Contents

Clinical Pbannarokinetics and Oi ..... Processes

Oin. Pharmacoltinet. 19 (6): 4624 90. 199() 0) 12-5%3/90/00 t 2-0462!S l4.SOIO C Adis InlCTTUIlional Limitw

All righ ts reservtd ,

~-

The Effect of Respiratory Disorders on Clinical Pharmacokinetic Variables

Anne-Marie Taburet, Corinne Tollier and Christian Richard Cli nical Pharmacy and Intensive Care Unit , Hopilal de 8icetre, Pans, France

Summary ................ . ..... .... ... ........ ... ........ ........ .. . . .......... ....... ....... 462 I. Pharmacokincl ic Implications of Pulmonary Disease

1.1 PathophY$iological Aspects ...................... . 1.2 Absorption .. .... .... ... ... ... ..... . ............. .............. .... .

... 463

. .. 463

. ." 1.3 Distri bution ..... .... . . 1.4 El imination

2. Drugs Used in the Managemrnt or R('$piratory Disorders 2, I Bronchodi lators ......... . 2.2 Anti- Inflammatory Drugs ........ .. .... .. .... .. .. . 2.3 BronchostimulanlS ......................... . 2.4 Cardiovascular Dru&s and Diuretics 2.5 Benzodiaupj,l('$ ...... ....... .... .. .... .. .. . 2.6 Anti- Inrectious Agents .......... .

3. Conclusion ... .. ... ...... .. .. ... ... .. .... ... ... ... .. . ... .. ............. .... ... .... ....... .

. ................. ...... 465 .. 467

.......................... 471

. ................................... 472 . 478

.. 479 .... 480

. ..... 481 ...... ... .... .... .. . .. ... 482 .. .... ............... ............ 484

Respiratory d isorders induce several pathophysiological changes involving gas C)l­

change and acid-base bala nce. regional haemodynamics. and alterat ions o f the alveolo­capillary membrane. The consequences for the absorpt ion, distribution and eliminat ion of drugs are evaluated.

Drug absorptio n after inhalat ion is nOt significantly impaired in patients. With drugs adm inistered by this route. an a verage o f 10% of the dose reaches the lungs. It is not comple tely c lear whether changes in pulmonary endothelium i n respi ratory fa ilure en­hance lung absorption. The effects of changes in blood pH on p lasma protein binding and volume o f distributio n are discussed, but re levant data are not available to explain the distribution changes observed in acutely ill patients. Lung diffusion of some ant i­microbial agents is e nhanced in patients with pulmonary infections. Decreased cardiac output and hepatic blood flow in patients under mechanical ventilation cause an increase in the p lasma concentration of drugs with a high hepat ic eu raction ratio, such as lido­caine ( lignocaine). On a theoretical basis, hypoxia s hould lead t o decreased biotrans­formation of drugs with a low h epat ic elltraction rat io, but in ~ivo data wi lh phenazone (antipyrine) or theophylline are conflicting. The effects of disease on the lung clearance of drugs are discussed but clinically relevant data are lacking..

Pllarmaco~mC II CS m RC'Splra!O!) Dlsordtrs 463

The pharmacokmellcs of drugs m pallen IS ","h asthma or chromc obslructlve pul­mona!) disease are reviewed. Stable asthma and chroniC obslructi\C pulmonary disease do nOt appear 10 affecl Iht dispoSition of theophylline or ,B~-agomsts such as salbutamol (albUiefol) or terbutahne. Imponanl variatIOns m Iheoph)lhne pharm~coklneliCS have ~n reported m crillCally ill patients. the causes of which are more lilely !O bt hnked to Ihl.' poor condition of Ihe pallents Ihan to a direct clTccl of h}polua or hypl'rcapma. Llltll.' IS kno\\<n regardmg the pharmacok1Oc\lcs of cromogi)cale. ipr.l.IfOplum. eOrileolds or anllmlcroblal agents 10 pulmonal') dlscase. In pallen IS undtr ml'Chanleal \'enlliallon. the half-hfe of mldalOlam. ant ... btnzodiazepme used as a se<lall\e. hn been found 10 be ltnglhcncd but Ihe undc-rI)lng mechanism IS nOI ... ell underslood. Pulmona!) al>­sorpllon of penlamldme was found 10 bt mcreased m palll'nlS under mechanical ven­IIlallon. Pharmacoklnetlc Impairment docs occur m pallents ","h SC\eff pulmonary diS­tase but morc work 15 needed 10 understand thc exact mechamsms and to proposc proper dosage regimens.

Pulmonary disease is one of the major forms of Illness in industrial countries. Understanding the physiopathological consequences of diseases such

as asthma, chronic obstructive pulmonary disease or acute respiratory distress syndrome is of major

concern. However. little attention has been paid to the pharmacokinetic consequences either during

chronic or acute stages o f the disease or during treatment by mechan ical ventilation. The normal

functioning of organs involved in drug disposition requires correct blood flow rate and blood oxygen pressure: impairment of these 2 parameters In sev­

eral lung disorders can lead to changes In drug ab­sorption. distnbutlon or elimination. Knowledge

of the extent of such changes is imponant in order to propose adequate dosage regimens, panicularly

for those drugs with a narrow therapeutic index. In 1978. Du Souich et al. reviewed current

knowledge in Ihe 'lung disorder' area and con­

cluded thaI much work remains 10 be done. This

review focuses on more recent developments in this field. including Ihe management of patients under mechanical ventilation.

Cigarette smoking, an aetiological factor for lung cancer. chronic obstructive pulmonary disease and

myocardial infarction. is an enzyme inducer and enha nces the metabolism of several drugs (Miller

1989). However. this point is not discussed as it is considered to be beyond the scope of this ankle.

I . Pharmacokinetic Implications of Pulmonary' Disease 1.1 Pathoph ysIOlogIcal Aspects

The pharmacokinet1cs of drugs may be altered by the ph)siopathologlcal changes mduced by the respirato!,) diseases: gas exchange and acid-base disorders (Du Souich e t a!. 1978): right ventricular function and regional haemodynamics such as he­patic and renal blood flow (Sham mas & Dickstein 1988): and alveolocapillary membrane alterations (Morel et al. 1985). Funhennore. the use of me­chanical ventilation in patients suffering from sev­ere hypoxic respiratory disorders may induce some negative effects on haemodynamic function and Ihus concomi tantly alter the pharmacokinetics of administered drugs (Richard et a!. 1986).

1.1.1 Gas Exchange and Acid-Base Disorders The onset of hypoxaemia is the common path­

way of most of the frequently observed respiratory disorders. In severe pneumonia. pulmonary oed­ema and pulmonary embolism. for example. hy. poxaemia is due to an increase in the shunt frac­tion and is associated with hrJ)ocapnia and respiratory alkalosis (West 1988). In patients suf· fering from chronic obstructive pulmonary disease. alveolar hypoventilation may occur and leads to hypercapnia and respiratory acidosis (Ocrenne et al. 1988). In the chronic phase, this respiratory

464

acidosis is compensated by a large increase in plasma bicarbonates.

J.J.} RighI Ventricular Function The long term consequence of the presence of

hypoxaemia is the onset of pulmonary hyperten­sion with increased pulmonary vascular resistance. Right ventricular dysfunction results from this pul­monary hypertension and is associated with an in­crease in pressure in the hepatic veins and inferior vena cava (congestive hepatomegaly) and a de­pressed regional blood flow to the vital organs such as the liver or the kidney (Braunwald 1988).

1,1.3 Afl'eolocapillary Membrane During viral infections or toxic pulmonary

aggression. an aileration of the alveolocapillary membrane might result in negati ve effects on the pulmonary gas exchange, leading to acute respira­tory dimess syndrome (Lemaire et al. 1984). Pul­monary extraction efficiency (alprostadil (prosta­glandin Et), serotonin) deteriorates once a very high threshold of respiratory dysfunction is achieved at the endothelial cell level.

1.1.4 Mechanical V~ntilalion Previous studies have demonstrated that inter­

mittent positive pressure ventilation induces an in­crease in intrathoracic pressure associated with a decrease in central blood volume, a fall in right transmural pressure, and a decrease in the cardiac index (Morgan et al. 1969; Suter 1983). The in­duced relative hypovolaemia explains the decrease in cardiac index according to the Frank-Starling mechanism. Once induced, the phenomenon ap­pears to be more prominent in previously hypo­volaemic patients with less compliant lungs ven­tilated with a high tidal volume (Morgan et al. 1969). The decrease in cardiac output might reduce regional blood flow such as hepatic flow (Bonnet et al. 1982); on the other hand, the elevation of intrathoracic pressure produces a rise in portal and hepatic venous pressure, inducing hepatomegaly and jaundice in prolonged ventilatory suppon (Medley-Whyte et al. 1976). The use of positive

elm. PharmQ, okmt't. 19 (6) 1990

end-expiratory pressure (PEEP) may reinforce these deleterious effects (Bonnet et al. 1982).

