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101 Cards in this Set

  • Front
  • Back
Affinity and Kd
affinity is inversly proportional to Kd

higher Kd = decr affinity
Indications for digoxin (2)
1)CHF due to systolic dysfunction
2)control supraventricular arrhythmias in pts w/ poor CO
Digoxin CI's (3)
1)obstructive cardiomyopathy
2)significant brady-dysrhythmias
3)pronounced hypokalemia or hypocalcemia
Digoxin Usage Problems (5)
1)narrow therapeutic range
2)endpt of therapy is difficult to determine and measure
3)toxicity can be severe and life-threatening
4)Assay specificity can be a problem due to endogenous DHEA
5)Large Vd and bound to tissues
Digoxin Absorption (5)
1)oral thru duodenum/jejunum via carrier mediated transport and passive diffusion
2)is hydrolyzed in gastric acid (so need big dose or EC)
3)can be reduced by intestinal bacteria
4)IM absorption is very painful and incomplete
5)Give PO or via slow IV push
ONLY factor that INCREASES digoxin absorption
Propantheline
6 of many that DECR digoxin absorption
1)biscodyl
2)metoclopramide
3)cholestyramine
4)antacid/kaolin-pectin
5)surgical gut removal
6)incr dietary fiber content
Effect of p-glycoprotein (MDR1) on digoxin CL (3)
1)MDR1 puts digoxin back in the GI lumen
2)so high expression of MDR1 = low serum []s
3)Competition for transport via MDR1 with macrolides
Drugs that increase MDR1 (2); result on digoxin
1)rifampin
2)St. John's wort

decr digoxin []s
Drug that inhibit MDR1 (3); result on digoxin
1)itra/ketoconazole
2)quinidine
3)atorvastatin

incr digoxin []s
Digoxin distribution (6)
1)complete by 8hrs after IV
2)binds to Na/K ATPase in kidney, heart, brain
3)50% of body digoxin is bound to skeletal muscle
4)albumin is primary plasma protein (25% bound)
5)partitions into erythrocytes
6)does NOT distribute into fat
Digoxin LD's must be broken up by...
atleast 6hrs
Digoxin site of axn and 1 property of it
Na/K ATPase is a Mg dependent pump
Digoxin factors INCREASING distribution and result on serum []s (5)
1)hypokalemia
2)hyperthyroidism
3)physical exercise
4)pregnancy
5)pediatrics

DECREASED serum []s
Digoxin factors DECREASING distribution and result on serum []s (5)
1)hyperkalemia
2)hypothyroidism
3)incr age
4)renal failure

INCREASED serum []s
PK model of digoxin
1)3 compartment linear
Digoxin and hemodialysis
little is removed by this due to drug behavior
Digoxin antidote
Digibind a digoxin Fab segment
Digoxin metabolism (2 pathways)
1)digoxin hydrolysis to digoxingenin then conjugated
2)digoxin reduction of lactone 2x bond to dihydrodigoxin
Digoxin is actively___ and can be blocked by... (3)
SECRETED

