King Saud University College Of Pharmacy Department of Clinical Pharmacy

King Saud University
College Of Pharmacy
Department of Clinical Pharmacy
Clinical Pharmacokinetics - PHCL 462
"With our best wishes to all of you"
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King Saud University
Clinical Pharmacokinetics - PHCL 462
College Of Pharmacy
Professor Dr. Mahasen
Department of Clinical Pharmacy
2
nd
A. Radwan
Semester 1430 H -2009
II. Drugs Eliminated Mainly by Renal Excretion
Clcr = CrCl = crCL = GFR.Fu
Since Fu = 1 for Cr, so Clcr = GFR =125 ml/min (90-150 ml/min)
𝑪𝒍𝒓
𝑬𝒙𝒄𝒓𝒆𝒕𝒊𝒐𝒏 𝒓𝒂𝒕𝒊𝒐 =
𝑮𝑭𝑹 ∗ 𝑭𝒖
Excretion Ratio:
<1 ……. TR " e.g. Phenobarb"
>1 …… ATS
=1 …… ATS  TR or only GFR
𝑪𝒍𝒓 = 𝑪𝒍𝑮𝑭 + 𝑪𝒍𝑨𝑻𝑺 ∗ (𝟏 − 𝑭𝑻𝑹 )
ClATS = Qr * EATS
Where, 𝑪𝒍𝑮𝑭 : 𝑪𝒍 𝒐𝒇 𝒕𝒉𝒆 𝑮𝒍𝒐𝒎𝒆𝒓𝒖𝒍𝒂𝒓 𝑭ilteration = GFR *Fu
𝑭𝑻𝑹 : 𝒇𝒓𝒂𝒄𝒕𝒊𝒐𝒏 𝒆𝒍𝒊𝒎𝒊𝒏𝒂𝒕𝒆𝒅 𝒃𝒚 𝒕𝒖𝒃𝒖𝒍𝒂𝒓 𝒓𝒆𝒂𝒃𝒔𝒐𝒓𝒑𝒕𝒊𝒐𝒏
𝑪𝒍𝑨𝑻𝑺 : 𝑪𝒍 𝒐𝒇 𝒕𝒉𝒆 𝒂𝒄𝒕𝒊𝒗𝒆 𝒕𝒖𝒃𝒖𝒍𝒂𝒓 𝒔𝒆𝒄𝒓𝒆𝒕𝒊𝒐𝒏
Qr : Renal blood / plasma flow
EATS: Excretion Ratio of the ATS
𝑻𝒐𝒕𝒂𝒍 𝑪𝒍 = 𝑪𝒍 = 𝑪𝒍𝒔 = ClH + Clr + CLNR = D/AUC
1.
Aminoglcosides antibiotics (AGAs)
Since their introduction into clinical use 50 years ago and despite the introduction of newer agents
(carbapenems, monobactams, and fluoroquinolones) , aminoglycoside antibiotics (AGAs) continue to
play an important role in the treatment of severe infections. This is because of:
 Therapeutic efficacy
 Synergy with the ß-lactam antibiotics
 Low rate of development of true resistance
 Low drug cost.
Their main drawback has been the occurance of:
 Nephrotoxicity (reversible)
In 5 - 25% of the patient
 Ototoxicity
 Examples: Gentamicin, tobramycin, amikacin, netilmicin, kanamycin, streptomycin, and neomycin
 Contain amino sugar linked to an aminocyclitol rings by glycosidic bonds
 Given as q8/12 hr (traditional) or now q24 to 48 hr or more (large dose extended interval, LDEI).
 Since   3 t1/2, therefore, minimal accumulation is expected.
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Efficacy:
Mainly gm-negative bacteria such as pseudomonus A., serratia M, E. coli, Klebsiella pneumoniae,
Proteus isolates Enterobacter A. etc.
They demonstrate concentration-dependent killing.
Mechanism of Action:
No anaerobic activity.
Bactericidal agents- irreversibly bind to the 30 s bacterial ribosome; protein synthesis is thereby
inhibited and cell death ensues.
Uptake into bacterial cells is facilitated by cell wall inhibitors (Vancomycin and beta-lactams).
Tobramycin, Kanamycin, Gentamicin, and Netilmicin inhibite the synthesis of cellular enzymes,
therefore, cross resistance is common with these agents.
Amikacin inhibites the cell-wall penetration. Used as a last resort when others have failed. Why?
Preference:
a.
b.
Pseudomonus A
1. Tobramycin 2. Netilmicin
Serratia M
1. Gentamicin
Neomycin is used for preoperative bowel sterilization, hepatic coma (adjunctive therapy); and
in topical form, for skin and mucous membrane infections (e.g. burns)
Netilmicin is active against many resistant gm-negatives .
Kanamycin has wide spread resistance.
Basic Pharmacokinetics
Absorption:



Poorly absorbed from GI after oral / rectal - Why?
Absorption increases with disease - ulcer, intestinal bowel disease
If it is given locally (in the intestine), what will be its fate?
____________________________________________________

Topically - long period to large wounds / burns  intoxication especially in renal dysfunction, or
might  bacterial resistance - Why?
____________________________________________________
Absorbed completely , highly variable, and rapidly after IM injection
 Peak concentrations in plasma occur 30 - 90 min after IM inj.
 Poor perfusion in muscle   absorption
 Painful
Intrathecally - absorption in brain and CSF is negligible - Why? ____________
Intraocular absorption – poor