1.2 Absorption

1.1. / GastrointflStinal Absorpllon Decreased splanchnic blood flow can lead to di­

minished perfusion of the gastrointestinal tract and, therefore, absorption of drugs can be unreliable. Several papers have reponed a decreased rate of absorption of theophylline, salbutamol (albuterol) and terbutaline at night-time, which leads to a higher trough concentration in the mornins. This has been attributed to the supine posture and to reduction in gastric emptying (Jackson et al. 1985; Jonkman et al. 19S8; Pauwels et al. 1986; Powell et al. 1987; Warren et al. 1985).

For drugs highly extracted by the liver, in­creased bioavailability can be the consequence of a decreased first-pass effect, due to ei ther liver im­painnent or decreased activity of gut metabolisins enzymes. Drugs such as ,82-agonisls are highly me­tabolised by gaSirointeslinal tract enzymes and, so far as is known, impainnent of metabolism has not been reported in patients with pulmonary disord­m.

A decrease in the bioavailability of furosemide (frusemide) has been reponed in patients with chronic respiratory failure (Ogata et al. 1985); how­ever, the values reported by these authors are within the nonnal range (see section 2.3.3 for discussion). Du Souich et aJ. (l978) have suggested the possi­bility of delayed or incomplete absorption of pro­cainamide in 20 subjects with chronic respiratory disease, bu t the reasons for such impai rment are not fully elucidated.

1.2.2 Lung Absorption - Aerosols The ideal profile of a drug to be administered

in pulmonary disease (bronchodilato~ or anti­infectious agents. for example) is to reach the site of action within the lungs quickly but with mini­mal uptake by other organs, which should min­imise side effects. Therefore, aerosol drugs have been extensively studied: ,8-sympalhomimetic drugs were recognised long ago as having bronchodila-

Pharmacokinetics In Rrsplr.lIOI') DI!oOrdrr.;

tory action. although thcir cardiac effects pre­cluded their systemic use. Nebulisation of isopren­alLne (isoproterenol), for example. was shown to provide local effects wllhout side effects. In fact, when the drug is nebulised only part of the dose reaches the lung and the rest is swallowed. More­over. isoprenaline is extensively metabolised in the gastrointestinal epithelium, thereby lowering bio­availability (Davies 1975). The clinical use of aero­sols has been proposed for newly marketed fh 3.gonists, for anticholinergic drugs such as ipra­troplUm. for conicosteroids and antimicrobial agents such as aminoglycosides or antiprotozoal agents such as pentamidine, which has been shown to be effective in l'neUmOC.l'SllS carinil pneumonia m AIDS patients. Administration by inhalatIOn for each of the abovementioned drugs is diSCussed In

more detailm section 2. However. general conSid­erations about inhalation therapy have been pro­posed (Brain & Valberg 1979: Newman 1985) and arc summarised below.

The first requirement of aerosol therapy in or­dcr to achieve a full therapeutic effect is to get an adequate amount of drug Into the small alrwa)s. There arc many wastage sites for respiratory s0-

lutions m nebuliser therapy: most studies show that the amount of the nebulised dose reaching the small airways does nOI exceed 15% (Clay & Clarke 1987).

The site reached within the respiratory tract de­pends on several factors. First is droplet size: par­ticles In the I to 5.11m ran~ are mostly deposited m the small conducting airways and alveoli. while for the majority of larger panicles the site is the large conduction airways. The second factor is speed of inhalation: slow, sleady inhalation increases the number of particles which penetrate 10 the peri­pheral parts of the lungs and, as the volume in­haled IS increased, the aerosol is able to penetrate more peripherally into the bronchial tree. Holding the breath for a period on completion of inhalation enables those panicles which penetrate to the lung periphery to settle into the airways through the ef­fects of gravity. Finally, patient factors will alter Ihe depositing of the aerosol. Airways obstruction and changes in parenchyma are often associated with decreased or zero depositing in the alveoli.

'"

Most abnormal states appear to enhance deposit­ing in thc airways at the expense of that m the lungs.

Many patients have a poor inhalation technique which further decreases depositing in the lungs. It must be kept In mind that if most of the aerosol is deposited in the oropharynx. the consequence is potential systemic absorption and adverse reac-110ns.

It is not completely clear whether changes in pulmonar) endothelium in respirator)' failure en­hance drug absorption from the lungs.

1.3 Distribution

J.1.1 Pro/eln Binding and Folume 0/ Dismbllfion One of the major determinants of the diffusion

of drugs thoughout the body is their plasma pro­tein binding. The apparent volume of distribution (Vd) is related to the unbound fraction (fu) as fol­lows:

where V p is the plasma volume. fu.t the unbound tissue fraction and VI the tissue volume.

Drugs can be divided into 2 groups according to their physiochemical propenies and binding characteristics: acidic drugs, which are highly bound almost excl usivel y to plasma albumin: and neutral and baSIC drugs, which are bound to several pro­teins Including albumin, lipoproteins and ai-acid glycoprotein. Any changes in the level of these pro­teins will consequently alter binding capacity.

A drop in plasma albumin levels, ollen seen in severe liver or renal failure, could cause an in­crease in the volume of distribution of a variety of drugs (pfiasky 1980; Tillement et a!. 1978): in­creased free fractions of drugs have been reported in these diseases as a consequence of competition with endogenous substances which accumulate. The level of aI-acid glycoprotein can vary considerably in several physiological and pathological condi­tions: see the recent review by Kremer et al. (1988). A 2- to J-.fold increase In at-aCid glycoprotein lev­els has bttn reported in chronic obstructive pul-

monary disease. inflammation of the lungs, respi­ratory tract infection and lung cancer. Paxton and Briant ( 1984) have shown Ihal, in 6 elderly palients with chronic obstructive pulmonary disease, un­bound propranolol was halved compared with the value in healthy young or elderly volunteers (6.8 ± 2.2 vs 12.9 ± 2.5 and 10.8 ± 2.1%, respectively) due to increases in the level of ai-acid glycoprotein (1.39 ± 0.41 vsO.62 ± 0.11 and 0.73 ± 0.15g/L, respectively). In most situations the average value in the acute phase is twice as high as that in healthy subjects. This large variation in the plasma at-acid glycoprotein level can have a profound effect on drug concentrations in the blood. Kremer et al. (1988) showed that the binding of many of the basic drugs studied increases linearly with al-aeid glyco­protein levels. For drugs like propranolol, binding to al-acid glycoprotein accounts for more than 50% of the total bound drug, so that any increase in the binding can be clinically relevant.

1.).1 Effects of Plasma pH on Dislribmion From a theoretical point of view. the degree of

ionisation of drugs with pKa values close to plasma pH shou ld be sensitive to small changes in the lat­ter. If the un-ionised lipophilic fraction of the drug increases, this should lead to increased tissue dis­tribution.

The effects of changes in plasma pH have been well documented in vitro for theophylline. Rela­tionships between pH, protein binding and volume of distribution are not as clear in vi~'o (see under Distribution in section 2,1.1),

Animal experiments have shown that changes in plasma pH do not alter the distribution of phen­obarbital (Monin et al. 1984) but metabolic acid­osis increases the volume of distribution of pheny­toin without a change in protein binding(Du Souich et al. 1986).

More work is needed in this area for a bener understanding of disposition changes observed in patients with respiratory disorders.

1.3.3 Lung Diffusion Many drugs are orally or parentally admini­

stered and should reach their site of action within the lung to produce their therapeutic effects. The

e/ll1. pnarmacQkIl1t'f. J9 (6) /990

pulmonary diffusion of drugs is difficult to assess apan from cases of surgery 10 remove a lung. How­ever, for drugs such as bronchodilators, there is in­direct evidence that they reach the bronchial site of action as there is a fairly good relationship be­tween plasma and pharmacodynamic parameters such as forced expiratory volume in I second (FEV I) - see section 2.

