pk & pd aspects of drugs in critically ill population

Dalia A. HamdyBPSc, MSc, PhD, RP(ACP), MRSC

5th February [email protected]

Pharmacokinetics and Pharmacodynamics Aspects of

Drugs in Critically Ill PopulationPart I

mailto:[email protected]

Dr. Dalia A. Hamdy (FS15AY)2

Learning Objectives1. Describe the changes in critically ill patients that alter drug absorption.

2. Explain how critical illness affects the distribution of drugs.

3. Depict the effects of changing hepatic blood flow and protein binding on drug metabolism.


Learning Objectives.4. Differentiate between different critically ill patient populations and the expected pharmacokinetic (PK) changes.

5. Incorporate the PK changes in a critically ill patient into the design and evaluation of an appropriate drug regimen.

6. Identify the desired pharmacodynamic parametersassociated with efficacy in select drugs.


Session Outline (Part I) Introduction to Clinical Pharmacokinetics and

individualization of therapy

Self Assessment Case

Quick discussion on routes of drug administrations

Critically Ill patients PK alterations in terms of -Absorption-Distribution-Metabolism


References Swanson JM. Updates in Therapeutics®: Critical Care

Pharmacy Preparatory Review Course. 2015 Edition. The American College of Clinical Pharmacy. Pharmacokinetics/Pharmacodynamics Chapter.

Shargel L, Wu-Pong S, Andrew B.C.U. Applied Biopharmaceutics and Pharmacokinetics. 5 th Edition. McGraw-Hil ; 2005

Gibson G and Skett P. Introduction to Drug Metabolism. 3rd Edition. Nelson Thrones ; 2001.

Russel F.G.M. Transporters: Importance in Drug Absorption, Distribution, and Removal. Enzyme- and Transporter-Based Drug-Drug Interactions. Elservier; 2010.


Clinical PharmacokineticsDiscipline that describes ADME of drugs in patients requiring therapy.


Clinical PharmacokineticsIndividualization of Therapy


Clinical Pharmacokinetics

Pharmacokinetics Variability

Effect of Special populations

Effect of different diseases and

conditions

PK drug interactions (ADME)


Special Population: Critically Ill Patients

Why are ICU/critically ill patients considered special population with respect to their drug PK and PD?



Visit Your Patient E.W. is a 48-year-old man (height 70 inches, weight 85 kg) admitted to the trauma ICU after a motorcycle collision. E.W. presents with a traumatic brain injury (TBI; head computed tomography [CT] reveals a depressed skull fracture, frontal subarachnoid hemorrhage, and right intraparenchymal hemorrhage), right acetabulum fracture, bilateral rib fractures, and abdominal trauma. According to his abdominal CT, E.W. must go to the operating room for an exploratory laparotomy to undergo repair of several serosal tears. After surgery, E.W. requires significant resuscitation in his first 24 hours of admission (12 L of normal saline). He is made NPO (nothing by mouth) to allow bowel rest.



Visit Your PatientE.W.’s laboratory values are as follows: serum creatinine (SCr) 1.1 mg/dL, blood urea nitrogen (BUN) 17 mg/dL, and white blood cell count (WBC) 19 × 10cells/mm3. Pulmonary artery catheterization values are cardiac index 4.2 L/minute/m2 (normal 2.8–3.6 L/minute/m) and central venous pressure 9 mm Hg. His medication therapy includes a fentanyl continuous infusion of 75 mcg/hour, a propofol continuous infusion of 15 mcg/kg/minute, pantoprazole 40 mg intravenously every 24 hours, enoxaparin 30 mg subcutaneously every 12 hours, and phenytoin 150 mg intravenously every 8 hours.


Special Population: Critically Ill Patients1. Routes of Administration:

What are the common routes of drugs administration ?

Pros?Cons?



IV -Bolus

-Infusion

- Most widely used in such population

- F=1, 100% bioavailability- Poor penetration to tissues as

bones, pulmonary and meninges- Septic shock, poor penetration

to subcutaneous and muscle tissues

- Extravasation!



Oral/Enternal

- Not commonly used in such population

- F<1, bioavailability?!- Variability increase



Subcutaneous

/Intramuscular

- Escape the first pass, better F than oral

- Still require absorption



Inhalation

- Commonly used for localized treatment

- To result in higher concentrations at site of action and decrease systemic side effects

- Examples?!