Distribution:
Volume of distribution is based on IBW for drugs that do not distribute well into adipose tissue &
On TBW for drugs that do distribute well into adipose tissue
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Drugs partially distributed into fat, an ABW (bet. Actual & ideal BW) is often used. Vancomycin is
exception TBW is used to calculate the V.
 Aminoglycosides is quite hydrophilic-distributes primarily in extracellular fluid with limited tissue
distribution Relatively poor tissue penetration
 Protein binding (20-30%, fu  0.8 - 1)-not clinically significant;
 Well distributed except for the eye, CNS, CSF.
 Must be given intrathecally for CNS infections.
 Increased V seen in CHF, peritonitis, ascites, acute burn injury, s/p surgery, immediately post
partum patients.
 Because of ____________________ they do not distribute into most cells, CNS, and eye
 V = 25% LBW  _______________ fluid
 Rapid distribution phase - 5 - 15 min
 Bile's concentration  30% plasma concentration
 Low concentration in secretion & tissues
 Compared to plasma, high concentration in :
 Renal cortex  __________ toxicity
 endolymph and perilymph of the inner ear  _________ toxicity
 Inflammation   penetration into peritoneal and pericardial cavities
 In late pregnancy - in fetal plasma and amniotic fluid e.g. streptomycin - hearing loss in
children
 About 10% distributes in adipose tissue.
 To calculate aminoglycosides V use this ABW
 ABW = IBW + 0.1 (TBW-IBW)
rarely used
 Populations estimate: V = 0.24 L/kg (IBW), V = 10 to 40 L
 0r use V = 0.3 L/kg * dosing weight
C. Elimination:
 Renally cleared. Dosing is based on a patient’s ideal or adjusted body weight and renal
function.
Excreted almost entirely by GF, no ATS
Hemodialysis removes  50% in 4 to 5 hrs.
Peritoneal dialysis is less effective, 25% of the dose is removed in 48 - 72 hrs.
Total body elimination = drug excreted unchanged +
drug metabolized
Drug excretion could be through:
 Urine
 Bile
 Sweat
 Expired air
 Breast milk
 Seminal fluid
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Renal Excretion:
 Glomerular filtration (molecular size, <60,000, Free, healthy)
 Active secretion
 Tubular reabsorption
𝐴(𝑡 1→𝑡 2 )
𝐶𝑙𝑟 =
𝐴𝑈𝐶(𝑡 1→ 𝑡 2 )
Where, 𝐴(𝑡 1→𝑡 2 ) : Amount excreted in urine from time t1 to t2. 𝐶𝑙𝑟 =
𝐶𝑙𝑟 =
𝐶(𝑚𝑖𝑑𝑝𝑜𝑖𝑛𝑡
2
Cl
Cl
𝐶𝑝𝑙𝑎𝑠𝑚𝑎
)
3
Slope =
0.002
K, h-1
1
𝐴(𝑡 1→𝑡 2 ) /(𝑡2 −𝑡1 )
𝐷𝑟𝑢𝑔 𝑒𝑥𝑐𝑟𝑒𝑡𝑖𝑜𝑛 𝑟𝑎𝑡𝑒
Intercept =
0.075
GFR
1. Only eliminated by GFR
GFR
2. Eliminated by GFR + NR
ClCr
3. E.g.
aminoglycosides, k can be Cl = slope *GFR
Cl = slope *GFR + intercept
predicted for gentamicin:
𝑼𝑽
𝐂𝐥𝐂𝐫 = 𝑷∗𝟏𝟒𝟒𝟎 (Cr by collecting 24 hr urine, this is the best but impractical)
k = 0.00293 ClCr + 0.014
Where, U = urinary Cr. Conc, V = urine volume, P=plasma Cr concn (at midpoint of Cr
collection), 1440 = 24*60.
Populations estimate:
 k = 0.00293 ClCr + 0.014

(k = 0.05 to 0.5 hr-1)
(Amikacin /Gentamicin/Tobramycin: K,/h= (0.00285 * CrCl, ml/min) + 0.015.
May also use:
k = (0.0024 * CrCl) + 0.010
The following may  the usefulness of these equations:

K  in Burn victims in cystic fibrosis
K  in patients with CHF, renal failure or severe hypotension ( renal perfusion)
Children (>1 -  13 yr will have the highest Cl, 0.13 L/h/kg, adults 0.08 L/h/kg)????
So the t1/2 varies with age & kidney function.
Dosage
Multiple-daily dosing “Traditional”:
 For the treatment of Gram-negative infections when “once-daily” dosing is not appropriate.
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 Traditionally Aminoglycosides are administered in multiple daily doses (q 8 or 12 h).
 PDR – recommends for multiple dosing: 3 to 5 mg / kg / day for Tobramycin and Gentamicin,
but some authors have given up to 19 mg / kg / day in certain clinical situation -Wide
variability.
 Objective is to achieve peak (4 -8 g / mL) and trough (1 - <2 g/ mL). Peak and trough
levels are monitored for __________ and __________.
 Depending on clinical situation (peaks): To get good penetration in the tissue where bacteria
actually is multiplying.
1. Bacteremia and Septicemia > 7 g / mL
2. Pneumonia or lung infection > 8 g / mL
3. UTI or bladder infection  5 - 6 g / mL
4. Soft Tissue infection  7g / mL
Agent
t1/2 ,
Hr
Administration
Route
Common Dosage
Range,
mg/Kg/d
Therapeutic Range,
g/mL
Peak
Trough
Amikacin
2–3
IV, IM
15
Gentamicin
2–3
Netilmicin
2.7
IV, IM
Topical
IV, IM
3
NA
3-6
Streptomycin
Tobramycin
2–3
2–5
IM
IV, IM
15 *
3-5
Neomycin
2–3
Oral
Topical
50 - 100
10 - 15
25 - 30
(5 - 8 )
4-8
<2
6 - 10
<2
---4-8
<2
---
* For TB, dosage is 1 g / day
Inclusion criteria:
 Suspected or documented Gram-negative infections not eligible for “once-daily” dosing.
 Documented serious Gram-negative infections (e.g. Pseudomonas) receiving aminoglycosides in
combination with a -lactam agent.
Exclusion criteria:
Patients using aminoglycosides for synergistic activity against Gram-positive organisms (see below):
1. Severe liver disease (e.g., ascites)
2. Severe renal disease (CLcr < 30 mL/min)
3. Neutropenic patients
4. Enterococcal endocarditis
5. Gram positive infections (when the aminoglycoside is used for synergy)
6. A history of allergy to aminoglycosides
7. A history or signs of a hearing loss or vestibular dysfunction.
8. Pulse dosing has not been well studied in children so not yet be recommended for this population.
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High-Dose, Large –Dose Extended-interval Dosing (“Once-Daily”) "Pulse"
Dosing:
1. They exhibit a significant post-antibiotic effect (PAE: continued suppression (2 - 8 hr) of bacterial
growth despite the decline of the antimicrobial concentration to zero). PAE may be:
2. The bactericidal action of aminoglycosides is concentration dependent:
 The higher the (peak/MIC) ratio the higher the kill rate (>10).
3. Aminoglycoside uptake into renal tubule cells and the inner ear appears to be saturated at
relatively low serum levels, suggesting that:
 higher peaks do not necessarily result in a greater risk of toxicity.
 Serum troughs, at or near zero, may
o promote tissue drug disposition
o shorten tissue exposure
o and promote recovery.
 Added to the well known risk factors (age, volume depletion, liver disease, coadministration of certain drugs, etc.), the duration of exposure to the Abs subjects the patient to
toxicity than their serum level.
 Animal and human studies strongly suggest that pulse dosing is less nephrotoxic.
 In vitro studies: More frequent dosing of aminoglycosides tends to reduce their uptake into the
bacterial cell of aerobic GNB "adaptive post-exposure resistance", lead to  in the MIC90,
i.e., reduced efficacy.
 Longer  appear to  the time required for the MIC to revert to its original
value.
There appears to be a general consensus that pulse dosing of aminoglycosides offers the following advantages:









