clinical pharmacokinetics in liver failure patients sendd

7/27/2019 Clinical Pharmacokinetics in Liver Failure Patients Sendd

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Clinical Pharmacokinet

Liver Failure Patient

Bygroup 7 class b half V

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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Liver

The liver is the largest gland in the body , there is

a cavity in the right upper abdomen , brownishcolor . The liver gets its blood supply from theartery ( hepatic artery ) and gate vessels ( portalvein ) of the intestine . Hearts wrapped bymembranes of the liver ( hepatic capsule ) .Liver blood vessels and bile are unitedconnective tissue membrane ( capsule glison ) .Liver cells also contained perombak red bloodcells called histiocytes yan gtelah old .

As a means of excretion of the liver producesbile which is a clear greenish liquid , in which thedye -containing bile ( bilirubin ) , bile salts ,cholesterol , and also bacteria and drugs . Zatrbile pigment formed from the debris oferythrocytes that have old or damaged will bearrested next histiocytes haeglobinnyaoverhauled and released


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Liver Function

The liver is the largest organ and the most important metabolism in the binvolved in the synthesis , storage and metabolism of many endogenous cexogenous krilens compounds , including drugs and other toxins from the blist of some of the functions of the liver :

Storage

Liver energy stores ( glycogen , fat ) , vitamins (eg, vitamin A , vitamin B(eg, Fe , Cu ) , the blood of other substances that play a role in the formregeneration of blood

Homeostasis

Example : glucose

Secretion

Example : bile salts

Excretion

Example : cholesterol , billirubin

Synthesis

Synthesis of plasma proteins , eg albumin , transderrin , lipoprotein ( VerLipo - protein - VLDIs , High Density Lipoprotein - HDIs )

Synthesis of coagulation factors , eg protombin , fibrinogen , factor V ,

heparin production


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Continuce..

The formation and destruction of red blood cells

25 - hydroxylation of vitamin D3 ( Vitamin D3 or cholecalciferol is the p

1,25 - dihydroxycholecalciferol , the active form of vitamin D ) . Produc- hydroxylation requires molecular dihidrosikolekalsiferol koleksiferol at pposition 25 Hydroxylation at position 25 occurs in the liver , whereas hyat the 1 - A occurs in the kidney ) .

Metabolism

Example : the metabolism of carbohydrates , fats , and proteins

Detoxification

Detoxification or degradation and metabolism and hormones , includ

alcohol and other foreign substances including antigens

Clearance

Example : aldosterone , drug

Filtration

Example : antigen

Selection and protection

Phagocytosis of microorganisms growing in the blood and red blerythrocytes ) which is not useful ( by kapffer cells)


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Heart Disease

Acute liver disease

Acute liver disease can be mild disease and can heal themselves (self - limiprogress to chronic liver disease . One example of acute liver disease was hwhich many attacks are mild and often passed unnoticed by the patient . H

spread through the faecal - oral route and is most common in the state of hsanitation is very low . Contaminated drinking water is a source of infection Moreover, it can also be caused by consumption of contaminated food , emussels , and the like . This infection occurs primarily in children and young aHepatitis A virus infection ( hepatitis A )occurs throughout the world and ofincidence of epidemics .

Other causes of acute hepatitis , including drugs , whether it be in the amoor overdose , toxins and chemicals that other .

Chronic liver disease

Chronic liver disease is defined as an inflammation of the liver which continany maintence more than 6 months . Such conditions may occur after an aacute viral hepatitis ( such as B or C ) and then occur secondary to diseasechronic active hepatitis tolerant ) or due to alcohol or drugs.

Chronic liver disease causes structural changes in the liver which eventuallycompromise liver function . This is leaversible and ultimately will lead to the cchronic liver disease ( especially cirrhosis ) are the most common in Westernwhile chronic hepatitis B infection is the leading cause of chronic liver diseacommon in East Asia .


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Heart Problems Resulting In Med

Drug-induced liver damage including comparatively rare , yethere is going to result in significant mobility and mortality . M

drugs are suspected to cause problems in the liver and drug-induced hepatotoxicity spectrum is very broad . The range ospectrum can be started from the asimpatomatis reversible cin liver function tests to acute liver mikrosis fatal , but the mostcommon is jaradice and hepatitis . Examples can be seen in 10.1

Mechanism of drug-induced damage to liver can be divide

intrinsic hepatotoxicity and idiosyncratic hepatotoxicity . Howboth types can cause liver damage patterns are almost the sand some medications can cause more than one type of daIn general , drug-induced hepatotoxicity give a good prognowhen stop taking the drugs , but the prognosis itself is influencthe type of liver damage , the length of the state and whethdamage is irreversible