In the area of antimicrobial agents, there are a considerable number of studies indicating that for efficiency in respiratory infections, the antibiotic must pass from the pulmonary capillaries into the submucosa and diffuse across the epithelium into the bronchiolar lumen. There is a large variability among the different classes of antibiotics; table I shows the antibiotic concentration ratio of respi­ratory secretions to serum (Bergogne-Berezin 1983). There is evidence that antibiotics reach the lung by passive diffusion which depends on several vari­ables; first, the physiochemical characteristics of the drug (since drugs which are in un-ionised form at serum pH levels, or highly lipid-soluble agents, should penetrate the vascular membranes to a greater extent); secondly. the higher the peak serum concentrations, the higher the degree of bronchial penetration with passive diffusion in accordance with the concentration gmdient: finally, bronchial inflammation may increase the penetration rate of some compounds (Barza & Cuchural 1985). An in­creased penetration rate with bronchial inflam­mation is well documented for ampicillin, amoxy­cillin and cefalexin. Among the aminoglycosides, tobramycin concentrations were higher in the bronchial secretions of patients with pneumonia than in those without inflammation ; in contrast, the passage of gentamicin is unaffected by bron­chial inflammation. Furthermore, it has been shown that the concentrations of aminopenicillins and oleandomycin in bronchial secretions increase with the degree of inflammation, whereas those of spi­ramycin, minocycline and thiamphenico\ remain unchanged (Bergogne-Bertz.in 1983). Smith and Lefrock (1983) suggested that a more meaningful penetration percentage may be determined by comparing the area under the concentration-time curve (AUC) for sputum with that for serum, These

l>harmacoklllc\LCS '" RespIrator) DIsorders 467

Table I. Mean (range In parentheses) serum and tlrOl'ld'llal concentra tlOllS of some antibiotICS 2 to 3 hours alter admln,stra,1OfI In

humans (Irom Bergogne·e.izln 1983. With p&rI'l'llUIOIl)

"" .. Oo~ ........ C. c". 8r : S

'g) (mg/l) (mg{L) "" .... mo.lCllhn , PO 14 7(128·172) 052 (023-0 98) 3S .... mpicllhn , PO 31 (24-45) 01 (0-0 15) 3 Mezloc,lhn 5 ,v 104 0 (26-221)) 100{1.0-220) 96

C.lota.,me '" 58(31-110) 14 (0 12-1 6) 25 C.lo_ltm , ,v 113(21-235) 28 (I " -36) " Ca"adlfle , PO 18{35-130) 12 (09-113) " CalUfo.orne 075 '" 106{7.6-155) 19 to " -3 5) " latamoxal (mo~alaclam) " '" 5-49 (24·99) 50 n 4-6.2) 9

Doxycychne OJ PO '" 105 (0 12-3 27) 38 Mlt'locycilne 02 '" 4 6 (1.2·5.3) 17 (0.4-5 4) 37 Tetracycline 02' PO 26(1.0-40) 05 (0 4"-0 56) 20

CIlI'IdamYCIn 03 PO <'6 (<' 2· j.f . .. ) I 6 (03-U ) " EryUlfomyCin ethylsuccll'llte " PO 1." (0.3'2 6) 059 (0 12-2 49) " OlunoomyCitl 05 PO 2." (0. 6-0& 0) 3_5 (I 8 .... 6) >I'" Spifamy<:1f1 " PO 3.3 p ... -7 2) 7.3 P 0-1 8 0) >I'" GentamICin 0.'- ." 6.15 1.8 (0.1 .... . 3) " Tooramyclt'l 17' " 0.65

Sulf.metho~Il()IeQ 0.' PO "7.4 ' .7 " TnmethopnmQ 0" PO " ,., >I'"

a All drugs given as Single doses except where otherWIse noted.

b Ttl,ee closes c Four doses d Two doses

e g/kg

I mg/kg 9 .... drillnostered concorrwtanliy as cotnmo.uole

Abbtev,.tI,Qrn· ~ _ serum (lfuog concenlfatJon; Cor • bronchl.1 dfug ooncentratoon. Bf: S • rabO 01 CIl< 10 C •• PO • or. 1 admlnostrltJon. IV • Intravenous aamlt'llSlfaUon; 1M • intramuscular Idmln,strabOn.

authors Itst the sputum concentrations of several antibIotics and compare them with the minimum inhibitory concentrations (MIC) of most pathogens responsible for bronchial tract infections. Review­ing previously published data, Wise (1986) clearly demonstrated that the cl inical effi cacy of various antibiotics is related to the sput um concen tration compared with the MIC of the responsible patho­gen rather than serum concentration. However. this does not appear to be so relevant in cystic fibrosis.

possibly due to the multifactorial nature of this dis­.. "'. 1.4 Elimination

The 2 major routes of drug elimination are he­patic biotransfonnation and renal excretion. How­ever, other organs such as the gu t or lungs have drug metabolising enzymes. The role of the latter is now recognised. and possible impainnent of lung clearance in respiratory disorders is discussed here.

46.

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FIg. 1. IndIVidual values for (a) $1~Y'$Ule plasma toTlC'tn· 1I1I110n of lidocaioc (lignocaine) and (II) loul hdocame dear­anor mcuuml In patients sulTenltJ from chromc respiratory fail ure. Dnla was administered in travenously IS an initial bolus of 1.5 mlfkl, fo llowed by an infulion of 1.0 10 1.7 mil min over 2 hours. Palients wert under ei ther mechanical venlila tion (MV) or spontaneous ventilation (SV). - - mean value of dau: * -p < 0.01.

Clift, PharmacoJ.;.ml't. 19 (6) 199()

J A. l lIepatic Biotransformation

General Principles The hepatic clearance (CLH) ofa drug is related

103 pa ramelcr5 (Rowla nd & Tozer 1980; Wilkin· son 1986): li ver blood now (~). unbound blood protein fraction (f ... ) and intrinsic clearance (CL.). which reneets hepatic enzyme activity.

The 'venous equi libration' perfusion model yields the followi ng relationship:

ClH - ~ IfuCltf(Cbi + fuCL;)]

where the term (fuCli/(~ + fuCl;) is the hepatic ex traction (EH).

However, these 3 parameters have a different influence o n ClH according to the hepatic extrac­tion ratio of the drug: the rate of elimination of drugs wilh a high Ell (>0.7) wi ll depend primarily o n liver blood flow. For these drugs. any fall in Cli will cause an increase in absolute bioavailability after oral administration, due to a decrease in the hepatic first-pass effect; a nd the rate of eli mination of drugs with a low EH «0.3) will depend on fu and Cli .

Decreased Hepatic Blood Flow As mentioned above. low cardiac output is one

o f the consequences of ri&ht ventricular failure . Hence. liver blood flow will be decreased as well as the clearance of drugs with high hepatic extrac­tion.

Mechanical ventilation with or without PEEP decreases cardiac output and hepatic visceral blood flow (Bonnet et al. 1982; Perkins et al. 1989a,b): the reported decrease in hepatic blood flow ranges from 2 to 40%. Richard et al. (1986) evaluated the pharmacokinetics of lidocaine (lignocaine) in 5 patients. first at the end of a period of at least 6 to 10 days of mechanical ventilation and secondly during spontaneous breathing when the patients had been weaned from the ventilator. The individual pharmacokinetic data are shown in figuR: I ; under mechanical ventilation, the mean systemic clear­ance of lidocaine (a high hepatic extraction drug) decreases by 22%, which leads to increased steady­state plasma concentrations. These increased con-

Pharmacoklnt li C'S In RespIratory Disorders

centrations are ofimponance for drugs which have a narrow therapeutic margin. As emphasised by Perkins et al. (I 989a), similar phannacokinetic im­pairment can be expected with other drugs highly cleared by the liver such as labetalol. pethidine (meperidine). metoprolol. propranolol and vera­pami!. all used in the intensive care unit. Since the level of respiratory suppon changes with the clinical condition of the patient. the pharmacokinetic para­meters may also change with time. Interventions that min imise the decrease in cardiac output and organ blood now (expansion of intravascular vol­ume. positi ve Inotropic agents decreasing mean airway pressure) theoretically reduce the risk of these ad verse drug reactions from decreased drug clearance.

Changes in Hepatic Enzyme Activity In a review on drug metabolism in extrahepatic

disease, Farrel (1987) has poi nted out that uncom­plicated asthma or chronic obstructive pulmonary disease is not associated with clinically imponant abnormalities of drug metabolism. and that severe hypoxia appears to be the factor most likely to cause impaired oxidative drug metabolism in cardiopul­monary diseases.

