clinical pharmakociketic clinis on obes, pediarty, and geriarti.pptx

8/11/2019 clinical pharmakociketic clinis on obes, pediarty, and geriarti.pptx

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LINICAL PHARMACOKINETICSON OBES, PEDIATRY ANDGERIATRI PATIENTS

STIFI BHAKTI PERTIWI PALEMBANG


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BY GROUP 7 CLASS B HALF VII :

Oktavia andriani (11.01.01.083)

Puri Handayani (11.01.01.084) Rahmad (11.01.01.085) Reni tania winanada (11.01.01.086)

Repi yuliasta (11.01.01.087)


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PHARMACOKINETICS OF DRUGS INCHILDREN

Failure on that pharmacokinetics in children is different than adults rang cancause tragic mistake in treatment. As a good example is the provision ofchloramphenicol which causes gray baby syndrome. Toxic syndrome occurs ininfants born prematurely or other neonates and are associated with high levels ofchloramphenicol in plasma. This is caused by a decrease in capacity and reducedfiltration glukoronidasi glomeruler the children in that age range, thus causingaccumulation of the drug. But in the age between 2 to 3 weeks, the toxic dose of thedrug for neonates may not provide therapeutic drug levels in serum of engagement

for older babies.

Clinical pharmacists play an important role in influencing the decision-makingrelated to dose. Therefore, it should be obvious reasons in advising on the dose (mg/ kg) or the frequency of the different between children and adults


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ABSORBSI

Absorption of oral dosage may be influenced by several factors, including transit time inthe stomach and intestines, stomach and intestinal pH and gastric emptying time of which aredifferent in neonates and infants. Gastric emptying time will equal adults in infants aged 6months and 2 years after the new stomach acid production will increase in proportion to thelevels of per kg as in adults. However, in older infants and in children there is evidence to showthat the oral dosage given not most absorbed in the rate and amount comparable to adults.

Percutaneous absorption is inversely proportional to the thickness of the stratumcorneum, was much greater in neonates and young infants than in adults. Use of the drugthrough the transdermal systems of it must be used very carefully because of the increased riskof systemic side effects. Some kind of preparation should not be used in children aged less than 1year. Pay special attention should be given when the stretcher is a protein drug, its use on brokenor inflamed skin as well as whether or not occlusive dressings are used.


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DISTRIBUTION

During the age of the baby, the total water content inthe body there is a total body weight had a greater

percentage than older children or in adults. This percentagewill decrease with age as listed in table 12.1 (walker &edwards, 1999). Drugs were dissolved in water should beprovided with larger doses in neonates to achieve the desiredtherapeutic effect. An example is requiring dose gentamicin 3

mg / kg / defining a dose in neonates compared with 2.5 mg /kg / administration in older children to achieve plasma druglevels were the same.


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TABLE 12.1 THE PERCENTAGE OF EXTRACELLULARFLUID VOLUME AND TOTAL WATER CONTENT IN

THE BODY WEIGHT.

Age Total water contentin the body (%)

Extracellular fluid(%)

Preterm neonatus 85 50 Term neonatus 75 45 3 months 75 30

1 year 60 25 Adult 60 20


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CONTINUE..

The amount of drug that binds

to a protein is the most influential in the

distribution of drugs. Protein binding may be

decreased in infants due to low levels of globulinand albumin. Research shows that after the age of 3

years ilatan protein becomes comparable to adult

values for acidic drugs. For alkaline medication takes

time till the age of 7-12 years.


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METABOLISM

At birth most of the enzyme systems involved in drugmetabolism has not been established or are there but in a verylittle amount. So that the capacity of metabolic degradation isalso not optimal.

But the size of the liver compared to the total weight on thedeveloping child greater than 50% as compared with adults.Therefore, in older infants and children there is a considerableincrease in the rate of metabolism. So for certain drugs dose (mg/ kg) greater may be required by children than adults. It is seenfrom Table 12.2 that showed the theophylline dose required atvarious ages.


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EXCRETION

Glomerular filtration rate (GFR) in newborns is lower than

adults because their kidneys are relatively not well developed. Forexample, renal function in neonates is about 30 to 40% or less,compared with adults. Thus, the ability to eliminate drugs in

neonates and very young infants certainly be not optimal and a

decrease in dose may be required. But GRF will increase rapidly afterthe first few weeks of birth and reaches values comparable withadults at the age of 1 year.