1)hypokalemia
2)spironolactone
3)quinidine
Digoxin Mechanism (6)
1)binds Na/K ATPase
2)results in increased INTRAcellular []s of Na, Ca
3)= incr Ca release and tension w/ an AP
4)increased contractility (incr inotropic)
5)incr Na = longer refractory period of AV node slowing conduction (decr chronotropic)
6)vagal nerve stimulated by digoxin to slow ventricular rate of atrial fibrillation
Delay in response of digoxin b/w [] and incr contractility?
due to digoxin distribution
What is needed to tell digoxin toxicity (3)
1)EKG (dysrhythmias)
2)symptoms (n/v, vision)
3)serum []s
Mean digoxin serum []s
0.8-2.0
Toxicity %ages in digoxin (3)
1)90% of pts w/ Cp less than 2 were non-toxic
2)85% w/ Cp's greater than 2 were toxic
3)Cp's do NOT differentiate toxicity; EKG changes, symptoms do
Digoxin LD for CHF
NEVER USE LD W/ CHF*******
Digoxin LD for supraventricular arrhthymias
based on total Vd; give 50% of this calculated dose, then 25%, then 25% all 6 hours apart
Factors altering digoxin toxicity (4)
1)enhanced via hypokalemia, hypomagnesemia, hypercalcemia
2)underlying cardiac disease like COPD
3)hypothyroid increases response
4)hyperthyroid resistant to digoxin effects
Empirically dosing digoxin (MD)
0.25mg/day w/ CLcr > 20; started 24hrs after first LD
Why check digoxin serum []s before a digoxin dose is given
to check for baseline DHEA in renal failure
Indications for serum digoxin monitoring (7)
1)assess compliance
2)assess deterioration after a good response
3)impaired renal fxn
4)suspected toxicity
5)evaulation of continued need for therapy
6)when conditions that alter digoxin response develop
7)when there is a suspected drug interaxn
Digoxin monitoring (2)
1)draw []s no earlier than 12hrs after a dose
2)monitor EKG, symptoms, serum []s ventricular response rate
Digoxin drug interaxns via ADSORPTION OF DIGOXIN and result (4)
1)cholestyramine
2)kaolin-pectin
3)bran
4)antacid

DECR digoxin []s
Digoxin drug interaxns via METABOLISM BY GUT FLORA (2) and results
1)erythromycin
2)tetracycline

INCREASED digoxin []s
Digoxin drug interaxns via DECR RENAL AND NONRENAL CL and results (4)
1)quinidine
2)amiodarone
3)verapamil
4)spironolactone

INCREASED digoxin []s
Digoxin drug interaxns via just a DECR in RENAL CL (2) and results
1)diltiazem
2)indomethacin

INCREASED digoxin []s
Digoxin drug interaxns via just a DECR in NONRENAL CL and results
1)Triamterene