Relatively easy, straightforward initial dosing.
Achieve a high aminoglycoside peak (>10 x MIC) to maximize efficacy.
Enhanced efficacy due to higher peak levels (stamps subtherapeutic dosing).
Enhanced safety due to shorter effective exposure time.
Convenience for both patients and nurses.
Likely on-time administration.
A much reduced need for serum aminoglycoside levels (reduced cost).
Facilitation of drug administration through home care services (reduce cost).
Patients with CLcr < 40 mL/min, the aminoglycoside level may remain significantly elevated (> 2
mg/L) for long periods of time which would further damage the kidneys.
o
Thus, if  > 48 hr, an alternative antimicrobial agent should be considered.
o
Also, in patients with high clearance (e.g., young adults, cystic fibrosis, burns, etc)  < 24 hr
may be more appropriate.
However, this strategy has not been adequately studied in all populations.
Exclusion criteria:
If there are any checks do not use once-daily dosing-use conventional dosing.
(1) Patient has febrile neutropenia
(2) Burn patient
(3) Spinal cord injury
(4) R/O meningitis, osteomyelitis or endocarditis
(5) CrCl < 40 ml/min
(6) Age < 18 or >70
(7) History of ototoxicity
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(8) Pregnant
(9) Being used for synergy for staph or strept infection.
Dosing: (Gent / Tobra)
* Mild infection: 4mg x dosing weight in kg. (Cystitis etc)
* Moderate infection: 5 mg/kg of dosing weight (wound infection, Pyelonephritis, intraabdominal or
pelvic infections, osteomyelitis, etc.)
* Severe infection: 6 mg/kg of dosing weight.
(Gram negative pneumonia, septic shock, etc.)
CrCl
Dose (Gentamicin,
* Life-threatening: 7 mg/kg of dosing weight.
Tobramycin)
(Round dose to the nearest 20 mg)
>60 ml/min
5 mg/kg IV q24h
1. Aminoglycosides Dosing & monitoring Strategy
There are a number of ways to estimate an appropriate starting dose regimen for aminoglycosides. A
simple step -by - step procedures for adults is described below. Remember that calculated doses are
estimates of limited accuracy, and follow up with drug levels are required when the drug is to be
continued for more than 36 - 48 hr
What should the clinician monitor CrCl/aminoglycosides concentration ? ________________
Why?
________________________________________________________________
Patient factors will affect accuracy of predictions, and patient status should influence dosing decision.
PS. all wt in Kg.
Step 1:
Obtain baseline data:
 Patient age, sex, ht, wt, allergies, diagnosis, infection site, current drug therapy, I/O's for past
24 hrs, Tmax, WBC with diff, albumin, Past medical history, Lab work-up: SCr, BUN, cultures
etc.
Step 2: To determine dosing wt:
Determine pt actual wt.
Estimate Ideal body weight in (kg): IBW= ideal body weight in kg = Lean body wt
Height in inches:
Males: IBW = 50 kg + 2.3 kg * (Height -60) 
Females: IBW = 45.5 kg + 2.3 kg * (Height -60) 
Height in cm:
Males: IBW = 50 kg + 0.9 * (Height - 152) 
Females: IBW = 45.5 kg + 0.9 kg * (Height - 152) 
For patient Ht < 60 inches tall (152 cm), the wt should be decreased more conservatively than
2.3/inch or 2.3/2.54 cm.
Children (1-18 yr:
< 5ft :
IBW = 2.05 e(0.02)Ht (Ht in cm)
 5 ft tall: IBW (male) = 39 + 2.27 (Ht-60)
IBW (female) = 42.2 + 2.27 (Ht-60) Ht in inches
Or
IBW (male) = 39 + 0.9 (Ht-152)
IBW (female) = 42.2 + 0.9 (Ht-152) Ht in cm
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SA, m2 = W0.5378 * Ht0.3964 * 0.024265 (For all) (W = wt in kg, Ht = Ht in cm
Compare actual wt to IBW:
 Patient who weighs < IBW, the actual body wt is used
 Pt weight/IBW = 0.9 - <1.2 use pt wt.
 Obese patient use ABW if TBW is > 25% IBW (wt > 20 - 40 Kg IBW)
ABW = IBW + 0.4 (Total body weight - IBW) = "adjusted" body wt
Step 3:
Calculate DL, if clinically necessary, - use actual wt OR ABW for obese patient:
 Gent / Tobra : 1 - 1.5 mg / Kg (Round dose to 60, 80, 100, 120mg, etc.)
 Amikacin:
6 - 7.5 mg/Kg (round off dose)
DL for traditional: For Gent/Tobra, amikacin (3-4 X) & netilmicin (1.3 X)
In adults, treatment failures may occur 2ry to a low first-dose peak.
Step 4:
Estimate Creatinine Clearance: (ml/min)
Cockcroft-Gault equation:
𝑪𝒓𝑪𝒍 =
(𝟏𝟒𝟎−𝒂𝒈𝒆)𝑰𝑩𝑾
𝑪𝒓𝑪𝒍 =
(𝟎.𝟖𝟓)(𝟏𝟒𝟎−𝒂𝒈𝒆)𝑰𝑩𝑾
𝟕𝟐∗𝑺𝑪𝒓
𝟕𝟐∗𝑺𝑪𝒓