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PROBLEMS IN THE HEART HepatotoxicityIntrinsic : ( Type A , predictable )

Hepatotoxicity Intrinsic predictable ,

dose-dependent and involves themajority of individuals who use the drugin a certain amount . The time spanbetween the start of treatment and theincidence of liver broke highly variable (from a few hours to a number of weeks )

For example :

Paracetamol ( acetaminophen ) cancause liver necrosis predicted in overdose

Methotrexate can cause fibrosis andcirrhosis in long -term continuous treatment

Tetracycline causes micyobesicular fattyliver

Cyclophosphamide can cause althoughrare , acute liver cell necrosis

Oral contraceptives may cause cholestasis( also increases the risk of adenoma

Type of liver

problems

Drug

Nikrosis Carbon tetrachloride drug abuse ( c

paracetamol ( in overdose )

Hepatitis Sodium valproate , steroids , tetrac

Alcohol ( after the consumption of

term period ) amiodarone , azathiop

methoxyflurane , isoniazid , MAO

) methyldopa , nitrofurantoin , rifam

sulfasalazine , sodium valproate

Hyphersensifi

ty

Allopurinol , methyldopa , penicilli

sulfonamides

Kolastasis Amitriptyline , cyclosporine , eryth

reported along with the estolate pre

glibenclamide , fenotiasin

( eg, chlorpromazine , prochlorpera

hormone

Fibrosis Vitamin A ( high dose for a long -te

term use )

Adenosis Oral contraceptives , anabolic stero

Table 10.1


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Idiosyncratic hepatotoxicity ( Type Bnot be predicted )Idiosyncratic hepatotoxicity may be associated with hypersensitivity

metabolic abnormalities . This response can not be predicted and adependent on the administered dose . This occurs in less than 1 % ofwho truncated . The incubation period varies , but usually several w

For example :

Klorpromisin kolestrin can cause severe and can occur for weeks agiven . Other drugs in them are erythromycin , fusidic acid , glibenclphenothiazines , and sodium valproate .

Halothane usually result in a slight increase in serum transamidase Although rare , halothane can cause severe necrosis of liver cells ansevere liver failure ( hepatic fulnment failture ) with high mortality

Isoniazid may cause an increase transmirase in 10 % of patients anjaundice in 1 % of patients in the first 2 months . Isoniazid can also cahepatitis and chronic active hepatitis

Hepatotoxicity caused by sulfonamides may resemble viral hepat

Nitrofurantoin causes cholestasis and acute and chronic hepatitis


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Importan Change of Heart DiseasePharmacokinetic

Changes in liver function will affect many aspects of the phaof the drug , for example, the total clearance , volume of distextraction by the liver . Pharmacokinetic parameters were mthe liver is a metabolic disease . However the extremely comdetermine to what level the drug treatment of liver dysfunctioindividuals affected and it can not be measured precisely frodata .


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Absorption of drugs

On drug absorption of fat -soluble drugs can be decreased .

Drug distribution

A large number of drugs that circulate bound protein , usually alalso globulin , lipoproteins and acid glycoproteins . This bond is reindicates a balance between drug molecule bound and unbounot only molecules that remain free and pharmacologically acti

bound to the circulating while a backup is not pharmacologicalchanges in plasma protein binding have a significant effect on tdistribution of the drug , the amount of free drug available for phaction and the extent to which the drug can be metabolized anHowever , protein binding in the adhesive is onlyimportant for soexample fenotoin , warfarin , and tolbutamide .


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Chronic liver disease can lead to hypoalbuminemia and increndogenous compounds ( such billirubin ) that can competesite on the protein . The use of drugs that are normally very laattachment to proteins should be of particular concern becaincreased concentration of diazepam , tolbutamide , phenywarfarin in a free state is shown in patients with the conditionan increase in toxicity . Special attention should also be given

with a narrow therapeutic range , the attachment to the prohigh because of toxicity can occur at plasma concentration


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Liver metabolism

Drug metabolism occurs primarily in the liver and untenzimsilokrom located in smooth endoplasmic mertikuluhepatogit ) . metabolism occurs in two phases .

Phase 1 : involves a change in the chemical structure of the , for example, by oxidation , reduction , or hydrolysis .

Phase 2 : involves konjungasi example by sulfation (

glukuronidasi , methylation , or acetylation . the final produccompounds and water soluble which can in eksresikan in bile


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First-pass metabolism ( firts pass / prsystemic metabolism )

First-pass metabolism can describe the phenomenon thatdrugs metabolized after absorption but before reachingthe systemic circulation . first-pass metabolism by the livermay occur after oral administration . importance of first-pass metabolism , in terms of quantitative depending onthe speed of drug absorption , the transformation speedand capacity of a particular drug biotransformation .