Intrathecal/intraventric

ular

- Commonly used for localized treatment

- No clinical evidence of superiority over other routes of administration

- Commonly used for treatment of multidrug resistant meningitis


Special Population: Critically Ill Patients2. AbsorptionClinicians must consider several factors if a route of administration other than intravenous is desired due to bioavailability variations

Bioavailability The rate and extent to which the active ingredients is absorbed and available at systemic circulation

Reminder


Special Population: Critically Ill Patients2. Absorption

Bioavailability

F = AUC test X Dose reference

AUC reference Dose test

If test=IV Absolute BioavailabilityIf test=other route Relative

Bioavailability

Time

Concentration

Ka K Cp Dose


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:1. Hypotension or ShockShifts away the blood from muscles, skin, splanchnic organs to vital ones as brain, heart and lung

-May decrease GIT (oral ) absorption ( no clinical studies evidence yet)

-subcutaneous, transdermal and intramuscular routes?!


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:2. Vasopressor effect Vasopressins (epinephrine, Dopamine,

norepinephrine) - reduces splanchnic blood flow in patients with distributive shock and severe septic shock - Conversely, it results in higher intestinal

perfusion in vasodilatory shock

The variable effect of vasopressors on splanchnic perfusion makes most clinicians abandon the use of orally or enterally administered drugs when vasopressors are being used.


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:2. Vasopressor effect

One study investigated the anti-Xa activity of the low-molecular-weight heparin certoparin in critically ill patients. Less than 50% of patients receiving standard doses of certoparin had anti-Xa activity in the antithrombotic range (0.1–0.3 IU/mL)

Crit Care 2005;9:R541-8


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:3. Intestinal Atrophy- After 3–5 days of fasting, gut mucosal crypt depth and villus height decrease Increase gut permeability- The decreased perfusion worsen this caseThus Increase drug absorption Decrease blood absorption No effect

Discuss!


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:4. GIT dysmotility- Has an incidence of 60% in such population- This results in delayed gastric emptying

SO? What is expected in the absorption curve profile?

GI dysmotility is generally treated using prokinetic agents such as metoclopramide or erythromycin.

Discuss!


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:4. GIT dysmotility


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:4. Intestinal drug transporters

What are drug transporters?!



- Drugs enter to cells through diffusion and active transport.

- Active transport is through transporters (Membrane transport proteins)

- Active transport can be divided into - Primary: does not require ATP- Secondary: uses energy



Transporters:- Play a critical role in absorption, distribution, and

excretion of drugs.

- There are two main classes of transporters - Solute carriers (SLC)

- ATP binding cassette (ABC)


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:4. Intestinal drug transportersSolute Carriers (SLC) Transporters:Can be further divided into:-- Organic anion transporting peptide (OATp)

- SLCO family of genes - Organic anion transporter (OAT)

- acidic drug transport - Part of SLC22A family of genes

- Organic cation transporter (OCT) - Basic drug transport - Part of SLC22A family of genes


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:4. Intestinal drug transportersATP binding cassette (ABC):The subfamilies mostly involved in drug transport are ABCB, ABCC, ABCG examples:

ABCB1 : P-glycoproteins (P-gp)/ Multidrug resistance protein (MDR)

ABCC2: Multidrug resistance associated protein (MRP2)

ABCG2: Breast cancer resistance protein (BCRP)


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:4. Intestinal drug transportersTransporters:- Mechanistically they are divided into

- Influx/Uptake transport proteinsImport drugs into the cells and do not usually require energy

- Efflux transportersExport drug out of the cell. Usually against concentration gradient therefore they need energy


Role of transporters in Absorption EnterocytesPEPT1: peptide transporter SLC15A family of genes -Role of P-gp in oral absorption?- Digoxin- Tacrolimus

Role of PEPT1:acyclovir oral bioavailability was enhanced by a factor of 2–3 via its valine ester (valacyclovir), which is a PEPT1 substrate


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:4. Intestinal drug transportersNo PK studies related to effect of critical illness on transporters.

