216
0.054 0.036 Yes
No
NOTE:
T l/2
*These
measurements
Comparison Chronic
= half-life;
of Mean Renal
“Metabolic
(hr)
51.6 r 1 .O
4.4*
155 * 40 p < 0.05
3.2 + 0.67 N.S. p > 0.3
tfs=
Clearance
Q
Elimination Constant (hr-‘1
1.0
0.270
? 0.08
0.533
Undetermined; probably no
Undetermined; probably no
of a single dose.
Between
Normal
Volunteer
Subjects
Metabolic Clearance* (liters/minj
and
Patients with
fst
with Chronic
Renal
0.817
r 0.039
0.254
T = 30 mg, threshold
AUC SF = fs (D-T) __. D
Journal
cl Medicine
Volume
62
* 0.04
0.158
+ 0.02
Disease
716 t 149 p < 0.05
0.637 r 0.04 p < 0.05
0.440 * 0.05 p < 0.05
= F X D
The Atnerlcan
FS
Group 274 k 49
0.366 + 0.07 N.S. p > 0.3
AUC where Q = hepatic blood flow of 1 .l liter/min,
April 1977
0.105
AUC (ng/ml.hr)
Q + D-T
534
1.8 (77 min)
chronic renal disease [ 17,181. These observations, in addition to the greater dosage per unit weight (mg/kg), may explain the early, higher plasma levels and AUC observed in the patients with renal disease. Because of the first-pass phenomenon, less drug normally reaches the systemic circulation, and the calculation of the volume of distribution would he theoretically inaccurate. A decrease in red blood cell mass, the decrease or absence of anatomic renal tissue and loss of muscle mass (and, therefore, body weight) from chronic renal disease all contribute to a decrease in the volume of distribution in patients with end-stage renal disease. These facts, too, may explain the high AUC in the patient group. Recent studies from our laboratory in patients with chronic renal insufficiency have shown that when
Parameters
Patients 1.44 f 0.2 p