Where,
CrCl = creatinine clearance (ml/min/1.73 m2 body surface are)
Age = patient's age in years
SCr = serum creatinine concentration, mg/dL
Note:
If the actual body wt is less than the IBW, use the actual body wt for
calculating the CrCL.
If the patient is >65 yo and creatinine <1, use 1 to calculate the creatinine
clearance (optional)
Step 5:
Calculate maintenance dosing Rate:
 Dose size of DM: (use actual wt OR ABW for obese patient)
Gent / Tobra :
Amikacin:
1 - 1.5 mg / Kg (Round dose to 60, 80, 100, 120 mg, etc.)
5 mg /Kg ( 7.5 mg/Kg if given q 12 hr)
Age
Neonate ( 4 wks)
Infants (>4wks – 1 yr)
Children (> 1  13 yr)
Adolescents(>13-18 yrs)
Adults (>18 -18 yrs)
Younger geriatric (>60-75
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Traditional, mg/kg/ ? hr
2 -2.5/12-24
2 -2.5/8-12
2 -2.5/8
1.5 -2.5/8
1 -1.7/8
1 -1.7/8-12
LDEI
3.5 – 5 / 24-48
4 – 5 / 24-48
4 –7.5 / 24-48
4 –7.5 / 24-48
3.5 – 7 / 24-48
4 – 5 / 24-48
yrs)
Older geriatric (>75 yrs)
4 – 5 / 24-48
1 -1.7/12-24
For LDEI:
 Amikacin DM = 15 mg/kg for adults & 20 mg/kg in neonates.
 Increase  more than the recommended in reduced renal function.
 Free period: Time of zero drug concentration (should not be long) about 4 h.
 Dosing:
In the internet there is sites aides in measuring CrCl, DL or DM,
1. 80 mg/8 h * 3 (4.5 mg/kg/24 h) [if trough is not < 2 then extend / reduce dose to
half.
2. 7 mg/kg (peak/MIC = 10) q24, 36 0r 48 acc to CrCl [Hartford method, see table
below]
3. Adjust dose of n-renal function downward acc to pt.'s CrCl.
4. As usual of Cpeak (Respiratory infection: 16-20 mg/L, 60-80 amikacin, others
inf.:
10-12 (40-60 amik ) & Ctrough of < 1 mg/L).
Acc to # 2 above:
  (frequency): The initial dosing interval is determined by the creatinine clearance
(CrCl):
   2-3 t1/2
 Hartford method (white filling in table), use actual body wt except in obese use IBW.
CrCL
(mL/min)
>60
>60
Dosing interval
8 hrs
24 hrs
30-60
12
40-59
20-39
36 hrs
48 hrs
10-30
24
To achieve 10:1 peak to MIC ratio (MIC = 2 mg/L), total dose exposure is related to
toxicity.
See the supported nomogram.
Important clinical information:

CrCL (mL/min) < 10 ......................Give DL & measure "C" after 24 Hr




Patient > 65 yr with normal CLcr should NOT get q8h - use q12h.
Patient with SCcr > 1.2 mg% should NOT get q8 hr dosing initially.
Pregnant patients or Cystic Fibrosis patients may use q6h dosing.
Amikacin may be given as 7.5 mg/kg q12h in normal renal function.
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Step 6: Monitoring
Why?
 Ensure therapeutic peak concentrations
 Enhance clinical response
 Reduce toxicity
 Not in heparinized tube to reduce micelle formation and show lower conc., Use
EDTA.
Indications for serum concentration monitoring:





Patients with compromised and/or unstable renal function (CrCl <50 ml/min)
Courses of therapy of > 7 days
Suspected treatment failures
Pt receiving higher dosing rate
If the results are conflicting ask for another sampling with restrict order condition to avoid
misinterpretation.
Patients not requiring levels




Dosage regimen is adequate
CrCl >50 ml/min and stable (< 0.3 mg/dl changes in serum creatinine)
Course of therapy is < 7 days
Infections are unlikely to be complicated.
Frequency of serum level determinations:


Weekly levels are advised for patients with stable renal function
More frequently than once weekly in patients exhibiting conditions predisposing them to PK
variability such as:
(1) Fluid overload or dehydration
(2) Rises in SCr > baseline of > 0.3 mg/dl
(3) Acute cardiac, and/or renal decompensation.
(4) Severe hypotension (decreased renal perfusion)
(5) Hyperalimentation
(6) Ascites (increased Vd)
(7) Burn patients (usually see increases in kel)
(8) Cystic fibrosis patients (increases in kel)
(9) Surgery patients

Draw levels off the first dose for:
- Patients with abnormal renal function based on BUN/SCR; I/O's, edema, history of renal or
cardiac
disease.
- Patients receiving other nephrotoxic drugs.
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


- Patient is neutropenic, febrile, and/or unstable.
- Patient has unstable or increasing serum creatinine.
When to draw levels: 1st level: aminoglycoside: 30 minutes post infusion. 2nd level: at least one
half-life (depending on drug) after the 1st level.
Measurement after 2nd day of treatment, for early adjustment, may be at ss at that time.
Peak concentrations: (Once daily dosing)
Mild: (Gent/tobra: 12-16 . Amik: 30-40)
Moderate: (Gent/tobra: 16-20. Amikacin: 40-50 )
Severe: (Gent/Tobra: 20-24 Amikacin: 50-60)
Life-threatening: (Gent/Tobra: 24-28 Amikacin: 60-70)
 Monitor BUN & Serum creatinine at least q3 days (more frequently if unstable).
 Order initial level to be drawn 18 to 24 hours after the dose WHY?________________
*****Scr should be rechecked at least once every week.
In patients with adequate renal function (CLcr >60 mL/min):
 A trough aminoglycoside level should be near zero (<<1 mg/L).
 The initial  may be maintained
 No further drug levels are necessary as long as CrCl remains unchanged.
 If the trough level is > 1:

An extension of the  will be necessary.
 Alternatively, an accurately timed random level may be obtained at 7 - 14 hrs after the end of
infusion.
 To determine the proper , Plot the reported random level on a special graph which is applicable
to the gentamicin, netilmicin, and tobramycin.
  > 48 hr are not recommended. In such cases, alternative therapies (e.g., a fluoroquinolone)
should be considered.
 Patients who are anticipated to receive aminoglycosides for ≥7 days should have levels
monitored.