However, inflammatory response syndrome (SIRS) and sepsis affect PGP activity. Therefore, enteral drug absorption has the potential to be altered in these states.

Further studies needs to be pursued.


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:5. Physical incompatibilitiesDrug enteral nutrition interaction-Ciprofloxacin bioavailability decrease when administered with food-levothyroxine, phenytoin, warfarin and voriconazole, reduced absorption

Suggested solution? Your own practice?


Special Population: Critically Ill Patients2. AbsorptionIn critically ill patients:5. Physical incompatibilities-pH changes alters the drug ionization thus their lipophilicity and potentially absorption. -Increased gastric pH caused by histamine-2 receptor antagonists or proton pump inhibitors,

decreased absorption of ketoconazole, itraconazole, atazanavir, cefpodoxime, and dipyridamole.

increased nifedipine ,digoxin and alendronate absorption

Aliment Pharmacol Ther 2009;29:1219-29


Special Population: Critically Ill Patients2. Absorption Clinicians usually avoid enterally administered drugs

because of variability in bioavailability

If the drug is given orally , we can withhold nutrition to avoid physical incompatibilities.

Subcutaneous and intramuscular routes also have similar problems with absorption. However, some clinicians advocate for using larger doses of drugs being administered subcutaneously.

(safety and efficacy studies needs to be further pursued)

Clinical Consideratio

ns


Special Population: Critically Ill Patients2. Absorption


Summary!

Dr. Dalia A. Hamdy (FS15AY) 43

Drug Absorption Distribution


Rate ExtentThe reversible movement of drug from one location to another in the body

3. Distribution

VdDistribution t1/2

Tissue permeability:

Depends on physicochemical properties of drug

Molecular size

Lipid solubility

Drug ionizationDr. Dalia A. Hamdy (FS15AY) 44


Drug Permeability

3. Distribution

Protein BindingPlasma Tissue



Drug-Protein

Protein + Drug

Elimination

Drug + Protein

Drug-Protein

3. Distribution


Special Population: Critically Ill Patients3. Distribution

Plasma proteins:

Albumin Binds mostly acidic drugs (diazepam, phenytoin)

AAG Binds mostly basic drugs (Lidocaine, diltiazem)

Lipoproteins Binds lipophilic drugs



Vc= Dose/Co

Vc= volume of distribution of central compartmentC0= concentration at zero time

Vdβ= CL/KK= elimination rate constant

Remember : Vd and CL are independent variables


Special Population: Critically Ill Patients3. DistributionIn critically ill patients:Shock states cause the redistribution of blood flow

- perfusion of the muscle, skin, and splanchnic organs.

- Hydrophilic drugs with a smaller Vd (ones that remain in the plasma water volume) may have decreased distribution to parts of the body with decreased blood flow.

Example: Animals with septic shock showed lower gentamicin concentrations in the microcirculation compared with the central vessels.


Special Population: Critically Ill Patients3. DistributionIn critically ill patients:Receiving significant volumes of intravenous fluid for resuscitation purposes.

volumes of total body water and interstitial fluid. Disease states such as sepsis, thermal injury, acute respiratory distress syndrome, AKI, heart failure, and cirrhosis

interstitial fluid volumes. In addition,


Special Population: Critically Ill Patients3. DistributionIn critically ill patients:surgery extracellular volume postoperatively.Thus Vd for hydrophilic drugs and decrease their serum/tissue concentration & Vd for lipophilic drugs

Examples:Compared with healthy volunteers, patients with septic shock had reduced piperacillin tissue concentrations.


Special Population: Critically Ill Patients3. DistributionIn critically ill patients:.

Unfortunately, increased Vd of drugs is not universally noted. Although one study found increases in aminoglycoside Vd, another study was unable to correlate fluid shifts with changes in the aminoglycoside Vd

Crit Care Med 1988;16:327-30


Special Population: Critically Ill Patients3. DistributionIn critically ill patients:. Stress

Albumin

AAG

What will happen?!


Special Population: Critically Ill Patients3. DistributionIn critically ill patients:. The clinical relevance of this was noted

when a decrease in the Vd of lidocaine correlated with an increase in AAG in post-cardiac surgery patients. It was suspected that arrhythmias were caused bythese PK changes

Clin Pharmacol Ther 1984;35:617-26



IMP!