Studies on drug metabolising enzymes at a bio­chemical level have shown that oxygen is required for many reactions. However, the sensitivity of these enzymes to hypoxia varies (Jones 1981); some enzymes (e.g. cytochrome P450 enzymes) are di­rectly dependent on oxygen concentration, since the heme is a binding si te for oxygen; all other enzyme processes require a source of energy which will be decreased under hypoxia. Therefore, on a theoret­ical basis. reactions such as alcohol oxidation or g1ucuronidation can be expected to be inhibited by hypoxia.

Depending on their metabolic pathways, the elimination of drugs will be differentially affected by the severity of hypoxia. A study performed in isolated perfused rat liver supports this conclusion: under hypoxia, propranolol clearance (which is at­tributed to efficient oxidation by hepatic micro­somal mixed function oxidase) is decreased, whereas sodium taurocholate uptake remains un-

469

impaired, affirming the lower oxygen dependence of this transport process which is dependent on Na+,K+-ATPase (Jones et a1. 1984).

In vim studies are more conflicting, and after reviewing in I'i~'o animal and human studies Du Souich et a1. (1978) and Farrel (1987) have sug­gested that. in contrast to acute hypoxia which is associated with impaired hepatic drug metabolism. chronic hypoxia may actually stimulate oxidative drug metabolising enzyme.

Phenazone (antipyrine) is a drug not bound to plasma protein, which is metabolised by the liver with a low extraction ratio; therefore, its phar­macokinetic parameters are often used as an in yivo index of hepatic drug metabolism capaci ty. The re­sults of 3 studies are summarised in table I I. Cum­ming (1976) showed that patients with low arterial oxygen tension (Pa02) [ <55mm Hg) have longer phenazone half-lives than those with higher Pa02 levels (>55mm Hg); simi larly. Layboum et a1. (1986) found phenazone clearance to be 18% lower in patients with chronic obstructive pulmonary disease, and in patients with a\-antitrypsine defic­iency with lung disease, than in healthy volunteers. On the other hand Agnihotri et al. (1978) found higher clearance in patients with respiratory failure (whether under oxygen treatment or not) than in controls.

Studies performed with theophylline, another low hepatic extraction drug (see section 2.1) tend to show that the effect of low Pa02 is minimal on the overall disposition.

These contradictory studies show that the ef­fects of Pa02 level on hepatic drug melabolising enzymes are not very well understood. and that in contrast with in vitro studies. many other factors such as age, consumption of tobacco, alcohol or coffee, duration of the illness and drug interaction effects may contribute to impairment of the he­patic clearance of drugs in patients. Centrilobar in­jury occurs following hypoxia in isolated perfused liver (Lemasters et al. 198 1) and hepatic function was claimed to be a major determinant of survival in patients with the adult respiratory syndrome (Schwartz et al. 1989); however. whether this find-

470 e lm. PharlllacQkmt'f 19 (6) /990

Table II. f'hf,rmllookinetoc PIIrllrnet8fS 01 pl'lenazone (antipyrine) in pulmonary din",.

Relerence Patients

Cummtng (1976}" Patients witn low Pa02 <55mm Hg In • 5) >55mm Hg In • 12)

AgnIhotri I' II. (1978)1' Acute Of chronic fespot.tory labe In • 8)

controll: orthop.HdiI;: Plltients

III - 6)

Laybourn a, al. (1986)b <w""tllryps!ne deficiency Wlltl lung diMa .. In • 35)

COPO In • 25) Healthy volunteers In • 31)

• Values given 'f. mean :I: SEM. b value. given .r. mean :t SO.

c p < 0.05 comPlred with controls. d P < 0.01 compared with controls.

I - CL " I") (L/h) [LJhfk91 (l/kg)

18.' j: 3.5 8.' :I: 1.0

8.1 .i: 1.9C 2.116 :I: 0.90 0.$5 % 0.08 [0.050 :I: O.OlJ<1]

14.8 :I: 3.7 2.16 :1: 0.79 0.60 :I: D.o. [0030 j: 0.009]

2.6 j: I.OC

2.1 :!: 0.11" 3.2 :t 1.1

AbtJfevflll~: I ... . eIir'oWIatioti half·~I.: CL • total bo<ty clearanoa 01 drug from pIfI$ITIII: Vd _ YOIume of distribution: P-<h • arterial o~ tension: COPO • chronic obstructi'la pullTIOI'Iary disease.

ing is linked to the impairment or the hepatic dis­position of drugs remains to be established.

1.4.2 Renal Excretion Pharmacoki netic data relating to the renal elim­

ination of drugs in pulmonary disease or under mechanical ventilation are not available. However. Perkins et a!. (1989a) have summarised the main changes in the renal excretion of drugs that could be expected due to decreased cardiac output and renal blood flow as the consequence of cor pul­monale and/or mechanical ventilation. Renal clearance of drugs (such as va ncomycin . ,8-lactam antibiotics. aminoglycosides and digoxin) whose clearance is predominantly dependent on the glo­merular filtrat ion rate would be decreased.

The extraction of drugs undergoing tubular se­cretion is dependent on the tubular ex traction ratio of the drug and blood fl ow 10 the site of tubular secretion. Therefore, any decrease in renal blood fl ow will reduce the clearance of drugs such as dig­oxin. furosemide. procainamide and several pen i­cillins.

Finally. as urine volume decreases. drug in the

glomerular filtrate becomes more concentrated and the gradient for drug reabsorption increases. and thus clearance is reduced. Aminoglycosides and possibly theophylline and phenobarbital are ex­amples of such drugs.

1.4.3 Lung Eliminalion It is now well rtCOgnised that the lungs are a

site for the uptake. accumulation and/or metal; olism of numerous endogenous or exogenous com­pounds. An early study reviewed current know­ledge on the pharmacokinetic function of the lungs (Bakhle & Vane 1974). Since then a number of re­views have appeared covering several features of the metabolic functions of this organ (Bend et al. 1985; Block 1986; Devereux et al. 1989; Gillis 1986; Minchin & Boyd 1983; Roth & Wiersma 1979; Ryan & Grantham 1989).

The handling of some endogenous and exoge­nous substances by the pulmonary endothelium involves several processes: uptake and biotrans­formation (serotonin. prostaglandin E and F), me­tabolism at the endothelium surface without up­take (angiotensin. adenine nucleolides. bradykinin)

Pharmacokinetics In Resplr.l101) Disorders

and uptake with gradual release unchanged (pro­pranolol, lidocaine, imipra mine).

Like the liver, the lung contains e nzyme sys­tems that can detoxify as well as activate chemi­cals. but the enzyme activi ty of many metabolic pathways appears to vary qui te significan tly among the many pulmonary cell populations. It is wonh noting that the lungs are in a umque position for drug metabolism as they receive the entire cardiac output. and Collms and Dedrick (1982) have em­phasised their contribu tion to IOtal body clearance. As reviewed b~ Roth and Wiersma ( 1979). several factors arc most likely to affect the pulmonary clearance of xenobiotics. Fi rst. cigarette smoking can induce several drug metabolismg enzymes and hence enhance the role of the lungs as an elimi­natmg organ. Secondly, changes m cardiac output Will alter pulmonary clearance for some drugs. Fi­nail). changes in plasma pH ma~' alter the ability of lung tissue to clear circulating substances. as demonstrated in isolated rabbit lung with which it was secn that pulmonary clearance of mescaline was elevated In condi tions of hyperventilation which led to alkalosis.

Another importan t factor is the integrity of the pulmonary capillary cell. Animal models have shown that some lung injuries. sueh as those caused b) hyperoxia. are associated With decreased uptake of endogenous compounds (Block & Fisher 1977: Gillis & Catravas 1982: Mais et al. 1982). Simi­larl y. m patients with acute respiratory distress syndrome. the removal of alprostadil and seroto­nin is decreased. which indicates a diffuse func­tional injury to the endot helium (Gi llis et a1. 1986: Morel et a1. 1985).

The consequences of pulmonary disease on lung uptake of drugs are unclear. Propranolol uptake. which is high in patients without evidence of lung disease (Geddes et al. 1979). was decreased in patients with pulmonary emphysema and pulmo­nary hypertension (Pang et al. 1982) but not in those with acu te respiratory distress syndrome (Morel et a1. 1985). Lu ng uptake of lidocaine is also high (Jorfeldt et al. 1979), but t his uptake has been shown to be unchanged in artificially ventilated patients with classic respiratory insufficiency syn-

411

drome (Jorfeld t et al. 1983). On the other hand. pulmonary uptake of morphine is very low (3% of the injected dose) in patien ts without ev idence of lung disease prior to surgery (Rocrig et a1. 1987). This removal remains unchanged in surgical patients under mechanical ven tilation (Persson et a1. 1986).