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DOSEOften medications for children are extrapolated from adult doses prevalent.

Often stressed, that children can not be considered small adults when it comes totreatment.

The most reliable method for establishing a dose that is 'Mediciens forChildren' is a good example. The following formula can be used to calculate bodysurface area in these patients.

Body surface area

At the boundary between drugs that have toxic dose therapy with broad, then themethod of "percentage" can be used to obtain the percentage of the adult dose

for various age and weight of children, as listed in Table 12.3.


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TABLE 12.3. PERCENTAGE OF THE

ADULT DOSE FOR VARIOUS AGE ANDWEIGHT OF CHILDREN

Ageweight loss

Ideal (kg)outer surface

Body (m)Percentage of the

adult doseNeonatus(full term) 3,5 0,23 12,5

1 month 4,2 0,26 14,5

3 month 5,6 0,32 18

6 month 7,7 0,40 22

1year 10 0,47 25

3 year 15 0,62 33

5 year 18 0,73 407 year 23 0,88 50

12 year 39 1,25 75

Adult-male 68 1,80 100

Mature-woman 56 1,60 100


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DRUG DELIVERYoral route

Oral route of administration is the most suitable for thechildren, especially the liquid preparation that isperfect for toddlers.

rectal route

This route is an alternative to the oral route is usefulfor nausea weight patients, patients who are reluctantto take medication by mouth or patients who can notor are not allowed to eat because of their physicalstate. rectal administration is also beneficial for

patients who require rapid absorption, for example,the use of diazepam to control spasms (seizures).

parenteral route

Intramuscular administration of drugs extremelypainful infants and children, and therefore should beavoided wherever possible.

respiratory route

Inhalation route may cause difficulties in children,because it requires coordination in the use of anaerosol inhaler. However, a number of tools are nowavailable to the efficiency and effectiveness of drugdelivery to the lungs better arrives.


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THE USE OF DRUGS IN THE

GERIARTIpharmacokineticsmedication must be in the workplace at appropriate concentrations to achieve theexpected therapeutic effect. Pharmacokinetic changes in elderly patients have animportant role in the bioavailability of the drug.

absorptionDelays gastric emptying, reduction of gastric acid secretion and tissue blood flow(splanchnic), it is theoretically affect absorption. But in reality, the change-change thatis associated with this age do not significantly affect the bioavailability of total drugabsorbed. Some exceptions include digoxin or drugs and other substances to theactive mechanism of absorption is reduced, for example, is thiamine, calcium, iron,

and some kind of sugar.distribution

The factors that determine the distribution of drugs, including body composition,plasma protein binding and organ blood flow. Everything will change with age, theresult will be different drug concentrations in elderly patients compared to younger

patients on the same drug dosage.


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body composition

Total body water and lean body mass decreased with age,causing a decrease in the volume of distribution of water-soluble drugs. Consequently, the drug concentration inplasma will rise, as the example is digoxin, and

cimetidine.Conversely, an increase in the total fat in the body will be,resulting in increased volume of distribution of lipid-soluble drugs. Furthermore, the concentration of drug inplasma will go down, but the long action of the drug willbe extended, for example, is a class of benzodiazepinessuch as diazepam.


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Plasma-protein bond

Total plasma albumin decreases with age. drugs that areacidic (eg, cimetidine, furosemide, warfarin) binds to theprotein, so the concentration of these drugs in a freestate will be increased in elderly patients. number 1-acid glycoprotein plasma (where the basic drugs, such aslidocaine, bound) does not change or increases to anamount not clinically significant.


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Organ blood flow

Changes in organ blood flow will result in a decrease in

perfusion in the limbs, liver, mesentery, muscle, heart and

brain. Perfusion decreased to 45% in elderly patientswhen compared with patients 25 years of age. Clinical

evidence does not demonstrate clearly about a change inthe distribution of drugs, but at least theoretically

decrease the velocity distribution velocity distribution

network to be reckoned with.


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ELIMINATION

Hepatic metabolism and renal excretion is an important mechanisminvolved in the removal of drugs from the workplace. effects of a single dose ofthe drug will be extended and the concentration of the saturated state will

increase if both processes decreases.