Special Population: Critically Ill Patients3. DistributionIn critically ill patients:pH acid-base disorders are common creating a plasma pH changes that alters the drug ionization thus their lipophilicity and tissue penetration. ionized drug has smaller Vd

Theoretically: drug that is a weak acid in a patient experiencing

acidemia would be expected to have a larger Vd the converse would be true for a basic drug.

Evidence in humans is lacking!


Summary!

4. Metabolism Xenobiotics undergo biotransformation

before being eliminated from our body.

Drug Metabolism, mainly in liver, is usually divided into 2 Phases:

Phase 1: Functionalization reactions (introduction of a functional group)

Phase 2: Conjugative reactions(Conjugation with endogenous compounds)Dr. Dalia A. Hamdy (FS15AY) 59


4. MetabolismPhase 1 metabolism

By introducing or unmasking more polar a functional gp

more readily excretable



Chemical reactionsOxidationReductionHydrolysisHydrationIsomerizationDethioacetylation

Phase 1 metabolism


Drug Metabolism

Chemical reactions

Enzymes involved Location

Oxidation Cytochrome P450, Flavin monooxygenase, Alcohol/aldehyde dehydrogenase, Monoamine oxidase

Smooth Endoplasmic reticulum

Reduction

Cytochrome P450, NADPH-cytochrome P450 reductase, carbonyl reductase

Smooth Endoplasmic reticulum

Hydrolysis

Epoxide hydrolase, Amidases Cytosol

4. MetabolismPhase 2 metabolismBy conjugation with an more polar endogenous substance and water

soluble

more readily excretable in

urine or bileDr. Dalia A. Hamdy (FS15AY) 62


Chemical reactionsGlucuronidation/glycosidationSulfationMethylationAcetylationAmino acid conjugationFatty acid conjugation

Phase 2 metabolism

- Conjugation reactions are mostly located in the cytosol except for glucuronidation which occurs in endoplasmic reticulum

1. UDP-Glucuronosyl transferase2. Glutathione S-transferase3. Sulfotransferase4. Amino acid transferase5. N-acetyl transferase6. N-, O-, S- methyl transferase


Drug Metabolism

Cytochrome P450-Dependant Mixed Function Oxidation Reactions:Mixed function oxidases are membrane proteins compose of

- CYP P450- NADPH dependent CYP P450- Phospholipids


Drug Metabolism

Cytochrome P450-Dependant Mixed Function Oxidation Reactions:


Drug Metabolism


CYP P450:- Terminal oxidase component of an

electron transfer system present in ER

RH ROH- It is a haem-containing enzyme

(haemoprotein called protoporphyrin IX)


Drug Metabolism


CYP P450:

- Nomenclature is derived from the fact that the cytochrome exhibits a spectral absorbance maximum at 450 nm when reduced Fe(II) heme binds to CO.

- Is a family of enzymes rather than a single enzyme


Drug Metabolism

Cytochrome P450-Dependant Mixed Function Oxidation Reactions:CYP P450 Nomenclature :

- Family: CYP + Arabic numerical (share > 40% homology of amino acid sequence ex: CYP1 , CYP2, CYP3..etc)

- Subfamily: Additional letter (share > 55% homology of amino acid sequence ex: CYP1A , CYP2D, CYP3A..etc)

- Isoenzyme : Additional Arabic number ex: CYP3A4


Drug Metabolism

Cytochrome P450-Dependant Mixed Function Oxidation Reactions:CYP P450 Nomenclature :

- Italics indicates genes (CYP3A4)

- Regular fonts indicate enzymes (CYP3A4)

- Small letters indicate mouse enzymes (cyp1a1)

http://study.hiberniacollege.net/novartis/2014/novartis_clpap/session3/task0/novartis_clpap_s3_t0_s3/presentation.html


Drug Metabolism





4. MetabolismRenal Metabolism – There is evidence that the kidneys express the CYP isoenzymes 2B6, 3A5, 1A9, 2B7. CYP 2C8, 2C9, and 3A4. are also expressed in

the kidneys. In addition, UGT (UDPglucuronosyltransferase)

No data related to effect of critical illness on such kidney enzymes



4. MetabolismRenal Metabolism – Critically ill patients with AKI have clinically relevant changes in insulin metabolism, as evidenced by increased hypoglycemic events and lower insulin requirements upon developing AKI

(Nutrition 2011;27:766-72).