Ho\\,ever. the consequences of pulmonary ex­traction on the overall bod) disposition of drugs are not full y known. One recent study has evalu­ated pulmonary extraction and the pharmacokin­etics of alprostadil in patients With acu te respira­tory distress syndrome (Cox et al. 1988). The drug was administered by continuous infusion and pu l­monary ex traction varied from 0.11 to 0.90. The extraction appears to decrease abruptly in patients with panicularly scvere respiratory insufficiency as a consequence of decreased intrinsic lung clear­ance. The wide range of extraction ratios Implies high interindividual varialion in steady-state plasma concentrations; in se\ere respiratory failure plasma concentrations may increase scveral-fold, and pat ients should be monitored accordingly. As poin ted out by Gillis ( 1988). th is study clea rly es­tablishes the clinical importance of the first-pass effect of the lung in determining circulating drug concentrations during sustained infusions. This point IS often neglected in considering drug dis­position.

1. Drugs Used in the Management 0/ Respiratory Disorders

Bronchodilators currently used in the manage­ment of acute or chronic asth ma or chronic ob­structive respiratory disease include theophylline, the newer .82-agonists such as salbutamol or ter­butaline and inhaled an ticholinergics such as ipra­tropium . Shon term oral corticosteroid therapy or inhaled formulations have been shown to restore (1-adrenergic responsiveness. probably by suppres­sion of inflammation or another. unknown. mech­anism of action. Sodium cromoglycate is an effec­tive prophylactic agent against ch ronic asth ma (Hendeles 1988: Kesten & Rebuck 1989). The methylxanthines (theophylline and caffeine) are also

412

used in the neonate for the treatment of apnoea in prematurity (Besunder et aJ. 1988; Galka & Re­buck 1985), Among the other drugs used in the management of lung disease, only those for which pharmacokinetic changes have been reponed are mentioned. Patients under mechanical ventilation in intensive care units are often given inotropic drugs such as dopamine or dobutamine to over­come the decreased cardiac output and organ blood flow. Alterations in the pharmacokinetics of such drugs, and others such as lidocaine, in critically ill patients have been recently reviewed by Boden­ham et aJ. (1988).

2.1 Bronchodilators

2.1.1 Theophylline Theophylline is a potent bronchodilator cltten­

siveiy used in the management of asthma and chronic obstructive airways disease. Its pharmac(). kinetics have been extensively studied in both volunteers and patients (for reviews see Hendeles & Weinberger 1983; Hendeles et al. 1985, 1986; Ogilvie 1978). After a brief summary of the main features of the pharmacokinetics, this review fo­cuses on those investigations performed in patients with lung disorders.

Absorption The absorption of theophylline from liquid and

plain tablets is rapid. The rate and extent of ab­sorption differ between the various slow release formulations (Hendeles et al. 1984); the influence of food on the rate oftheophylline release has been recently reviewed by lonkman (1989). The abso­lute bioavailability of oral formulations is almost complete so that, when therapeutic concentrations have been achieved with aminophylline infusions in patients with acute severe airways obstruction, an immediate oral administration of an equivalent dose of a slow release formulation will enable ad­equate concentrations to be maintained (Silins et al. 1984).

Distribution The mean protein binding of theophylline

measured in 42 patients with asthma and 6 adult volunteers was 70% (58 to 82% in patients and 66

c/in. Pharma(okinl't. It} (6) 1990

to 79% in volunteers) (Simons et al. 1979J. In a group of 51 patients with obstructive airways dis­ease, the extent of binding ranged from 31 to 83% (mean 60%: Lesko et al. 1981); in the same study, it was shown that the interpatient variation was high but that variation in binding in patien ts from whom 2 or more serum samples were collected was relatively small. Concentration-dependent binding was discussed but is unlikely to occur at therapeu­tic plasma concentrations of drugs (Buss et al. 1985; Shaw et al. 1982). Plasma pH variations were pro. posed as another explanation of differences in binding: in vitro data indicate that approximately 30% oftheophylline is bound at pH 7.0, 49% at pH 7.4 and 65% at pH 7.8 (Vall ncr et a!. 1979). Shaw et al. (1982) studied factors affecting in vitro meas­urement of binding and found similar variations with plasma pH , though their values were some­what lower (38% binding at pH 7.4); they also showed decreased binding with increasing temper­ature, which is an important factor to take into ac­count concerning in vitro measurements.

Theophylline protein binding was found to be significantly lower in a group of9 acutely ill patients who were under ventilatory assistance than in a group of 13 patients with stable chronic obstructive pulmonary disease (30 ± 5 vs 45 ± 5%: Zarowitz et al. 1985). The major determinant of decreased theophylline binding was the severity of the clinical condition, and binding was linearly correlated with serum albumin level ; plasma pH (ranging from 7.22 to 7.47 in the acutely ill patients) was found to play a minor role in altering protein binding.

The mean volume of distribution averages 0.45 to 0.50 L/kg, although intrasubject variability was considerable in critically ill adults (Zarowitz et al. 1988). In 2 studies, an inverse relationship has been found between volume of distribution and arterial pH in patients with severe chronic obstructive pul. monary disease (Cusack et al. 1986; Resar et al. 1979). These results cannot be explained by pro­tein binding impairment. Rather, Cusack et al. (1986) attributed the changes to concomitant changes in arterial carbon dioxide tension (PaC02). In contrast, in vivo animal studies do not show any influence of respiratory acidosis or alkalosis on the

Pharll1aco~m ... u('s m Resplr:llol) DIsorders 473

Tab! e III. l'tlarmacolunelJC parlmelers 01 IMophylhne on pabenlS WI,h pulmonary dIsease (,.Jl9fIII'I parenlheses)

Reference Subf&cts/dlsease Do..,. '. CC '" Commen,s

1"1 (LJh/kg) (l/kg)

Plafsky el al Pallflnts wllh pulmOnary 2.3 01 ' .5 mg/kg IV IS) 23 (3·82) 0.~1 '" ' '''' P < 00 1. CL (1977) oedama (1'1 .. 9) (0 0001·0 141) (0 40·080) p < o OS. Vd NS

Heal!"y subfe<;ts (1'1 .. 19) 4 5 mo/kg IV (5) 7 ( 4.12) "" ' " (0029·0 124) (035·070)

Powell el al Heal!hy voluntaers lOll amlnopl"lylhne (1 9781" (n .. 31 ) Inlusoon

smokers 0063 :!: 0019 '" '" nonsmokers 0~2 0010 '" '" Patients wltn , "'. , '" 0.50 '" uncompllcaled aOfways obst.uctlOn (1'1 .. 2l))

smokers 0055 "" nonsmokers 0039 0019 Coogesllve 1\81.tl111ure 0026 0013 '" '" and c"ronlC bronctu"s (1'1 .. 3] PneumonIa WIt" asthma or 0027 :!: 0009 035 - OOS chron.c broncMIS (1'1 .. 3)

V.cuna el al Patlen,s WIt" COPO LoadIng dose" Inlusoon 0~8 :!: 0025 CL p < 0001 (1979)" In " 28) COPO 076 mg/h/kg

PatlenlS wlln COPO + COPO .;. cor pulmonale 0029 , 00001 cor pulmonale (1'1 ..- 78) 0.66 mg/h/kg

Arnold el al Children wIth c"'on.c AmInophyllIne 2 10 4 1'1191 (198 11" aSthma (1'1 ..- 8) kg O>ter 5 mIn

acute phaSf.l " , L' 0079 :!c oo.3 0 40 ! 006 .ecovery phase " ,

" 0073 :0: 0030 0.39 :!c 008

remlSSIOf'I phase " , L' 0082 :. 0028 0 44 :< OOS

Baue. & BlouIn COPO. smokers Am!fll)ptlylllnfl 11'I1U$1OIl 0063 :!c 0.016 (1981)" 22·79y (mean 4.y) to steady·state.