Liver blood flow velocity plays an important role in terms offirst-pass metabolism and metabolic rate . in severe livercirrhosis , the liver cell disruption and also the developmentof the channel that delivers blood to the systemiccirculation without passing through the liver , first-passelimination will decrease and systemic availability systemicavailability will increase


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The reactions were included in tphase include :

a) Oxidation reaction is a reaction that is most common . This reaction occumolecules according to specific process depends on each of its chemicnamely the hydroxylation reaction on the alkyl group , aryl , and heterocyalcohols and aldehydes ; reaction forming N - oxide and sulfoxide ; oxidareaction ; core opening and forth. The oxidation reaction is divided into toxidation involving cytochrome P450 ( the enzyme responsible for the oxiand oxidation which does not involve cytochrome P450 .

b) Reduction reaction ( reduction of aldehydes , azo and nitro ) . This reactioimportant than the oxidation reaction . Reduction mainly play a role in ni

derivatives ( azoik and nitrate ) , sometimes on carbon . Only a few drugsby the reduction , both in the location of the microsomal and non- micro

c) Hydrolysis reaction ( deesterifikasi ) Another process that produces a morcompounds are hydrolysis of esters and amides by enzymes . Esterase locmicrosomal and nonmikrosomal will hydrolyze drugs containing ester grohydrolysis reactions are more prevalent and concentrated , as peptidin henzyme . Non microsomal esterase present in the blood and some tissues


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Phase II reactions ( synthetic pha This reaction occurs in the liver and

involves the conjugation of a drug or

its phase I metabolites withendogenous substances . Theresulting conjugate is almost alwaysless active and is a polar moleculethat is easily excreted by the kidneys.Conjugation reaction works on avariety of natural substrates byenzymatic processes bound to the

reactive groups of pre-existing orformed in phase I. The reactions thatoccur in phase II conjugation includeglukoronidasi , acylation , methylation, formation merkapturat acid , andsulfate conjugation. Phase II reactionsconsist of :


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Conjugated glucuronic acid

Conjugation with glucuronic acidconjugation is a common way in the

process of metabolism . Almost all drugconjugate experiencing this because alarge number of functional groups cancombine drugs enzymatically withglucuronic acid and D - glucuronic acidavailability in sufficient quantities in thebody . Between the coenzyme ( UDPGA :uridine diphosphoglucorinic acid) Reacts

with the drug by the enzyme UDPglukoronosil - transferase ( UGT ) to moveglukoronida to O atoms in alcohols ,phenols , or carboxylic acid ; or S atoms inthe thiol compounds ; or N atoms in theamine compounds and sulfonamides


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Continuce.. Metilasi

Methylation reaction have an important role in the biosynth

endogenous compounds , such as norepinephrine , epinhistaminserta for drug bioinaktivasi process . Coenzymmethylation reactions is S - adenosil - methionine ( SAM ) . catalyzed by a methyltransferase enzyme found in the cmicrosomes

Sulfate conjugation

Especially occurs in compounds containing phenol groups a

also occur in alcohol compounds , aromatic amines ancompounds . Sulfate conjugation in general to improve the compound in water and made into non-toxic compounds.

An acetylation

Metabolic pathways of drugs containing a primary asulfonamide , hydrazine , hidrasid , and primary aliphatic amfunctions of acetylation is made inactive compounds and fo


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Not all drugs are metabolized through the second phase that had corrected phase I only ( one or several kinds ophase II reactions only ( one or several kinds of reactions ) , are metabolized through multiple reactions simultaneously into several kinds metabolites . For example , phenoba

reaction requires as a condition of conjugation reactions . Gmajor metabolite of the drug which has a phenol groupcarboxylic acid . These metabolites are usually inactivexcreted through the kidneys and bladder . Glucuronide whthrough bile can be hydrolyzed by the enzyme

-glukuronidase produced by intestinal bacteria and releasedbe reabsorbed . This enterohepatic circulation prolong

Biotransformation speed generally increases when the concdrug increases , it is valid until the point where the concentrso high that the entire molecule enzyme that does tcontinuously occupied by drug molecules and reached a cof biotransformation


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Besides the concentration of unisex other factors that can affect the spebiotransformation , namely :

1 . Includes intrinsic factors such as the nature of the dphysicochemical properties of the drug , lipofilitas , dose administration . Many drugs , especially lipophilic can formation and activity of liver enzymes . Conversely also kthat inhibit or inactivate the enzyme ,

For example :

anti koagulansia , antidiabetika oral , sulfonamide , antidemetronidazole , allopurinol and disulfiram


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2 .Factors include physiology traits inthings such as : the type or species ,genetics , age , and gender .