4. MetabolismHepatic Metabolism

Hepatic ClearanceCLT= CLr + CL nr

=CLr + CLH + CL other



Hepatic clearance

First PassPortal vein

Hepatic ClearanceHepatic artery

Extraction ratio (E)The fraction of the drug that is extracted

(removed) by the organ upon each pass of blood through the organ

E= (Cin-Cout)/(Cin)


Liver CoutCin


Extraction ratio (E)

Factors affecting rate of drug extraction by organ:

1. Blood Flow (Q)2. Intrinsic ability of organ to remove drug(Number and affinity of enzymes)

CLorgan= Q. E

Q of liver is 1500 mL/min in a healthy 70 Kg man (learn)Dr. Dalia A. Hamdy (FS15AY) 74


Hepatic extraction ratio is dependant on the1. Hepatic Blood Flow (Q)2. Clearance intrinsic:Maximum volume of blood that could be cleared

from drug over a period of time

E= CLint/(Q+CLint)

CLorgan= Q. CLint



Q+CLin

t

Hepatic Clearance and unbound fraction

Organ Clearance is dependant on unbound fraction

WHY?




Organ Clearance is dependant on unbound fraction

CLint = fu . CLint’

CLint = intrinsic clearance total (unbound+bound)fu = unbound fractionCLint’= intrinsic clearance for unbound drug






CLhepatic= Q. fu.CLint’Q+ fu.CLint’

Classification of E

1. High E > 0.72. Intermediate E between 0.3 and

0.73. Low E < 0.3



1. High E > 0.7

Clhepatic = Q. CLint



Q+ CLint

Clint>>>>>Q

1. low E < 0.3

Clhepatic = Q. CLint



Q+ CLint

Q>>>>>CLint

fu.CLint’

Relationship between E and FF=1-ER

F = hepatic Bioavailability

E = Hepatic extraction ratio




High Extraction Ratio Drugs Discuss


Low Extraction Ratio Drugs Discuss

1. Increased hepatic blood flow2. Decreased hepatic blood flow

-Low cardiac ourput In hypovolemia or hemorrahgic shock, myocardial

infarction, acute heart failure

-Mechanical ventilation increase intrathoracic pressure, thus decrease venous return to the heart, compresses the ventricles, and reduces ventricular filling.The result is a decrease in cardiac output and hepatic blood flow

-Adding inotropic improves hepatic blood flow




End of Part I

Dalia A. HamdyBPSc, MSc, PhD, RP(ACP), MRSC

12th February [email protected]

Pharmacokinetics and Pharmacodynamics Aspects of

Drugs in Critically Ill PopulationPart II

mailto:[email protected]


Session Outline (Part II) Critically Ill patients PK alterations in terms of --Elimination

Pharmacodynamics of drugs and special considerations in critically ill patients

Quick overview of TDM

Solving questions

1. Increased hepatic blood flowCritically ill patients in the hyperdynamic phase of sepsis or septic shock have an increased cardiac output and increased hepatosplanchnic blood flow.

However, This was not confirmed in all studied, Thus

such patients are left with a potential of……..?



2. Decreased hepatic blood flow

-Low cardiac ourput In hypovolemia or hemorrahgic shock, myocardial

infarction, acute heart failure

-Mechanical ventilation increase intrathoracic pressure, thus decrease venous return to the heart, compresses the ventricles, and reduces ventricular filling.The result is a decrease in cardiac output and hepatic blood flow

-Adding inotropic (ex. Dobutamine) improves hepatic blood flow




Special Population: Critically Ill Patients3. Effect of Changes in Intrinsic Clearance- Drug interactions Critically ill patients do not have major altered intrinsic clearance

However, polypharmacy, complex pharmacotherapeutic regimens, in such patients can result in drug interactions

Many drugs used in critically ill patients are substrates, inducers, inhibitors, or combinations of these.