Metabolism in the liver after absorption, drugs are given orally will passthrough the portal circulation to the liver. Fat-soluble substances will bemetabolized extensively here, resulting in a decrease in systemic bioavailability.Therefore, a decrease in metabolism in here (first-pass metabolism -'frist-pass

metabolism ') will increase systemic drug bioavailability. In elderly patients itappears the first-pass metabolism disorders for several kinds of drugs, includingklortrimetiazol, labetalol, nifedipine, nitrates, propranolol, and verapamil.


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CONTINUE..There is a reduction of the heart as much as 35% ranging in

age from 30 to 90 years, resulting in lower capacity intrinsic livermetabolism in elderly patients. These circumstances, together

with a decrease in liver blood flow, the main cause of the increase

in drug bioavailability experiencing first-pass metabolism. As anexample of this is the hypotensive effect of nifedipine were

increased significantly in elderly patients.

Another major factor that affects the metabolism of drugs by the

liver associated with enzymatic changes that appear with age. Forexample, the speed of metabolism by the cytochrome P450

system may decrease to premises 40% when compared with anarrow therapeutic index, such changes may be clinically

significant .


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RENAL ELIMINATION

Decrease in renal blood flow, organ size, filtration, glomeruler and tubularfunction, all of which are changes that occur at different rates in the elderly.Glomelurus filtration rate decreased sekitar1% per year starting at age 40 years.

These changes resulted in the elimination of some drugs more slowly on the age,such as the effect on renal function. Some had evidence shows that the drugconcentration in tissue increased by 50% as a result of those changes.In practice, highly variable renal function in elderly. Therefore, the dose of drugs thatare primarily excreted by the kidneys should be customized for each individual. Drugswith a narrow therapeutic index should be administered with dose reduction, forexample, is digoxin and aminoglycosides and dosage reduction of as much as 50% as

the initial dose is recommended in most cases. Dose adjustment may not benecessary for drugs with a wide therapeutic index, eg penicillin. However,pharmacists should be alert to potential drugs that cause problems with impairedkidney function is.


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OBESITY

The presence of excessive adipose tissue can alterthe pharmacokinetics of drugs by changing thevolume of distribution. The general physiologicequation for volume of distribution can be brokendown into separate parameters for individual tissue

types:


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CONTINUCE

Because of this, the sheer amount of adipose tissue will be aprimary determinant of how much obesity will effect the volume

of distribution of the drug. Also, the magnitude of effect thatadipose tissue has on the volume of distribution for a drug isdependent on the binding of drug in the tissue itself. If the drughas a large afnity for adipose tissue and is highly bound there,the free fraction in adipose tissue will be small (f ), and a large

amount of drug will accumulate in that tissue. Medications thathave high lipid solubility tend to partition into adipose tissue, andthe volume of distribution in obese patients for these drugs canbe dramatically larger than in normal weight patients.


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CONTINUCE

Examples of lipophilic drugs with larger volume of distribution values in obeseindividuals are diazepam 34 , carbamazepine 35 , and trazodone 36 . However,hydrophilic drugs tend to not distribute into adipose tissue so that the volume ofdistribution for many water-soluble drugs is not signicantly different in obese andnormal weight patients. The volumes of distribution for digoxin, 37 cimetidine, 38 andranitidine 39 are similar in overweight- and normal-weight subjects.

Although the presence of excessive adipose tissue is the most obvious change thatoccurs in obese individuals, other physiologic changes are present. While adiposecells contain >90% fat, there are additional supportive tissues, extracellular uid, andblood present in adipose tissue. Also, some lean tissues hypertrophy in obese

individuals. The net result of these changes is that hydrophilic drugs with smallvolumes of distribution may experience distribution alterations in obese patients. Forexample, the aminoglycoside antibiotics are water-soluble molecules that haverelatively small volumes of distribution similar to the value of extracellular uid (V =0.26 L/kg).