Species and strain differences

In the process of drug metabolism , the chemical changethe species and strains of the same or slightly different posometimes there are significant differences in metaboObservations of species and strain differences influence thedrugs that has been done on the type of metabolicdifferences in the qualitative and quantitative differences i

metabolism or.

Genetic factors

Individual differences in the metabolic processes of a numbsometimes occurs in living systems . This suggests that genetifactors contribute to the rate of drug metabolism.


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Differences in age

In old age , the metabolism of drugs by the liver might be usually the more important is the decrease in renal function 65 years , glomerulus filtration rate ( GFR ) decreased to 30 next year again decreased 1-2 % ( as a result of cell loss arenal blood flow ) . Therefore , the elderly in need of sosmaller doses than younger people.

Gender Differences

In several animal species showed no effect of gender on thmetabolism . In humans little is known about the influence of on drug metabolism .

Example : nicotine and aspirin is metabolized differentlywomen .


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3 . Factors Pharmacology

Includes inhibition of the enzyme by the inhibitor and enzyme inductinductor . The increase in enzyme activity causes a faster medeactivation of drug ) . As a result , reduced plasma levels and half drugs . Because of the intensity and pharmacological effects is redvice versa .

4. Factors Pathology Regarding the type and condition of the disease . For example in strok

, administration of phenobarbital along with warfarin reduces theagonist anti koagulasinya ( blockage of blood vessels that can oSimilarly, cimetidine ( H2 receptor antagonist ) would inhibit the cytochrome P - 450 in metabolize other drugs .

5 . Dietary factors

The existence of the consumption of alcohol , cigarettes , and

Charcoal grilled foods and cruciferous vegetables known to induenzymes , grape juice is known to inhibit the metabolism by CYP3Adrugs given simultaneously.

6. Environmental factors

The presence of insecticides and heavy metals . Cigarette smokers msome drugs more quickly than non-smokers , due to enzyme inductdifferences complicate the determination of the effective and safdrugs that have a narrow therapeutic index .

En me ind ction


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Enzyme induction

Many drugs can boost the capacity of its own metabolis


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Many drugs can boost the capacity of its own metabolisinduction ( increase capacity biosynthetic enzymes ) . Inddivided into two according to the enzyme in the induction things :

1 ) Type phenobarbital 2 ) Type metilkolantrena For drenzyme inductor gives the following result :

1. In the long-term treatment with enzyme inductors dconcentration of drug that can reach the level of conthe plasma at the beginning of treatment with certain

2. Efficacious levels of the body 's own material in the

be decreased to below the normal rate . 3. At the joint administration with other drugs there ar

interactions that are sometimes dangerous . administration of the enzyme inductor , a sconcentration in the blood can also declined so redoses to get the same effect


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Inhibition of enzyme

inhibition ( inhibition ) enzymes can cause druginteractions are not expected . This interaction tends tooccur more rapidly than those involving enzymeinduction because this interaction occurs after the druginhibited reach concentrations high enough tocompete with the drugs affected


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Factors affecting the metabolism

Genetic factors

Physiological factors

Factors pharmacodynamic

Environmental factors


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Summary

There are two important factors in drug metabolism in the live

1. Heart rate to eliminate a drug from the blood

This depends on the efficiency of the heart and blood flowthe liver cell extraction ratio . if ratio extraction is very highclearance depends on liver blood flow ( propranolol , lidocflow was less of an effect on drugs that have a low extelimination of most drugs at a speed being affected by chaand kapasisatas extraction .

2. Interistik metabolic capacity of liver cells

Reduction of liver cell mucosa can be caused cirrhosis , activand chronic , and acute alcohol intoksiskasi . the drug withratio . reduction of the liver cells will end up in the liver celpass metabolism , and this is also going to result in increasedrug . the drug with a low extraction ratio (theophylline , wareduction of the liver cells will lead to a decrease in the elim

and may lead to accumulation .


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Excretion of drugs

Some drugs , such as rifampicin and fusidic acid , bile inexretion through without change and may accumulatein patients with extrahepatic obstructine javesticeintrapeutic or so in need dosage adjustments


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Bibliography

Websie :https://www.academia.edu/7009941/LAPORAN_metabolism

Book :

Aslam Mohamed, Farmasi Klinis (clinical pharmacy),MenuRasional Dan Penghargaan Pilihan Pasien.
https://www.academia.edu/7009941/LAPORAN_metabolisme_obathttps://www.academia.edu/7009941/LAPORAN_metabolisme_obathttps://www.academia.edu/7009941/LAPORAN_metabolisme_obat


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Thanks to attention ....

Grup 7 class B half VII

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clinical pharmacokinetics in liver failure patients sendd

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