COPO. smokers _ CHF dose adlusted accordIng 0.028 :< 0.01 2 No el1eel ot age 41·88y Imean 62y] to clInICal COfIdlllOf\ '" eaCh g'oup

R.cher at al B.onchlal asthma TheophyllIne 600mg PO 6.6 :. 0.5 3.0 :< 0.2 '" CL In l/h. Vd In (1982)" {n .. 31] L/kg, no

d,l1erences Irom voluntee.s

ChronIC all1tow obS1tuctlOf\ 7.8 :. 0.8 2 5 :!:. 0.4 0 40 (1'1 .. 8)

Au et al EIde.ly sub/e<:ts with loadIng close Improvement 01 (1985)" stable COPO 5-6 mo/kg (05h) sp!.ometrH:

smokers .;. IntuslOf'l 6.5 ! 05 0.OS7 :!: 00005 051 :!c 003 l unctlOf'l al nonsmokers 0.9 mg/kg/h (5 Sh] 11.0 • 08 0 033 :. 0003 0 48 :!:001 mean serum

MIOdIe-aged subjects concentratlOl'l WI1~ COPO 116 mg/l

smokflfS S. 8 ! 0 8 0.065 :!: 0003 0 51 ! 003 non$lTlOkafS 7. 4 .t 0 8 OOSI :. 0008 048 !002

a Values gIven ara mean :1: SD.

b V alues gIven are mean :1: SEM.

Abble~iafi<:>M: S • single dOse: NS • rIOt S'!Inilicant: CHF • congestIve heart fa Ilure: for o th!lr abbre~iatlOf1s. sea tabla It.

volume of distribution of theophylline (Kolbeck et al. 1979)_

Elimination Up to 90% of a dose of theophylline is biotrans-­

formed by the li ver with a l ow extraction ratio. Many factors can alter theophylline clearance, such

as age, diet and smoking.. and so interpatient var­iability in clearance is large (Hendeles et a1. 1986). Funhennore, several clinically significant phar­macokinetic interactions with altered theoph ylline clearance have been reponed with drugs admini­stered in combination (Jonkman 1986; Jonkman & Upton \984) including some of the new fluor-

474

oquinolone antibacterial agents (Edwards el al. 1988).

Within-subject variability in theophylline clear­ance has been demonstrated in volun teers (U pton et at. 1982) as well as in patients with mild 10 mod­erate asthma (Slaughter et a1. 1987). However. dur­ing acute illness (Vozeh el at 1978) and acute epi­sodes of respiratory failure, variability is larger both in adults (Zarowitz el al. 1988) and in children (Ar­nold et aL 1981; Kubo et at. 1986). These results cannot be related to nonlinear kinetics as Massey et al. (1984) found no evidence of dose-dependenl clearance in a group of 2 1 patients with airways obstruction , except in I patient.

Several studies ha ve attempted 10 relate theo­phylline clearance and severity of pulmonary dis­ease, and the results are summari sed in table III. It appears that patients with uncomplicated asthma or chronic obstructive pulmonary disease have clearance values in the same range as volunteers. In elderly groups, age has not been found to affect theoph ylline clearance significantly. bul patients who smoked had higher clearances. In contrast to this. patients with congestive heart failure, cor pul­monale. pulmonary oedema or pneumonia had sig­nificantly lower clearances (Au et al. 1985; Bauer & Blouin 1981; Massey et al. 1984; Piafsky et al. 1977; Powell et al. 1978: Richer et al. 1982; Vicuna et al. 1979).

The contribution of hypoxia has been evaluated in patients and several studies, summarised in table IV, indicate that reduction in PaOz does not alter theophylline elimination (Cusack et al. 1986; Du Souich et a1. 1989: Westerfield et a1. 1981; Zarow­itz et al. 1988). It should be pointed out that Du Souich et a\. (1989) found that changes in PaCOz were inversely related to theophylline clearance values, but the clinical significance of this finding remains to be established. In vivo animal studies are conflicting; Letarte and Du Souich ( 1984) have shown that hypercapnia and/or hypoxaemia de­crease theophylline biotransformation in rabbits, but Clozel et al. (1981) and Saunier et a!. (1987) have reported that neither acute nor chronic hy­poxia nor respiratory acidaemia in dogs affect theophylline disposition. Therefore, the contribu-

Clm. Phormacokm('{. /9 (6) 1990

tion of such studies in explai ning what is observed in patients is fairly small.

The influence of birth asphyxia on theophylline clearance in the neonatal period is quite variable, and was recently discussed by Moore et al. (1989).

The Concentration-Effect Relationship Variability in clearance as a function of patient

cl inical status will lead to variation in steady-state plasma concentration , which can reach toxic levels. The relationships between concentrations ofbron­chodilators and clinical efficacy or signs of toxicity are well established. Concentrations ranging from )0 to 20 mg/L appear to lead to a maximal ther­apeutic effect, without toxicity in most patients (HendeJes et al. 1986). Furthermore, bronchodi­lator effects parallel serum concentrations in patients with bronchial asthma while the correla­tion is less evident in patients with chronic airflow obstruction, despite similar concentrations (Richer et al. 1982). In patients with severe exacerbation of bronchial obstruction, a serum theophylline concentration close to 20 mg/L will result in a more rapid recovery of the pulmonary function than will concentrations in the 10 mg/L range (Voteh et al. 1982). The need to individualise theophylline dos­age is now acknowledged (Bierman & Williams 1989; Bukowsky et al. 1984; Hendeles et al. 1978); several pharmacokinetic methods have been pro­posed to maintain steady-state concentrations within this narrow therapeutic range. Hurley and McNeil ( 1988) have tested the accuracy of 4 dif­ferent methods. For clinical use, they recommend either the Bayesian method (as the easiest of the computer-based methods) or, in nonursent simple cases, the steady-state clearance method.

2.1.211:l-Slimulants Besides their tJ2"<Idrenoceptor selcctivity, the new

compounds such as salbutamol and terbutaline have improved pharmacokinetic properties com­pared with older agents such as epinephrine (ad­renaline), isoprenaline or orciprenaline (metopro­terenol): oral bioavailability and half-life are increased and they are therefore longer acting. Some tJ2-agonists (fenoterol, pirbuterol, bitoiterol) are

I'harmafolmcllcs m RespiratOr) !)lsordcl"li

Tlble IV. Ellecl 01 oxygen on the pharmacokmetlcs 01 tlleOphylhne

Relerence Sub/tlClsldl$8a$8

Cusack et al Patoents W1th COPO In - 10) (1986~ AA pC2 43 - 3mm Hg

AA+02 p0269 • 4mm Hg

au SouICh el Pallents W1lh COPO and al . (1989", hYPOXia (n _ 10)

belOfe oxygen therapy pa0255' 1 mmHg

aher oxygen therapy pa02 73 ~ 2mm Hg

WeSlIrloeld et PatlBnlS in • 20)

al { t981)'> ACute reSpiratory lallure and assisted ventilatiOn {n • 16)

a Values given are me",n !: SEt.! o V.'utS given are mean • SO

Dosage

Usual Of" dOse + IV siable IsotOpe

Ammophythne 4

rngfkg (20 mon)

Amooophythne

lOading dose 5·6 rng/kg + 20 mm

in tusion to

achlev' plasma concentration 01 1().2O mgIL

t,,,(h)

68 06

" 08

59 ! 06

58 ~ 0 7

CL

IL/h/kgj

0.050 • 0004 0048,.. 0005

0.062 :! 0(107

0.068 ~ 0010

0.043 ,.. 0015 (0.020-0.089)

V, ILfkg)

0" 'OS

GO, GO,

415

Comments

Vd inversely retaled 10 anBrial pH

P02 P < 0.001 . I, ., CL and Vd NS

Trend tOf decreasing CL as pC02 increases Cl.NS

No correlation W,lh tIIood

gases

AODr'VI"IOl1$ RA . pau,nts breathing room air only. R"'+02 • pallents Ilfeath'ng room aor plus nasal oxygen. P<h ,. panlsl pressure 01 oxygen. pC02 • parMI pressure ot carDOn dioxide. IV • Intravenous. IOf Other .bDl'evial oons. see table 11

used on I) b) inhalauon. and there is little mfor­mmion about their systemic pharmacokinetics [but readers are referred t o the recent review of Morgan (1990)). Inhaled ft~·agonist s are the lTeatmcnt of choice fo r a cute exacerbations o f ast hma (Barnes 1989: Ben-Zvi et al. 1982). The d iscussion here fo­CU5CS on salbutamol and terbutaline. for which there are more pharmacokinetic data available. Most pharmacokinetic in vestigations related to these 2 agents were performed in Ihe 19805. as sufficiently sensitive methods o f drug analysis were not avai l­able until recenlly. The pharmacokinetic paramet· ers of bolh compounds are listed in table V .