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CONTINUCE

Since the volume of distribution is so small (~18 L in a 70-kg person), theaddition of just a few liters of extracellular uid can alter the pharmacokineticsof these antibiotics. The additional extracellular uid contained in excessive

adipose tissue and other organs that hypertrophy in obese individuals causeslarger volumes of distribution for the aminoglycoside antibiotics in overweightpatients. Formulas that correct aminoglycoside volume of distribution forobese individuals are available. 40 43 however, if the volume of distributionfor a hydrophilic drug is intermediate or large, the additional extracellular uid contained in adipose tissue and other sources in obese individuals may notsignicantly alter the distribution of the agent. Examples of medications with

larger and intermediate volumes of distribution are digoxin (V = 500 L) andvancomycin (V = 50 L); the addition of a few extra liters of extracellular uid due to obesity will not substantially change the volume of distribution for theseagents


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CONTINUCE

Another change that is found in obese individuals is increased glomerular ltration rates. This alteration primarilyaffects hydrophilic drug compounds that are renally eliminated and will increase the renal clearance of the agent.Vancomycin, 44 the aminoglycosides, 40 42 and cimetidine 38 all have higher clearance rates in obese patientscompared to normal weight individuals. Special methods are used to estimate creatinine clearance for obesepatients, as previously noted in the Measurement and Estimation of Creatinine Clearance section of this chapter.

Obesity has variable effects on the metabolism of drugs. For many agents, such as Carbamazepine 35 andcyclosporine, 45 obesity does not signicantly effect hepatic clearance. While for other drugs, obesity increaseshepatic clearance, as with diazepam, Or decreases metabolic clearance, as with methylprednisolone. 46 Cliniciansshould be aware of this variability and dose hepatically metabolized drugs cautiously in obese individuals in theabsence of specic recommendations.

Half-life changes vary according to the relative alterations in clearance (Cl) and volume of distribution (V): t =(0.693 V) / Cl, where t is half-life. In the case of the aminoglycoside antibiotics, clearance and volume of distributionincreases are about the same magnitude in obese patients, so half-life does not change. 40 42 If the volume ofdistribution increases with obesity, but clearance is unaffected, half-life can increase dramatically as withcarbamazepine. 35 Finally, if clearance changes and volume of distribution remains constant, obesity may also causea change in the half-life of a drug as is the case for methylprednisolone.


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DRUG INTERACTIONS

Pharmacokinetic drug interactions occur between drugs when one agent changes theclearance or volume of distribution of another medication. There are several druginteraction mechanisms that result in altered drug clearance. A drug can inhibit or

induce the enzymes responsible for the metabolism of other drugs. Enzyme inhibitiondecreases intrinsic clearance, and enzyme induction increases intrinsic clearance. Iftwo drugs are eliminated by the same enzyme, they may compete for the metabolicpathway and decrease the clearance of one or both compounds. Two drugseliminated by the same active renal tubular secretion mechanism can compete for thepathway and decrease the renal clearance of one or both agents. Another type ofdrug interaction displaces a drug from plasma protein binding sites because the twocompounds share the same binding site, and the two compete for the same area onplasma proteins. By virtue of its pharmacologic effect, a drug may increase ordecrease blood ow to an organ that eliminates or metabolizes another medicationand thereby decrease the clearance of the medication.


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CONTINUCE

Changes in plasma protein binding also cause alterations in volume of distribution. If two drugs share thesame tissue binding sites, it is possible for tissue-binding displacement drug interactions to occur andchange the volume of distribution for one of the medications.Half-life may change as a result of druginteractions, or, if clearance and volume of distribution alterations are about equal, half-life may remainconstant even though a major drug interaction has occurred.

The same graphical scheme introduced in the hepatic disease section of this chapter can be used tounderstand the clinical impact of drug interactions (Figures 3-6 3-10). To use these charts it is necessary toknow if the drug under discussion has a low extraction ratio or high extraction ratio. The hepatic clearanceof drugs with low hepatic extraction ratios equals the product of free fraction in the blood and intrinsicclearance (Cl = f B Cl ), while the hepatic clearance of drugs with high hepatic extraction ratios equals liverblood ow (Cl int = LBF). Whether a drug has a high or low extraction ratio, the volume of distribution (V = VH B + [f = [0.693 V] / Cl) relationships are the same. The unbound steady-state concentration of drug inthe blood equals the product of the total steady-state concentration and the unbound fraction of drug in theblood: Css u = f B B /f T ]V T ) and half-life (t Css. The effect of the drug increases when the unboundsteady-state concentration increases and decreases when Css u declines.