Patients who require monitoring, draw both Peak and Trough level.
Peak levels should be drawn 30 min after the end of infusion. Trough levels should be drawn
immediately before the next dose. Levels should be drawn around the 3rd or 4th dose to allow
the drug to reach steady-state.
Trough
Peak
Desired level (gentamicin, tobramycin)
<2 µg/ml (<1 mcg/ml optimal)
4-8 µg/ml
"Pulse" Dosing: Monitoring:
It should be noted that:
 A 24-hr  for patients with CLcr > 60 mL/min selected for convenience rather by pharmacokinetic
considerations.
12-PHCL462Handout#2/2




Indeed a 12 hourly dosing regimen may be more appropriate for young patients with CLcr >100 mL/min or
when the non-renal aminoglycoside clearance is elevated as in cystic fibrosis patients.
Using the 24-hrs  in these patients, the aminoglycoside level is likely to be nil for a period > PAE.
Ideally, the Peak/MIC ratio should be > 10, which is easily achieved in most patients.
Therefore, there is usually no need to measure the peak level except in patients with markedly expanded
volume of distribution. In these patients higher doses may be necessary to achieve an adequate Peak/MIC
ratio.
Patients who anticipated receiving aminoglycosides for ≥7 days should have levels monitored.
Draw a single trough level. Peak levels are not useful.
Trough level should be drawn <30 min before next dose.
It is not necessary to wait until before the third dose to draw this level.
Trough
Desired level (gentamicin, tobramycin)
<1 mg/ml (<0.3 mg/ml optimal)
Gram-positive combination dosing (“SYNERGY”) Combinations:
a. Aminoglycoside (Tobra, Gent) with beta-lactam antibiotics (PCN, semi-synthetic PCN,
cephalosporins) have shown synergistic activity towards staph. Aureus, Strep. faecalis etc.
b. In the treatment of pneumonia, meningitis, complicated urinary tract infections, osteomyelitis,
bacteremia, and peritonitis
c. Recommended in compromised host.
d. Streptomycin with PCN for acute brucellosis, bacterial endocarditis
e. Serious Gram-positive infection (e.g. endocarditis) being treated with a -lactam or
vancomycin.
Dosing & monitoring:
Draw peak and trough level.
CrCl
>60 ml/min
Dose (gentamicin)
1 mg/kg/dose IV q8h
Peak levels should be drawn 30 min after the end of infusion.
Trough levels should be drawn immediately before the next dose.
Levels should be drawn around the 3rd or
Desired level (gentamicin)
4th dose to allow the drug to reach steady≤1 mg/ml
state.
Trough
3 µg/ml
Peak
Adverse effects:
Major: Vestibular toxicity; auditory toxicity; renal toxicity (reversible); neuromuscular toxicity
(post-synaptic curare-like action).
Minor: skin rash; drug induced fever.
What to look for: Changes in urine output; BUN, creatinine, ototoxicity (hearing tests).
Aminoglcosides can cause serious adverse effects. To prevent or minimize such problems, plasma
drug concentrations, blood urea nitrogen (BUN) and SCcr levels should be monitored. Gentamicin and
streptomycin can cause primarily vestibular damage (manifested by tinnitus, vertigo, and ataxia). Such
damage may be bilateral and irreversible. Amikacin, kanamycin, and neomycin cause mainly auditory
damage (hearing loss). Tobramycin can result in both vestibular and auditory damage
Monitoring for toxicity:
1. Auditory and neuromuscular toxicity (2 - 26%): are not evaluated in most patients.
 Baseline and periodic assessment of hearing with audiometry are recommended.
13-PHCL462Handout#2/2
Neuromuscular toxicity (Associated with high - dose aminoglycoside therapy): Preexisting
neuromuscular disease / hypocalcemia.
Risk factors:
 advanced age
 renal dysfunction
 concurrent administration of other ototoxic/ a neuromuscular blocking or anesthetic drugs
 previous aminoglycoside exposure - prolong therapy

Elevated peak - trough concentrations.
 Preexisting hypocalemia , parkinsonism or myasthenia gravis (muscular disorder)
 intraperitoneal or rapid IV drug administration
Apnea and respiratory depression may be reversed with administration of calcium or an
anticholinesterase.
2.
Nephrotoxicity:
Mild renal dysfunction develops in up to 25% patients receiving these drugs
for several days or more because aminoglycosides accumulate in the proximal tubule, urine
concentration 5 - 10 times plasma, usually , this adverse effect is reversible on stopping the drug.
a. Neomycin is the most nephrotoxic aminoglycoside
b. Streptomycin is the least nephrotoxic
c. Gentamicin and tobramycin are nephrotoxic to about the same degree
d. Serum creatinine/serum drug should be monitored !!!!!!! ______________
e. Risk factors:
Renal dysfunction - concurrent administration of other nephrotoxic drugs
Previous aminoglycoside exposure
Prolong therapy
Elevated peak - trough concentrations
trough levels above _ g/mL for gentamicin and tobramycin and above __ g/mL for amikacin
Drug Interactions
IV loop diuretics - furosemide -ototoxicity: Furosemide may  ____   V and  __
concentrations

Other aminoglycosides, cisplatin, amphotericin B, and methoxyflurane - nephrotoxicity with
streptomycin

Collect Blood samples in heparin free tubes.

Cases & PK calculations - By Using:
1. The given Nomograms
2. PK equations for intermittent IV infusion & others in equation sheet.
C peak
Ro
ek t
 kt

(1  e )
Cl
(1  e k )
14-PHCL462Handout#2/2
Ctrough  C peake  k ( t t )
2. Vancomycin, Vancocin ®
It is a tricyclic glycopeptides bactericidal AB that is active against many gm-positive
organisms.
Treatment of severe &/resistant staphylococcal & enterococcal infections in pt. who
may be allergic to first-line AB (penicillin /cephalosporins)
No clear relationship between concentration & Clinical response.
o In fluctuating renal function
o Taking another nephrotoxic drugs
o Require higher than usual doses (> 4 g/day)
o Patients with unpredictable vancomycin PK e.g. dialysis, obese, pediatrics
Exhibits Concentration-independent killing.
o Time (T) > MIC (≤ 4 mg/L) is the critical determinant of therapeutic efficacy.
Minimal Bactericidal concentration (MBC) to the MIC ratio is used to monitor or
predict the response to therapy, only used in serious infection. MBC : MIC > 32
poor response to therapy.
Pharmacokinetics
The disposition is best characterized by 2or 3 C- model with t1/2s of α = 7 min, β = 0.5 1 h & γ = 3-9 h.
IV administration of vancomycin may results in Phlebitis and or a histamine- like
reaction: flushing, tachycardia, rash in the neck, back,… “Red neck syndrome” & may
hypotension or shock (slow infusion to ≤ 15 mg/min & pretreatment with antihistamine).
Key Parameters
Absorption:
Therapeutic plasma
Peak: 30-50
Poor oral absorption (<5%)
concentrations, mg/L Trough: 5-15
PO for local treatment of GI
<5
F (PO)
overgrowths of gm +ve
Not IM: irritation
0.7 (0.5 – 1)
V, L/kg
> 50 mg/L  ototoxicity
0.65 ClCr
Cl
MIC < 5 mg/L, therefore, trough is
7
t 1/2, h
better to maintain above 10 mg/L
45-70%
Fu
Volume of Distribution:
 A 2 or 3 C-model
 0.5 – 1 L/kg
 Bound to plasma protein 30-55%
 Reduced in end-stage renal disease to 19% and in burn patient to 29%.
Clearance:
 80-95% renally
15-PHCL462Handout#2/2