Special Population: Critically Ill Patients3. Effect of Changes in Intrinsic Clearance-Drug interactions Inflammation : SIRS, Systemic Inflammatory response syndrome, Early sepsis, increase inflammation.

-The inflammatory cytokines interleukin (IL)-1α, IL-6, and TNFα (tumor necrosis factor alpha) decrease the expression and activity of CYP enzymes.

Effect?? Discuss


Special Population: Critically Ill Patients3. Effect of Changes in Intrinsic Clearance-Hypothermia – Animal models have shown that hypothermia affects drugs metabolized through the CYP system.

Phenytoin PK showed increased concentration and reduced metabolism during mild hypothermia but no changes in protein binding. (Ther Drug Monit 2001;23:192-7)

Midazolam, fentanyl, remifentanil, phenobarbital, and vecuronium have decreased hepatic clearance during hypothermia..

Discuss


Special Population: Critically Ill Patients3. Effect of Changes in Intrinsic Clearance- AKI – AKI results in impaired CYP3A activity

Example Patients with worsening AKI, as determined using the RIFLE (risk, injury, failure, loss) criteria, had increasingmidazolam concentrations.

(Intensive Care Med 2012;38:76-84)


Special Population: Critically Ill Patients3. Effect of Changes in Intrinsic ClearanceNote

Critically ill patients generally have more than one changeoccurring at the same time.

Septic shock patients have -increased hepatic blood flow, increased cardiac output

-inflammation and decreased intrinsic clearance .The clinician needs to monitor patients and be ware of potential toxicities

This would affect who?? Discuss


Summary!

5. ExcretionA. Renal Excretion:The processes by which drug is excreted:

1. Glomerular Filtration

2. Active Secretion

3. Tubular reabsorption

ICU patients clinical condition result in altered renal excretion



5. ExcretionA. Renal Excretion:1. Filtration GFR is used to describe kidney function. The National Kidney Foundation defines normal kidney function as

140 ± 30 mL/minute/1.73m2 for young healthy men126 ± 22 mL/minute/1.73m2 for young healthy women



5. ExcretionA. Renal Excretion:1. FiltrationCL due to glomerular filtration CLgf

CLgf= fu X GFR

fu= unbound fraction




Dose adjustment in Renal and hepatic diseases

Measurement of glomerular filtration rate

1. Inulin: Fructose polysaccharide, a standard

reference for measurement of GFR

However, time consuming procedures

Thus not frequently used in clinical practice



Measurement of glomerular filtration rate2. Creatinine clearance

Extensively used as measure for GFR

Creatinine: an endogenous substance formed during muscle metabolism. Varies according to age, weight, and gender Filtered mainly at the glomerulus , no renal reabsorption but

small amount is actively secreted.

GFR values from CLcr > that obtained from inulin



5. ExcretionA. Renal Excretion:

1. FiltrationIn critically ill patientssurgery, trauma, burns, and sepsis

Increased cardiac output and vasodilatation

Increased renal blood flow Thus?



5. ExcretionA. Renal Excretion:1. Glomerular hyperfiltration (CrCl elevated)

2. Vancomycin, ciprofloxacin, imipenem, fluconazole, and aminoglycoside renal elimination was found to increase in burn patients



5. ExcretionA. Renal Excretion:

3. Fluid administration improve cardiac output and thus renal blood flow in animals but not in humans

4. Vasoactive drugs, vassopressors, norepinephrine; would be expected to improve cardiac output and thus renal blood flow.



5. ExcretionA. Renal Excretion:Impaired renal function

Critically ill patients have 78% incidence of AKIDecreased renal excretion of drugs




As per the updated guidelines, It is important to have at least one GFR estimate for all patients.



5. ExcretionA. Renal Excretion:Secretion and reabsorption:

No data about important clinical variability in critically ill patients



5. ExcretionA. Renal Excretion: AKI Patients may undergo hemodialysis. Drug removal by dialysis depends on the method of

dialysis used.

Acute intermittent hemodialysisIntermittent hemodialysis can significantly remove drugs that are not much removed by regular hemodialysis

Drug removal depends on physicochemical properties of the drug as well as equipment used Discuss!Dr. Dalia A. Hamdy (FS15AY) 116


5. ExcretionA. Renal Excretion:Renal Replacement therapyContinuous renal replacement therapies (CRRTs)CRRT refers to several methods of renal replacement.