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PLASMA PROTEIN BINDINGDISPLACEMENT DRUGINTERACTIONSFor a drug with a low hepatic extraction ratio, plasma protein bindingdisplacement drug interactions cause major pharmacokinetic alterations butare not clinically signicant because the pharmacologic effect of the drug

does not change (Figure 3-7). Because the clearance of the drug isdependent on the fraction of unbound drug in the blood and intrinsicclearance for a low hepatic extraction ratio agent, addition of a plasmaprotein binding displacing compound will increase clearance (Cl = ftribution [V = V B + (f B /f T )V T B Cl int ) and volume of dis- ]. Sincehalf-life depends on clearance and volume of distribution, it is likely that

because both increase, half-life will not substantially change = [0.693 V] /Cl). However, it is possible that if either clearance or volume of distributionchanges disproportionately, half-life will change.


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CONTINUCE

The total steady-state concentration will decline because of the increasein clearance (Css = k 0 / Cl, where k 0 is the infusion rate of drug).But, the unbound steady-state concentration will remain unaltered

because the free fraction of drug in the blood is higher than it was beforethe drug interaction occurred (Css u = f Css). The pharmacologic effectof the drug does not change because the free concentration of drug inthe blood is unchanged. An example of this drug interaction is theaddition of diunisal to patients stabilized on warfarin therapy. BDiunisal displaces warfarin from plasma protein binding sites, but does

not augment the anticoagulant effect of warfarin. If drug concentrationsare available for the medication, it can be difcult to convince cliniciansthat a drug dosage increase is not needed even though totalconcentrations decline as a result of this interaction. When available,unbound drug concentrations can be used to document that no changein drug dosing is needed.


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CONTINUCE

For drugs with high hepatic extraction ratios given intravenously, plasma proteinbinding displacement drug interactions cause both major pharmacokinetic andpharmacodynamic changes (Figure 3-9). Because the clearance of the drug is

dependent solely on liver blood ow for an agent of this type, total clearance does notchange. However, bothvolume of distribution [V = V B + (f B /f T )V T ] and half-life[t = (0.693 V) / Cl] will increase because of plasma protein binding displacement ofthe drug. Since total clearance did not change, the total steady state concentrationremains unaltered. However, the free concentration (Css u = f B Css) andpharmacologic effect (effect Css ) of the drug will both increase. Currently, thereare no clinically signicant drug interactions of this type. But, clinicians should be onthe outlook for this prole for highly protein-bound drugs with high hepatic extractionratios given intravenously because the interaction is very subtle. Most noteworthy isthe fact that although total concentrations remain unchanged, the pharmacologiceffect of the drug is augmented. If available, unbound drug concentration could beused to document the drug interaction.


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CONTINUCEIf a drug with a high hepatic extraction ratio is given orally, a plasma proteinbinding displacement drug interaction will cause a simultaneous increase inthe unbound fraction of drug in the blood (f ) and the hepatic presystemicmetabolism of the drug. Hepatic presystemic metabolism increases because

the higher unbound fraction of drug in the blood allows more drug moleculesto enter the liver where they are ultimately metabolized. The increase inhepatic presystemic metabolism leads to an increased rst -pass effect anddecreased drug bioavailability (F ). Total steady-state drug concentrations willbe lower because of decreased drug bioavailability [Css = ( F[D/t]) / Cl].

However, the unbound steady-state drug concentration and pharmacologiceffect remain unchanged due to this type of drug interaction because theincrease in unbound fraction is offset by the decrease in the total steady-stateconcentration (~Css B u= f Css). Route of administration plays an importantrole in how important plasma protein binding displacement drug Interactions

are for agents with high hepatic extraction ratios.


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INHIBITION DRUG

INTERACTIONS Inhibition of hepatic drug metabolism is probably the most common drug

interaction encountered in patients. For drugs with low hepatic extractionratios, this type of drug interaction produces clinically signicant changes

in drug pharmacokinetics and effect (Figure 3-6). The addition of ahepatic enzyme inhibitor will decrease intrinsic clearance and totalclearance for the drug (Cl = f B Cl ). Since volume of distributionremains unaltered, the half-life of the drug will increase (t int = [0.693 V]/ Cl). As a result of the total clearance decrease, total steady-statedrug concentrations will increase (Css = k 1/2 /Cl) . The rise in unboundsteady-state drug concentration will mirror that seen with total drugconcentration, and the effect of the drug will increase in proportion tounbound concentration. An example of this drug interaction is theaddition of ciprooxacin to a patient stabilized on theophylline therapy.