Absorption Oral administralion: the absolute bioavailabil-

ily ofsalbutamol is about 51)% (Morgan el al. 1986) and that of terbu lali ne is even lower at 12 10 34% (mean 22%) as observed in 5 subjects by Da vies (1 984a ), A yet l ower bioavai lability has been re­pon ed in 7 asthmatic c hild ren (9.5%: Hultqu ist et al. 1984), Metabolic s tudies have shown Ihal ex­tensive presystemic metabolism of these 2 drugs occurs in the g ut wall (George 198 1): besides Ihls firs t-pass effect. only 52% of terbutaline is ab­sorbed. whereas the absorption of salbutamol i s a l­most complete.

After administration of a solulion or p lain t ab­lets of salbulamol or t erbutaline. peak concen lra­tion occurs in I to 4 h ours (Morgan et al. 1986: Nyberg 1984). Several sustained release fo rm ula­lions are available, which lead to smaller fl uctua-

476 Cfin. PhamracQkinet. 19 (6) 1990

T,bIoI V. Ph,rmacokinetic par.meIB~ 01 tlrldrlnerglc agotH,ls. Values Ire mean :to SD: ligures In 5QI.Ilre brackets indicate tinge

Drug Subjects {mean welght)/dose '- CC C," YO F (re ference) ,h, tLfhJk9l (Lfh/kg) (Llkgl '''' salbutamol Heallhy volunteers (62.2kg: 3.9 :I: 0.8 29 :t. 1- 17 :I: ,. 156 :t 381>

(albuteroll n .. 10) (O • .t6) (2.S) (Morgan II al. IV: 400~!iI + 10 I'glmin lor 2ft

"'6) PO: 3 )( .mg day before 50 " Sludy + "mo on study day

Terbutaline Healthy voIunt88fS (70 :t. Skg: n ,.. 7) (Leferink It ai. IV 2.9 :t 0.2 "gfkg 3.6 :t. 1.0 0.26 :t 0.09 1.01 :t 0.14 1982) SC 5.9 :I: 0.5 I'g{kg 3.7 :t. 1.0 94 :t 18

Patients with asthma (75 :t Tkg: n .. 8) SC 5.5 :t. 0.6I'g/kg 3.6 :t 0.8 0.25 :t 0.04 PO SS :t 6 "gfkg 3.' :t 0.7 10 :I: 3

(Oostertlul, 81 Patients with asthma (32 :t 17y; n .. 10) ' .0 :t 1.0 19.' :I: ' .S- 112 :t 351> al. 1986)

(Hultquist 81 Children with asthma (S-lly: n .. 7) .1. 1984)

IV 5.S :t 0.3 .. glkg 12.1 [9-16J 0.23 0.14 1.57 :I: 0.13 [0.16-<1.321 (0,II-o,18J

PO SO :t: 0.3 $Og/kg 9.5 (7-14J

{BorgSlfom et Healthy volunteers (n • 6) at 1989) tV 0.25mg 13,7 :!: 1.3 0.20 :!: 0.04 0.13 :!: 0.01 1.79 :!: 0.13

POS"" 14.2 :!: 1.5

• L.jh .

b L Abbteviat!oM; ClR - renal clearance; F • bioavailabllity; lor other abbreviallons. 1M tables I end II.

tions in plasma concentrations. Maesen and Smeets (1986) have shown that in patients with chronic obstructive pulmonary disease, the use of con· trol led release tablets ofsalbutamol8mg twice daily is bioequivalent to standard 4mg tablets 4 times daily. The mean bioavailability of slow release ter­butaline compared with plain tablets is 75 to 80% (Nyberg & Kennedy 1984). Food has minimal ef­fects on the absorption of repeat action salbutamol tablets (Bolinger et al. 1989).

Subcutaneous injection: absorption is rapid, leading 10 a high peak concentration (Cmax) at tmax = 0.37 ± O.JOh in 7 volunteers and 0.43 ± 0.13h in 8 patients with bronchial asthma; the bioavail­ability is complete (94 ± 18%: Leferink et at. 1982).

Inhalation: aerosolised salbutamol or terbuta­line are used in all types of clinical situations en·

countered with asthmatic patients; they can be ad· ministered by several techniques which have been reviewed elsewhere (Ahrens & Smith 1984; Oolov­ich et a\. 1981 ; Kelly 1985; Noseda & Yemault 1989; Popa 1986).

Whatever the device used, only a small fraction of the dose is delivered to the lungs. A recent reo view of the pharmacokinetics of ji.agonis1s has shown that there is a greater pulmonary delivery of drug by nebuliser than by aerosol (Morgan 1990).

Plasma concentrations after inhalation of ter· butaline are lower than after oral adm inistration, which eltplains the absence of side effects with the former route (Davies J984b). Walters et al. (1981) have shown that increasing doses of salbutamol ad­ministered by nebuliser (1.5, 3.0 and 7.5mg) lead to an increase in ventilatory capacity; there is also

Pharmacokmelu:S m Kcspmllor) Disorders

an increase in plasma concentrations related to in­creased salbutamol absorption and subsequent dose-related side effects (increased pulse rate and tremor). In a recent study Vaisman et al. (1987) compared the pharmacokinetics of salbutamol given intravenously and by inhalation to healthy adults, and found the bioavailability of the inhaled formula tion to be 2.3%: an increased AUe was found in 10 patients with cystic fibrosis (0.292 ± 0.07 1 vs 0.076 ± 0.025 ~g/l· h); the authors es­timated the bioavailability at 7.6% in these patients and postulated that the chron ically diseased tracheobronchial tree in cystic fibrosis leads 10

higher permeability of salbutamol.

Distribution Following an intravenous infusion of 10 ~g/min

for 2 hours. an apparent volume of distribution of 156l (2.5 L/ kg) was documented for salbutamol (Morgan et al. 1986). Fagerstrom (1984) and Oos­terhuis et al. (1986) reported a mean value of Il0l (1.6 L/kg) for terbutaline. These large volumes of distribution suggest extensive tissue distribution . Lu ng uptake has been shown in animal studies and. in I asthmatic patient treated with terbutaline. postmortem measurement showed a lung to plasma concentration ratio of2 (Ryrfeldt & Ramsay 1984).

The plasma protein binding of terbutaline has been estimated as being about 14 to 25% (accord­ing to the technique used) of which about 5% binds to serum albumin (Ryrfeldt & Ramsay 1984). Sal­butamol protein binding is low (7 to 8%: Morgan et at. 1986).

Elimination Biotrans/ormation: Studies using tritiated com­

pounds have demonstrated route-dependent dif­ferences in the pattern of metabolism (Davies et at 1974; Evans et al. 1973). The major identified metabolite is the sulphate conjugate. More recent studies have shown that following intravenous administration about 60% of the dose of salbuta­mol or terbutaline is recovered unchanged in urine and 10% as the sulphate conjugate; no metabolite could be detected in plasma. Following oral administration, the fraction of the dose excreted

471

unchanged decreases. whereas the excretion of the conjugate increases: plasma concentrations of thc metabolite are much higher than those of the par­ent drug (Davies 198401: Morgan et at. 1986). These data strongly suggest a presystemic metabolism in the gastrointestinal mucosa. as previousl y men­tioned by George (198 1).

Using chiral high performance liquid chroma­tography (HPLC), Tan and Sold in (198 7) have shown that the sulphoconjugation of salbutamol is stereoselective, the most acti ve isomer R(- ) being preferentially conjugated with sulphate. Borgstrom et al. (1989) have shown that systemic biotrans­formation of both enantiomers of terbutaline is similar. but absorption and to a lesser extent me­tabolism in the gut wall are stereoselective pro­cesses.

A glucuron ide metabolite ofterb utaline has been found in asthmatic children but does nOt exceed 5% of the total rad ioactivi ty (R ipe et at. 1984).

C/('aranc(' and halflife: The average total clear­ance of salbutamol is 29 L/h. The renal clearance is about 17 L/h. indicating renal secretion. Renal clearance of the sulphate conjugate is 6 L/ h which is more or less in the same rang" as creatinine clearance, suggesting free filtration at the glome­rulus (Morgan et al. 1986). The total clearance of terbutaline is '" 13 L/ h. with two-thirds coming from renal clearance, which is stereoselective (Borgs­trom et at. 1989; Nyberg 1984: Oosterhuis CI at. 1986). Clearance data in asthmat ic children (8 to 12 years old) are in the same range as in adults (Hultquist et a!. 1984).