Cl = 0.6 – 0.7 ClCr
Several regression equations
have been tried to calculate
Vancomycin Cl as example:
Age
Infants (≥1 mo-<1yr)
Children (≥ 1- <16 yr)
Adults (≥ 16- <65 yr)
Geriatrics (≥65 yr)
Clr, L/h/??
3.47 ± 0.83/1.73 m2
8.45 ± 0.85/1.73 m2
0.073 ± 0.025/kg
0.053 ± 0.0034/kg
For Neonate and infants:
Cl (L/h/kg)= [(0.411*Clcr) + 0.541]*0.06 …… where, Clcr in ml/min
For Adults: Assume 1C:
Cl (L/h)= [(0.0.711*Clcr) + 18.9]*0.06 ……..… where, Clcr in ml/min
Caution in renal impairment .
Half-life:
 Terminal half- life 6-10 h
 7 days in end-stage renal disease (so   1-2 weeks)
 Intermittent IV doses of 500 mg over 30 to 60 min q12h (daily up to 2 gm but with
caution)
 K = 0.00083 Clcr + 0.0044……..… where, Clcr in ml/min
Dosing Nomograms: You should know how to use it, it is available
Time to sample:
 Wide swings in concentrations, so peak & trough should be monitored, trough if
only one!
 Peak 1-2 h after the end of infusion!!!!!!
 Measure trough after ≥ 5 days in stable renal function patient (it should be within ±
20% of the target value).
 1 hr after dialysis, get blood sample.
Vancomycin dosing methods
Below is a table summarizing the most popular vancomycin dosing methods. Stating the obvious, even
the experts can't agree on a single dosing strategy for all patients.
Vancomycin Dosing Methods
Source
Dose
Interval
500mg
Q 6 hrs
1g
Q 12 hrs
Package insert
Lake &
Peterson
16-PHCL462Handout#2/2
8 mg/kg
CrCl
90 and above
Interval
6 hrs
70 to 89
46 to 69
30 to 45
15 to 29
Matzke
DL = 25 mg/kg
DM = 19 mg/kg
See Figure 1 below
Moellering
See Figure 2 below
See Figure 2 below
Nielson
DL = 25 mg/kg
DM = [(15 x CrCl) + 150]
mg/day
Not specified
Rotschafer
6.5-8 mg/kg
Q 6-12 hrs
Figure.
17-PHCL462Handout#2/2
Matzke Vancomycin Dosing
8 hrs
12 hrs
16 hrs
24 hrs
Figure . Moellering Vancomycin Dosing
Concentration-related toxicity:
Ototoxicity (2%)
Nephrotoxicity (5%): with trough ≥ 10 mg/L
Scr should be monitored q3days for stable and qd for unstable renal function patients or
receiving nephrotoxic drugs (aminoglycosides, loop diuretics (frusimide) or
amphotericin B).
3. Digoxin
It is an inotropic agent.
 Primarily used in the treatment of Congestive heart failure
(CHF) & atrial fibrillation.
 Its molecular formula is C41H64O14, molecular weight is
780.95.
 Digoxin is supplied as 125 µg (0.125 mg) or 250 µg (0.25
mg) tablets for oral administration.
 Drug Product: Lanoxin, lanoxicaps, Digoxin Nativelle,
Lanoxin PG (WELLCOME, UK)
 Route of Administration: PO and IV
18-PHCL462Handout#2/2


Avoid IM injections-can lead to severe pain (If it must be given by this route, give
deep IM followed by massage).
Has a narrow therapeutic index
CLINICAL PHARMACOLOGY:
Mechanism of Action:
Digoxin inhibits sodium-potassium ATPase, an enzyme that regulates the quantity of sodium and
potassium inside cells.


Digoxin increases the contractility of myocardial contraction - Heart failure patient
C.O.P.;  heart size, venous pressure, and blood volume; dieresis - relief of edema
Slow the ventricular rate in atrial fibrillation or flutter

The effects of digoxin in heart failure are mediated by its positive inotropic and
neu-rohormonal deactivating effects, whereas the effects of the drug in atrial
arrhythmias are related to its vagomimetic actions.

In high doses, digoxin increases sympathetic outflow from the central nervous
system (CNS). This increase in sympathetic activity may be an important factor in
digitalis toxicity.
Therapeutic Uses:
1.
2.
3.
4.
Congestive heart failure: used regardless of whether the failure is predominantly of
left or right ventricle or both
Atrial fibrillation: even in absence of CHF
A trial flutter: large doses may be required
Paroxysmal tachycardia: Extremely important to be certain of the diagnosis and
etiology before using digitalis - it may be digitalis intoxication
Pharmacokinetics:
Two - Three compartmental models, linear PK within the therapeutic range
Therapeutic Range: 0.8 to 2.0 ng/ml (0.5 -1 ng/ml could be effective with less toxicity in
CHF)
For Atrial Fibrillation, patients may require higher concentration (2.6 ng/ml)
Neonate can tolerate higher concentration than adults due to in part to endogenous digoxin –like
substances.
Absorption:
Variable depending upon the formulation used:
Following oral administration, peak serum concentrations of digoxin occur at 1 to 3 hr.
Absorption of digoxin from Digoxin Tablets has been demonstrated to be 60% to 80% complete
compared to an identical intravenous dose of digoxin (absolute bioavailability) or LANOXICAPS®
[Digoxin Solution in Capsules] (relative bioavailability).
19-PHCL462Handout#2/2
Absorption is affected by Food, Delayed Gastric Emptying, Mal absorption Syndrome, MO
degradation of Digoxin to dihydrodigoxin-could be avoided by Neomycin or steroid-binding resins.
When Digoxin Tablets are taken after meals, the rate of absorption is slowed, but the total amount of
digoxin absorbed is usually unchanged.
When taken with meals high in bran fiber, however, the amount absorbed from an oral dose may be
reduced.
Comparisons of the systemic availability and equivalent doses for oral preparations of digoxin are
shown in Table 1.

In some patients, orally administered digoxin is converted to inactive products (e.g.,
dihydrodigoxin) by colonic bacteria in the gut.