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CONTINUCE For drugs with high hepatic extraction ratios, this category of drug

interaction produces variable effects depending on the route ofadministration for the drug. If the drug is given intravenously andan enzyme inhibitor is added, the decrease in intrinsic clearance isusually not substantial enough to cause major pharmacokinetic andpharmacodynamic effects because clearance is a function of liverblood ow (Figure 3-8). However, if the drug is given orally and anenzyme inhibitor is added to therapy, presystemic metabolism of

the medication may be greatly depressed, and the rst -pass effectcan decrease dramatically leading to improved drug bioavailability.This effective increase in administered oral dose will increase thetotal and unbound steady-state drug concentrations and lead to an

increase in the pharmacologic effect of the drug.


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INDUCTION DRUG

INTERACTIONSDrugs with low hepatic extraction ratios exhibit clinically signicant druginteractions that alter drug pharmacokinetics and pharmacologic responsewhen hepatic enzyme inducers are coadministered (Figure 3-17). Enzyme

inducers increase intrinsic clearance of the drug and thereby increase thetotal clearance of the medication (Cl = f). The increase in total clearancewill cause a shorter half-life since volume of distribution remains unchanged(t = [0.693 V] / Cl). Increased total clearance will also cause decreasedtotal steady-state concentration ( Css = k / Cl), unbound steady-stateconcentration ( Css u = f B 0 Css), and pharmacologic effect (effect

Css ). Carbamazepine is a potent enzyme inducer that, when added to apatients therapy, can cause this type of drug interaction with many othermedications such as warfarin.


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CONTINUCE

FIGURE 3-17 Changes in physiologic parameters ( L BF = li ver blood ow, Cl =intrinsic clearance, f = free fraction of drug in the blood), pharmacokinetic parameters ( Cl= clearance, V = volume of distribution, t B = half-life), and drug concentration and effect(Css = total steady-state concentration; Css u = unbound steady state concentration; effect= pharmacologic effect) for a low hepatic extraction ratio drug if intrinsic clearanceincreases (indicated by arrow). An uptick in the line indicates an increase in the value ofthe parameter, while a downtick in the line indicates a decrease in the value of the

parameter. Intrinsic clearance could increase due to a drug interaction that induces drug-metabolizing enzymes.


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FIGURE 3-18 Changes in physiologic parameters ( L BF = l iver blood ow, Cl = intrinsic clearance, f = free fraction of drug in the blood), pharmacokinetic

parameters ( Cl = clearance, V = volume of distribution, t B = half-life), and drug

concentration and effect ( Css = total steadystate concentration; Cssu

= unboundsteady-state concentration; effect = pharmacologic effect) for a high hepaticextraction ratio drug if intrinsic clearance increases (indicated by arrow). Anuptick in the line indicates an increase in the value of the parameter, while adowntick in the line indicates a decrease in the value of the parameter. Intrinsicclearance could increase due to a drug interaction that induces drug-metabolizingenzymes. int


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ALTERATION IN ORGAN BLOOD

FLOWBy virtue of the pharmacologic effect for a drug, it may be possible for an agent tochange liver blood ow. For instance, -blockers can decrease heart rate and cardiacoutput which decreases liver blood ow. Since liver blood ow is the predominatefactor that Determines clearance for high hepatic extraction ratio drugs, this type ofinteraction is Only important for this category of medication. -blockers decreaselidocaine clearance by Decreasing liver blood ow. If a drug with a high hepaticextraction ratio is administered to a patient, and another agent that decreases liver

blood ow is then added to the patients therapy, total clearance will decrease (Figure3-10). Since volume of distribution remains unaltered, the half-life of the drug willincrease (t = [0.693 V] / Cl). As a result of the total clearance decrease, totalsteady-state drug concentrations will increase (Css = k /Cl) . The rise in unbound

steady-state drug concentration will mirror that seen with total drug concentration,and the effect of the drug will increase in proportion to unbound concentration. If Thecoadministered drug increases liver blood ow, as can be the case with vasodilatorsLike the calcium channel blockers, 51,52 0 all of the aforementioned changes will occur inthe opposite direction (Cl =LBF ; t = [0.693 V] / Cl ; Css = k 0 /Cl ; Css

Css), and the decline in unbound steady-state concentration will cause a decrease in pharmacologic Effect of the drug.


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THANKS TO

ATTENTIONGRUP 7 CLASS B HALF VII

clinical pharmakociketic clinis on obes, pediarty, and geriarti.pptx

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