Dosen = normal dose of a drug, Qeff = effluent rate, SC = sieving coefficientClnorm= normal clearance of the drug nonrenal


Extracorporeal removal of drugs: Dialysis

Dialysance: is a clearance term process of drug removal from the dialysis machine

CLD= Q(Ca-Cv)/(Ca)

CLD= dialysance, dialysis clearanceQ= rate of blood flow in kidney machineCa= drug concentration in arterial blood (blood entering the

machine)Cv= drug concentration in venous blood (blood leaving the machine)

Dose adjustment in Renal diseases


Extracorporeal removal of drugs: Dialysis

The average plasma drug concentration

Css average= FD/(CLT+ CLD )τ

CLD= dialysance, dialysis clearanceCLT= Total ClearanceF= fraction of dose absorbedτ= dosing intervalD= dose

Dose adjustment in Renal diseases

5. ExcretionB. Hepatic Excretion:Hepatic excretion of drugs is less important for most drugs than renal excretion. It can be affected by critical illness sp. for some

neuromuscular blocking agents.

Nine patients undergoing surgery for total biliary obstruction showed a significant increase in pancuronium half-life compared with normal patients with no change in urinary excretion of pancuronium and its metabolites.

(Br J Anaesth 1977;49:1103-8).Dr. Dalia A. Hamdy (FS15AY) 120


5. ExcretionB. Hepatic Excretion:

Similar results were found for vecuronium in patients with cholestasis, where the mean half-life was 98 minutes in patients with cholestasis and 58 minutes in normal patients (Br J Anaesth 1986;58:983-7).



5. ExcretionC. Pulmonary Excretion

Pulmonary excretion is important for volatile gases such as anesthetics. Acute respiratory distress syndrome

impaired gas exchange affects body’s ability to remove volatile

gases

- No data regarding ability of critically ill patients to excrete anesthetics.



6. Pharmacodynamics

-Is the biochemical and physiologic effects of a drug, “Mechanism of action”, “drug/receptor binding and clinical effect”

- Effect can sometimes be measurable as blood pressure or unmeasurable as the gastric pH



6. Pharmacodynamics

Sigmoid Emax model

Emax: maximal effectEC50: plasma conc needed to get 50% Emax



concentration

Effec

t

6. Pharmacodynamics

Sigmoid Emax model

(Hill equation)Effect = Emax. Cn

n= shape factor



concentration

Effec

tEC50 + Cn

6. Pharmacodynamics

Sigmoid Emax model

(Hill equation)Effect = Emax. Cn

n= 1 simple Emax model



concentration

Effec

tEC50 + Cn

6. PharmacodynamicsAntibioticsgenerally fall into three PD categories, (1) time-dependent killing (T>MIC), (2) Concentrationdependent killing (Cmax/MIC)(3) a combination of time- and concentration-dependent killing (AUC/MIC).



6. PharmacodynamicsAntibiotics β-Lactam antibiotics: A percentage of time the free drug concentration remains above the MIC. (fT>MIC) needs to be 100%. However, For critically ill patients it is assumed to have

suggested breakpoint ranges from 50% to 100% (fT>MIC) (Br J Clin Pharmacol 2012;73:27-36).



6. PharmacodynamicsAntibiotics β-Lactam antibiotics: -Many institutions have adopted the practice of prolonged or continues infusions.

-Modelling can be used but there is still discrepancies between modelling results and clinical trails results in such population



6. PharmacodynamicsAntibioticsAminoglycosides: -Gentamicin,Tobramycin, Amikacin, netilmicin Efficacy: concentration-dependent killing.

(Cmax/MIC). Peak-to-MIC ratios of 8–10 resulted in around

90% clinical response (J Infect Dis 1987;155:93-9).-Postantibiotic effect :A phenomena of continued bacterial killing when Css < MIC



6. PharmacodynamicsAntibiotics Aminoglycosides: once-daily aminoglycoside dosing has been used. Taking advantage of high peak concentrations maximizes the PD of aminoglycosides.