Data suggest that one in ten patients treated with Digoxin tablets will degrade 40% or more of the
ingested dose. As a result,
o
Certain antibiotics may increase the absorption of digoxin in such patients.
o
Although inactivation of these bacteria by antibiotics is rapid, the serum digoxin
concentration will rise at a rate consistent with the elimination half-life of digoxin.
o
The magnitude of rise in serum digoxin concentration relates to the extent of bacterial
inactivation, and may be as much as two-fold in some cases.
Table 1: Comparisons of the Systemic Availability and Equivalent Doses for Oral Preparations of
Digoxin
Dosage Form
Absolute
Bioavailability
Equivalent Doses (µg)*
Among Dosage Forms
Digoxin Tablets
60 - 80% (0.7)
62.5
125
250
500
Digoxin Elixir Pediatric
70 -85% (0.8)
62.5
125
250
500
90 - 100% (0.9)
50
100
200
400
100%
50
100
200
400
Digoxin Solution in Gelatin Capsules
Digoxin Injection/IV
Table 2: Times to Onset of Pharmacologic Effect and to Peak Effect of Preparations of Digoxin
Product
Time to
Time to
Onset of Effect*
Peak Effect*, hrs
Digoxin Tablets
0.5 - 2 hrs
2-6
Digoxin Elixir Pediatric
0.5 - 2 hrs
2-6
Digoxin Solution in Capsules
0.5 - 2 hrs
2-6
Digoxin Injection/IV
5-30 min†
1-4
* Documented for ventricular response rate in atrial fibrillation, inotropic effects and
electrocardiographic changes.
† Depending upon rate of infusion.
Distribution:

Two–C model with Vc  1/10 Vβ.
20-PHCL462Handout#2/2
 Distributed slowly in the body, It has a large volume of distribution & is widely distributed to lean
tissues, including the heart, brain, erythrocytes and skeletal muscles.
 Tissue concentrations > 60 -100 times plasma concentrations.
 Heart Failure will increase the time to reach steady state
  K+, Mg++ , or Ca++ ions (also in hyperthyrodism) in extracellular fluid will ____ Digoxin
plasma concentration and tissue binding.

Following drug administration, a 6- to 8-hr tissue distribution phase is observed.

This is followed by a much more elimination gradual decline in the serum concentration of the
drug,

The peak height and slope of the early portion, (absorption/distribution phases) of the serum
concentration-time curve are dependent upon the route of administration and the absorption
characteristics of the formulation.

Clinical evidence, with chronic use, the steady-state post-distribution serum concentrations are
in equilibrium with tissue concentrations and correlate well with pharmacologic effects.

In individual patients, these post-distribution serum concentrations may be useful in evaluating
therapeutic and toxic.

Digoxin is concentrated in tissues and therefore has a large apparent volume of distribution.

Digoxin crosses both the blood-brain barrier and the placenta.

At delivery, the serum digoxin concentration in the newborn is similar to the serum concentration
in the mother.

Approximately 25% of digoxin in the plasma is bound to protein.

Serum digoxin concentrations are not significantly altered by large changes in fat tissue weight,
so that its distribution space correlates best with lean (i.e., ideal) body weight, not total body
weight.

Decreased in patients with renal impairment! Why? Therefore, the DL should be decreased.

In patients with reduced renal function the following equations are the most used ones to
estimate V:
𝑽 𝑳/𝟕𝟎𝒌𝒈 = 𝟐𝟐𝟔 +
𝟐𝟗𝟖+𝑪𝒍𝑪𝒓
𝟐𝟗+ 𝑪𝒍𝒄𝒓
[Where, Clcr /70 kg if pt >/< 70 adjusted to 70 kg]
V (L) = 3.8 (L/kg) * IBW (kg) + (3.1) * Clcr
Metabolism:
Only a small percentage (16%) of a dose of digoxin is metabolized Clm = 0.57-0.86 ml/min/kg. It may
be decreased to ½ its value in CHF.
The metabolism of digoxin is not dependent upon the cytochrome P-450 system, and digoxin is not
known to induce or inhibit the cytochrome P-450 system.
Excretion:

Follows first-order kinetics
Excreted by GF & ATS; TR also occurs.
 t1/2 depends upon the renal function - CrCl, age…

21-PHCL462Handout#2/2
 Renal Failure-  elimination and  uric acid in the blood so  V
 Vasodilators administration - change renal perfusion - affect elimination rate
 Following IV administration to healthy volunteers, 50% to 70% of a digoxin dose






is excreted unchanged in the urine.
Its excretion is proportional to GFR and is largely independent of urine flow.
In healthy volunteers with normal renal function, digoxin has a half-life of 1.5 to
2.0 days.
The half-life in anuric patients is prolonged to 3.5 to 5 days.
Digoxin is not effectively removed from the body by dialysis, exchange
transfusion, or during cardiopulmonary bypass because most of the drug is
bound to tissue and does not circulate in the blood.
The clearance of digoxin can be primarily correlated with renal function as
indicated by CrCl.
Plasma digoxin concentration profiles in patients with acute hepatitis generally
fell within the range of profiles in a group of healthy subjects.
Cl (ml/min) = (0.8 ml/min/kg) (IBW kg) + CLCr (ml/min)
(Without CHF).
Cl (ml/min) = (0.33 ml/min/kg) (IBW kg) + (0.9)*CLCr
(With CHF).
If concomitant quinidine, multiply by 0.559
Review of main points:
Average DL , PO
0.75 - 1.25 mg
IV (digitalization)
1.0 - 1.5 mg/70 kg
________________________________________
Average DM, PO
0.125 - 0.5 mg
IV
0.25 mg/day
________________________________________
Plasma Protein binding
20 - 30%
________________________________________
Elimination t1/2 , Normal
1.6 days
Renal failure
 4.4 days
_________________________________________
Therapeutic range
0.5 - 2.0 ng/ml
_________________________________________
Volume of Distribution*
7.3 L / kg
_________________________________________
Cl**
57 ml/min + 1.02 Clcr
_________________________________________
*Cardiac tissue concentration may be > 100 times plasma
V is reduced in patients with renal disease, hypothyroid & on quinidine
** Altered by renal, thyroid diseases & CHF & quinidine.
22-PHCL462Handout#2/2
Dosing information
ADULT DOSE:
Safe digitalization: 0.015 mg/kg (0.01 - 0.02 mg/kg)
Rapid digitalization: ( mod. to sever cases )
DL = V / Kg * IBW * C
V = 7.3 L/kg
C = 1.0 - 2.0 ng/mL
Loading dose:
CHF: 8-12 µg/kg in divided doses (q4-8h) over 12 to 24 hours. [Normally, give 50% of the total
digitalizing dose in the initial dose, then give 25% of the total dose in each of the two subsequent
doses at 8 to 12 hr intervals
Obtain EKG 6 hours after each dose to assess potential toxicity (AV block, sinus bradycardia,
atrial or nodal ectopic beats, ventricular arrhythmias); Other: vision changes, confusion.]
Renal: If pt has renal insufficiency give 6 to 10 µg/kg IBW.
The purpose of this method is to:
** to minimize toxicity
** to rapidly achieve therapeutic effect
Procedure of Loading Patient:
Maintenance dose:
DM is based on patient's CLr / Clcr
Predicted Css= (Dose/) (F)/ Clearance.
F = 0.65 to 0.8
Or % ELIMINATED DAILY = 14 + (Clcr/ 5)
DM