INCREASED digoxin []s
Cyclosporin absorption (4)
1)erratic, highly variable @ best
2)biphasic
3)F varies w/ dosage form (ranges from 5-90% w/ average of 30%)
4)F is 35-40% w/ neoral (solution)
Factors affecting absorption (5)
1)incr w/ high fat food
2)co-medications
3)type of transplantation
4)bile production and delivery to the gut
5)condition of GI tract
Which criteria for drug monitoring does Cyclosporine meet
ALL OF THEM
Problems w/ cyclosporin F (5)
1)differing assays
2)time dependent changes in absorption following transplant (incr w/ more time)
3)changes in Hct and whole blood binding and temperature
4)interindividual variability in gut CYP and MDR1
5)measurement in plasma or serum vs. whole blood []s
Cyclosporin distribution (4)
1)biphasic- bound to RBC, WBC and lipoproteins
2)highly tissue bound
3)fub in blood is 0.01-0.02
4)binding to RBC is saturable and dependent upon temperature
Absolute CI of cyclosporin
statins; will cause muscles to lyse
Best fit PK model of cyclosporin
non-linear, time dependent
Cyclosporin binding to RBC (4)
1)50-90% of drug bound in blood is to RBCs
2)binding in RBCs is altered by external temp changes (decr temp = incr RBC binding)
3)binding in RBCs is altered by Hct (decr Hct = incr plasma cyclosporin)
4)metabolites also bind to cyclosporin
Cyclosporin metabolism (4)
1)by CYP3A4 (is a substrate and inhibitor)
2)14 characterized metabolites (but 30 known)
3)interacts w/ MDR1 (p-gp) in gut
4)less than 1% excreted in urine unchanged
2 major metabolites of cyclosporin
1)AM9/M1
2)AM1/M17
Nonlinearity of metabolism and PK of cyclosporin (2)
1)Vss incr and ke/CL decr w/ increasing dose
2)w/ incr []s less binds to RBC due to saturation (= incr Vss)
Factors affecting metabolism of cyclosporin (5)
1)age dependent CL (CL/V incr in pediatrics)
2)decr and more variable absorption in blacks
3)incr V/CL in females
4)hepatic fxn
5)CL changes @ night (diurnal)
Adverse effects of cyclosporin (4)
1)decr renal fxn due to decr in renal blood flow and GFR (dose dependent--reversible)
2)decr renal fxn due to structural changes (irreversible)
3)seconardary malignancies
4)HTN
Assay methods for cyclosporin (4)
1)monoclonal RIA (CHEAP AND EFFECTIVE)
2)monoclonal FPIA
3)HPLC (gold standard)
4)all use whole anticoagulated blood which has a cyclosporin extraction process
Cyclosporine must... (2)
1)must be infused over time
2)must use IBW even in obesity
Neoral doses for:
a)renal transplants
b)liver transplants
c)heart transplants
a)9mg/kg/day
b)8mg/kg/day
c)7mg/kg/day
AUC(0-4) w/ cyclosporine is a good predictor of...
rejection or toxicity
Major drug interaxns w/ cyclosporin (10)
1)acyclovir
2)clarithromycin
3)erythromycin
3)diltiazem
4)fluconazole
5)itraconazole
6)ketoconazole
7)lovastatins
8)isoniazid
9)phenytoin
10)verapamil
Verapamil and cyclosporin
good w/ cyclosporin to decrease the amount of cyclosporin you need to use & lowers HTN
Cyclosporin drug interaxn w/ INCR NEPHROTOXICITY
acyclovir
Cyclosporin drug interaxn w/ INCREASED CSA BLOOD []s (via inhibition of HEPATIC metabolism) (7)
1)clarithromycin
2)erythromycin
3)diltiazem
4)fluconazole
5)itraconazole
6)ketoconazole
7)verapamil
Cyclosporin drug interaxn w/ DECREASED CSA BLOOD []s (via induction of HEPATIC metabolism) (2)
1)isoniazid
2)phenytoin
Cyclosporin drug interaxn w/ INCREASED CSA BLOOD []s (via impaired metabolism)
grapefruit juice
___ are usually used w/ transplant ppl, not ___
Ca blockers; not ACE inhibitors
Rationale for monitoring phenytoin (3)
1)direct relationship b/w [] and effect
2)narrow therapeutic index
3)PK variability (dose correlates poorly w/ serum drug []s)
PK variability of phenytoin (3)
1)absorption problems
2)M-M kinetics
3)highly protein bound
Clinical response of phenytoin seen by Buchthal
reduction in seizure frequency by 50% in 85% of pts w/ []s over 15
Clinical response of phenytoin defined by Kutt and McDowell (2)
1)defined therapeutic range (10-20)
2)provides high probability of seizure control and low probability of SEs
Clinical response of phenytoin seen by Lund (3)
[]=6; 6% had seizures
[]=11; 4% had seizures
[]=16; 1% had seizures
Toxicity of phenytoin seen by Lund
incr toxic effects at []=25-30
Clinical toxicity of phenytoin seen by Haerer and Grace (4)
1)nystagmus in 20% of pts @ [15]
2)nystagmus in 60% of pts @ [20-25]
3)50% have toxicity @ [29.9]
4)100% have toxicity @ [30]
Clinical toxicity of phenytoin seen by Kutt (3)
1)nystagmus seen @ 15-40 (mostly @ 20-30)
2)ataxia seen @ 30-40
3)mental status changes @ 40-60
Solubility and pKa of phenytoin
1)low solubility of phenytoin acid (Na-salt readily soluble in water)
2)pKa=8.3
Formulations of phenytoin ACID and S=?? (2)
1)suspension (125mg/5mL)
2)chewable tablets (5mg)

S=1
Formulations of phenytoin Na salt and S (3)
1)injection w/ PEG & alcohol diluent
2)XR release capsule (phenytek)
3)IR