Critically ill patients show Vd variability as well as ARC raises issues about appropriately dosing these agents, especially in critically injured trauma patients, whose drug levels can be undetectable for more than 12 hours (J Trauma 2000;49:869-87)Dr. Dalia A. Hamdy (FS15AY) 131


TDM? Side effects? EfficacyPractice!


Aminoglycosides

What do we monitor?-Peak and trough levels-Serum creatinine (in renal insufficiency)

TDM

-Ototoxicity (irreversible)-Nephrotoxicity (reversible)

6. PharmacodynamicsAntibiotics Vancomycin: Current guidelines use the available literature to recommend an AUC/MIC of 400 or greater

(Am J Health Syst Pharm 2009;66:82-98).

The guidelines suggest that continuous-infusion regimens are unlikely to improve patient outcomes and that standard intermittent infusions should be sufficient to achieve the desired PD end pointsDr. Dalia A. Hamdy (FS15AY) 133



6. PharmacodynamicsAntibiotics Vancomycin: However in critically ill patients, vancomycin-associatedNephrotoxicity was reported with intermittent dosing rather than continuous infusion (odds ratio 8.2; p≤0.001)

(Crit Care Med 2014;42:2527-36).




6. PharmacodynamicsAntibiotics Vancomycin:

critically injured trauma patients being treated for ventilator-associated pneumonia require aggressive dosing as high as 20 mg/kg administered as often as every 6 hours were needed to optimize PK parameters

(J Trauma Acute Care Surg 2012;72:1478-83).





VancomycinDose:1. Estimate creatinine clearance2. For very sick patients Loading dose of 20-25 mg/KgFollowed by Maintenance dose based on actual body weight (ABW) and nomograms

TDM

OtotoxicityNephrotoxicityRed-man syndrome


VancomycinDose: TDM

OtotoxicityNephrotoxicityRedman syndrome


VancomycinDrug interactions: Pharmacodynamic rather than PK

+Aminoglycosides = nephrotoxicity

+warfarin= augmented hypothrombinemic effect

6. Pharmacodynamics

Anticoagulants

Concern for a variable response in critically ill patients has led to the development of dosing nomograms/protocols. Researchers have found a shortened time to therapeutic aPTTs in critically ill patients receiving unfractionated heparin and direct thrombin inhibitors (argatroban and bivalirudin).



6. PharmacodynamicsGeneral tendencymost PD studies of drugs have shown a decreased response in critically ill patients. For example, septic shock patients have reduced response to dobutamine Trauma patients with edema have lower AUCs for anti-Xa activity



7. Therapeutic Drug MonitoringTherapeutic drug monitoring (TDM) refers to the measurement of medication concentrations in theBlood

TO(1) maximize efficacy(2) reduce toxicity.



When???

143

Is about using Plasma/serum drug concentrations, PK, PD for

Dr. Dalia A. Hamdy (FS15AY)

Therapeutic Drug Monitoring(TDM)

144

Is a multidisciplinary function involving

Scientists, Clinicians, Nurses and Pharmacists



ALL Drug

s?

145

TDM is specifically important For drugs having narrow therapeutic index



MEC

MTC

146

Drug Therapeutic RangeDigoxin 0.5-2 ng/mLLidocaine 1.5-5 ug/mLGentamicin, tobramycin, netilimicin

5-10 ug/mL (peak), <2ug/mL (trough)

Vancomycin 20-40 ug/mL (peak), 5-10 ug/mL (trough)

Phenytoin 10-20 ug/mLphenobarbital 15-40 ug/mLCyclosporine 150-400 ng/mL (blood)Theophylline 10-20 ug/mLlithium 0.6-1.4 mEq/L




Special Population: Critically Ill Patients In critically ill patients TDM is very important

for few drugs Example


Special Population: Critically Ill PatientsIndividualization of therapy is quite importantTo calculate half life?


Special Population: Critically Ill PatientsIndividualization of therapy is quite importantWhy Cmax and Cmin?


Special Population: Critically Ill PatientsIndividualization of therapy is quite important


Special Population: Critically Ill PatientsIndividualization of therapy is quite important

DRUG REGIMEN and Dose Modification

Discuss!


Special Population: Critically Ill PatientsIndividualization of therapy is quite importantNomograms?!


Good Luck

pk & pd aspects of drugs in critically ill population

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