= V/Kg * IBW * C * ( % Eliminated Daily )
F
SLOW DIGITALIZATION: ( mild cases )
DL should be given over 3 day period & DM same calculation
Pediatric dose:
Total digitalizing dose ( TDD ):
Premature baby
= 20 g/kg ( IV )
Full term baby
= 30 - 50 g/Kg ( IV )
60 - 80 g/Kg ( PO )
2 - 6 YEAR OLD = 20 - 40 g/Kg ( IV )
40 - 60 g/Kg ( PO )
Greater than 10 Yr = 0.75 - 1.25 mg ( IV / PO)

Procedure of giving dose:
1. Give 1/2 of TDD initially
2. Then 1/4 of TDD q 6 - 8 hr
3. Then give remaining 1/4 of TDD

Maintenance Dose:
< 10 yr 20 - 30 % OF TDD/day in 2 divided doses
PO DOSE IS 1.3 times the IV dose
Therapeutic serum level = 0.5 - 2 ng/mL
23-PHCL462Handout#2/2
Parameters to monitor:






2. K level
1. Scr
3. serum digoxin level
4. ECG
5. Fluid/electrolyte status
Obtain blood samples at least 4 hrs after IV dose and 6-8 hrs after oral dose.
Obtain first level within 24 hours of digitalization.
Monitor BUN and serum creatinine q 2 days (qd if unstable).
Monitor apical pulse daily.
Onset/peak:
o IV: 5-30 min/ 1-4hr
o Oral: 1-2hr/ 2-8 hr.
Time to steady state: 5-7 days (average) ESRD: 15-20 days. Half-life: 38-48 hrs.
(anephric: 46 days).
 Conversion from oral to IV:
 Decrease IV dose by 20 to 25%.
 When the maintenance dose is given IV, the onset and peak will occur earlier, however
the duration of action is the same.
 Patients' on the "floors" may receive once daily IV maintenance doses, however, IV
loading regimens (multiple doses) are restricted to pts on a monitor- ICU's. [Oral
bioavailability (tablets): 70 to 80%].
Factors that increase likelihood of digoxin toxicity: Hypokalemia, hypomagnesaemia,
hypothyroidism, renal dysfunction, interacting drugs (eg quinidine, verapamil).
Obtaining levels:
Due to long distribution phase and long t1/2 determine serum digoxin levels at least 4 hours after
an IV dose or 6 hours after an oral dose in order to allow sufficient time for drug distribution.
An annual sampling is enough for stable patients.
Storage conditions:
AIR TIGHT CONTAINER; PROTECT FROM LIGHT
Contraindications:






Ventricular fibrillation
Hypertrophic obstructive cardiomyopathy
Wolf-parkinson-white syndrome especially if accompanied with atrial fibrillation since it may
precipitate vent. tachyacrdia or fibrillation
Use with caution in heart block; complete heart block may be induced if cardiac glycosides are
used in partial heart block.
Use with caution in acute myocarditis
Give with care in patients who have received cardiac glycosides before.
24-PHCL462Handout#2/2
Pregnancy: Digoxin is not known to be teratogenic to treat



fatal CHF
Maternal digitalis toxicity has been associated with fetal toxicity and miscarriages
Maternal plasma level should be monitored closely, because as pregnancy progresses this leveldecreases due to an increase in the volume of distribution
Breast feeding:

Digoxin is excreted in milk in levels approaching maternal plasma level - this constitutes an
insignificant dose for the infant. Therefore, breast feeding is safe during digoxin therapy.
Adverse effects
Sinus bradyarrhythmias; AV block; N/V/D; yellow vision and hallucinations; supra and
ventricular arrhythmias. Contraindications: V-fibrillation; hypokalemia; WPW syndrome with
wide complex.
These adverse effects occur due to the fact that digoxin has a narrow therapeutic index
______________________________________________________________________________
GIT
CNS
VISUAL
CARDIAC
______________________________________________________________________________
Nausea
Headache
Hazy Vision
Abnormal ECG
Vomiting
Facial Pain
Impaired RedAtrial Or Vent.
Green Color
Arrhythmia
Anorexia
Weakness
Photo Yellow
Cause/Aggravate HF
Diarrhea
Dizziness
Green Tinge
Defect In Conduction
Abdominal Pain
Drowsiness
Difficulty In Reading
Disorientation
Hallucination
Convulsions
______________________________________________________________________________
Drug Interaction
________________________________________________________________________
DRUG NAME
EFFECT
________________________________________________________________________
ANTACID, KAOLIN-PECTIN
 F- by  absorption (Time – dependent: 20% if 2 hr apart
CHOLESTYRAMINE
or 62% if given concomitantly)
________________________________________________________________________
Neomycin
Mal-absorption of digoxin.
Sulphasalazine
________________________________________________________________________
Laxatives
 F- via hypermotility
________________________________________________________________________
Metoclopramide
 F -via enhanced gastric emptying
________________________________________________________________________
Propantheline
 F - via slowed gastric emptying
25-PHCL462Handout#2/2
________________________________________________________________________
Erythromycin
F IN PERSONS NORMALLY METABOLIZE DIGOXIN IN
GIT
________________________________________________________________________
Quinidine
 Serum digoxin level - 24 hr - 2X – ( Clr & FuT)
You may  digoxin dose by 50%
________________________________________________________________________
Amiodarone
(Displace Digoxin from tissue binding and  Clr/ClNR
Ca channel blockers
(40 ->70%) Dose - dependent)
_______________________________________________________________________
St. John’s Wort
Reduced digoxin absorption (inducing P-gp)
26-PHCL462Handout#2/2