S=0.92
Phenytoin Na salt injection (4)
1)CV collapse and CNS depression w/ rapid injection
2)do NOT exceed 50mg/min
3)ONLY stable diluent is 0.9% NaCl (but can be given undiluted)
4)avoid IM injection (precipiates and erratic/slow absorption)
Fosphenytoin
a)properties (3)
b)only adv
a1)Cerebyx
a2)prodrug
a3)75mg/mL = 50mg phenytoin equivalents

b)easier on vein and tissue
F of phenytoin (4)
1)dependent on formulation
2)Na salt soluble in water but precipitates in acidic medium of stomach
3)absored in duodenum
4)F=1
Rate of absorption of phenytoin (2)
1)varies among dosage forms and manufacturers
2)once daily dosing due to slow absorption and relatively slow elimination (NOT being XR)
Decreased absorption of phenytoin can be due to...(2 categories w/ 3 each)
1)diseases like diarrhea, gastric resecretion, malabsorption syndrome
2)drugs: nutritional supplements (major), sucralfate (mod), antacids (minor)
Protein binding of phenytoin (2)
1)90%
2)unbound fraction is 0.1
Drugs increasing free phenytoin Cp (3 and 1 other thing)
1)valproic acid
2)salicylic acid
3)sulfamethoxazole
4)usually displacement is insignificant UNLESS drug displacing has [] greater than 25
Endogenous displacers of phenytoin from protein (3)
1)hyperbilirubinemia
2)renal failure
3)severe jaundice
(Phenytoin) Albumin is decreased in...(3 of many)
1)burns
2)cirrhosis
3)CF
Cp adjusted for low bilirubin equation****
= (Cp observed) / 0.2[Albumin] + 0.1
Phenytoin metabolism
hepatically via hydroxylation to p-HPPH using 2C9/2C19
Phenytoin elimination (2)
1)60-90% of po recovered in urine as p-HPPH and its glucuronides
2)5% filtered unchanged drug
M-M kinetics and phenytoin (2)
1)Vmax = max rate of metabolism (Vmax= 7mg/kg/day)
2)Km = Cp2 which metabolism is 1/2 of max rate (Km=4mg/L)
Effect on phenytoin []s and cause/ex if VMAX INCREASES
1)enzyme induction
2)total Cp decreases
Effect on phenytoin []s and cause/ex if KM INCREASES
1)competitive inhibition
2)cimetidine
3)total Cp INCREASES
Effect on phenytoin []s and cause/ex if VMAX DECREASES
1)hepatic cirrhosis
2)decr enzyme activity
3)total Cp INCREASES
Effect on phenytoin []s and cause/ex if KM DECREASES
1)decreased protein binding
2)uremia
3)total Cp DECREASES
RENAL DISEASE effects on phenytoin PK (3)
1)albumin [] and affinity DECR
2)fub incr 2-3 fold
3)as fub incr, Vd incr too
HEPATIC DISEASE effect on phenytoin PK (3)
1)fub incr b/c DECR albumin &/or displacement by bilirubin
2)CLint DECR due to decline in abilable enzyme
3)Vd INCR
HEMODIALYSIS effects on phenytoin PK
ONLY 2-4% removed during an 8hr period
NEWBORNS effects on phenytoin PK (3)
1)fub INCR due to low albumin
2)Vd INCR
3)CLint DECR b/c hydroxylation enzyme not mature
BURN PTS effects on phenytoin PK (3)
1)fub INCR b/c of decr in albumin b/c of loss due to burns
2)Vd INCR
3)CL hepatic INCR
Drug interactions that DECR absorption of phenytoin (3)
1)enteral formula
2)sucralfate
3)antacids
Drug interactions that alter protein binding in a way that INCR fub phenytoin (2)
1)valproic acid
2)sulfamethoxazole
Drug interactions that induce phenytoin metabolism (6)
1)phenobarbital
2)theophylline
3)valproic acid
4)carbamazepine
5)warfarin
6)omeprazole
Drugs whose metabolism may be affected by phenytoin (resulting in DECR []s of that drug) (4)
1)corticosteroids
2)tegretol
3)valproic acid
4)theophylline
Which phenytoin always has a larger dose and why?
phenytoin Na dose always larger than ACID b/c acid F is smaller
For avg pt what is LD of phenytoin?
15mg/kg
Average phenytoin MD for a
a)adult
b)children
c)neonate
a)4-7mg/kg/day of acid
b)4-10mg/kg/day
c)3-5mg/kg/day