Most studies agree on a salbutamol elimination half-life ranging from 3 to 6h either after intraven­ous or oral administration in liquid form or with plain tablets (Price & Clissold 1989). In contrast to this, different terminal half-life values have been reponed for terbutaline: 4h either in volunteers or in asthmatic patients after single intravenous or subcutaneous injection (Bengtsson & Fagerstrom 1982; Lererink et al. 1982), 14h in a more recent study (Borgstrom el 011. 1989), which is close to the value calculated from urine collected up to 96 hours (average 17h: Nyberg 1984) and to the 16h re­poned by Bengtsson and Fagerstrom (1982) and

478

Nyberg and Kennedy (1984) after cessation ofmul­tiple dose treatment. Half-lives of 12h have been reponed in asthmatic patients (Hullquist et at 1984). These discrepancies are probably the con­sequence of a Jack of sensiti vity in some analytical assays.

After repeated administration, the pharmaco­kinetics of salbulamol and terbutaline remained linear in both volunteers and patients with asthma (Lipwcnh ct al. 1989; Lonncrholm et al. 1984; Powell el al. 1986).

Pharmacokinctic-Pharmacodynamic Relationships Several studies have demonstrated clear rela­

tionships between plasma tcrbutaline concentra­tions after subcutaneous or oral administration and bronchodilator effects, in patients with asthma, for both adults and children (lonnerholm et a\. 1984; Oosterhuis et al. 1986: Ripe et al. 1984: Van Den Berg et al. 1984). After 3 successive constant rate infusions of terbutaline in children with asthma, Fuglsang et al. (1989) established that maximal bronehodilation was obtained at mean terbutaline concentrations of 6.7 JlB/L (range 4.5 to 13.5 JIB/ L), but that effective concentrations were associ· ated with side effects such as headache, tremor and a slight increase in heart rate. From these results a dosage regimen was proposed for the treatment of severe bronchoconstriction in children, which con­sisted of a loading dose of 2 JIB/kg over 5 minutes followed by continuous infusion of 4.5 JIg/kg/h.

Slow release oral formulations of terbutaline or salbutamol have been evaluated over a 12·hour pe­riod in patients on a multiple dose regimen (Mae­sen & Smeets 1986; Pauwels et al. 1986). Both studies show that controlled release tablets are as effective as standard formulations. The variations in bronchodilator effect measured using FEV I were closely related to the plasma concentrntions of the P2'"agonist administered. Furthermore, Maesen and Smeets (l9g6) have claimed that a mean plasma salbutamol concentration of 10 JlB/L represents a satisfactory therapeutic concentration.

elm. Pharmarokmft. 19 ( 6) / 990

Drug Interactions Jonkman et al. (1988) have s hown in 12 healthy

volunteers that the addition of theophylline 300mg twice daily to a regimen of terbutaline 7.5mg con­trolled release formulation twice daily for 7 days did not influence any of the calculated pharmaco­kinetic parnmeters of terbutaline.

1.1.3 Anticholinergics

Atropine Since atropine absorption after inhalation is

nearly complete, this route can produce significant systemic toxicity (Harrison et al. 1986).

lpratropium Bromide After inhalation, the amount of ipratropium

bromide reaching the lungs is low (40 10%) and the rest of the dose is swallowed. Absorption through the gastrointestinal tract is slow, as peak plasma concentrations have been recorded 3 hours after drug intake. and absolute bioavailability after oral intake is only 30%. The elimination of the ab­sorbed dose occurs in metabolised form in the urine and bile. Whatever the route of administration, the mean half-life is about 3.5h. Plasma concentrations observed with inhaled ipratropium were 1000 times lower than those observed with an equibroncho­dilatory dose administered ornlly, which explains why systemic anticholinergic effects do not occur with normal inhaled doses (Pakes et al. 1980).

2.2 Anti- Inflammatory Drugs

2.2.1 Corticoids Despite a medanism of action which is un­

known there is widespread agreement that gluco­corticoids are of value in the treatment of acute episodes of asthma refractory to standard bron­chodilator therapy (Barnes 1989; Fanta et al. 1983; Fiel et al. 1983; Harris et al. 1987). An overview of the use of corticosteroids in asthma has been recently published by Siesel (1985), and this author recommends the use of short acting preparations such as prednisone. prednisolone or methyl-pred-

nisolone in patients with asthma who require oral corticosteroid therapy.

The climcal phamlacokinetics of prednisone and prednisolone have been reviewed by Ga mbertoglio ct at. (1980) and Pickup (1979). Both drugs arc in­terconvertible. and prednisolone is assumed to be the pharmacologically active agen\. They arc rap­idly absorbed after oral administration. Predniso­lone is bound to serum albumin with low affinity but high binding capacity. and 10 transcortin (cor­ticosterOid binding globulin) with high affinity but low capacity. It is cleared from Ihe body primarily by hepatic metabolism. The large range of clear­ance (0.06 to 0.12 L/ h/ kg) and volume of distri­bution (0.2 10 0.6 L/ kg) were attributed to nonlin­ear protein bi nding. The plasma half-life of prednisone is slightly longer (3.4 10 3.8h) than that of prednisolone (2.1 to 3.5h), although shorter half­lives have been reported in patien ts receiving long term therapy, and the half-lives in children arc shorter than those recorded in most adult stud ies.

Marked variations i n concentrations of these drugs have been reported in patients with respi­ratory disease. suggesting variabili ty in absorption and el imination. Recently Morti mer et at. ([987) evaluated the pharmacokinetics of prednisolone in 10 asthmatic patients on long term corticosteroid therapy for at least 2 years who had failed to re­spond to ordinary doses of corticosteroids. Follow­ing intravenous administration the mean half-life was 2.9 ± O.4h: clearance and volume of distri­bution were 0.17 ± 0.03 L/ kg/h and 0.66 ± 0.15 L/ kg. respectively. and bioavai lability was com­plete (113 ± 16%). The data are in the same range as those reported earlier in healthy volunteers and failed to support phannacokinelic impairment as an expla nation of 'steroid resistance'. As expected from the much shorter eli mination than biological half-l ife. no apparent relationship has been dem­onstrated between blood concentrations and thera­peutic effects (Pickup 1979: Siegel 1985).

Steroids given by inhalation have proved to be a great advance in the management of asthma, and prevent the side effects associated with l ong lenn systemic corticosteroid therapy (Barnes 1989). Meltzer et al. (1985) have shown that in paediatric

479

and young adult patients. in halations of beclome­thasone for al least 3 months 2 or 4 times daily allow asthma symptoms to be controlled without side effecls. As with other d rugs. most of the in­haled dose of bcclomethasone is swallowed but is rapidly inactivated due to first-pass liver biotrans· formal ion (Martin et at. 1975).

112 So(/il/III Crollloglycate (Crom olyn SOOlllm) Only a few pharmacokinetic stud ies have dealt

wilh this drug. which has been used as an inhaler fo r the treatment of asthma fo r over 15 years.

Following intravenous bolus or infusion in healthy volunteers. caleulated terminal half-life ranged from 22 to 63 minutes (Fuller & Collier 1983: Neale e l at. 1986; Richards et al. 1987). Neale et al. (1986) reported a total body clearance of 0.47 ± 0.05 L/ h/ kg and a volume of distribut ion of 0.32 ± 0.06 L/kg. Sodium cromoglycate is excreted un­changed in the urine and bile (Clark & Neale 198 1).

After in halation only a small proportion of the dose reaches the airways but is completely ab­sorbed, whereas there is little gastrointestinal ab­sorption. It fo llows that lung absorption, and con­sequen tl y plasma concen trations. are related directly to inspiralOry fl ow rate and can be affected by manoeuvres used to assess lung fu nction (Rich­ards et al. 1987, 1989). Following inhalation. ter­minal half-life is longer than after intravenous administration; pharmacokinct ic analysis ind icates that absorption within the lungs is rate-limiting and therefore 'flip-flop' kinetics apply (Fu ller & Collier 1983: Neale el al. 1986; Richards et at. 1987). The disposition of sodium cromoglycate in patients wi th mild asthma docs not differ from that in healthy volunteers (Richards et at. 1988). In patients with asthma. the administration of increasing doses us­ing a metered-dose inhaler (2. 10 and 20mg) leads to a proportional increase in pea k plasma concen­trations (Cmalt) (Patel et at. 1986\.

2.3 Bronchostimulants

2.3.1 Almilrine This drug, used as a bismesilate salt, is a p i­

perazi ne derivative that specifically stim ulates peripheral chemorcceptors and increases total vol-

480

urne and respiratory frequency while simultan­eously improving ventilation/blood flow mis.­matching by its effect on pulmonary blood flow distribution. More extensive clinical evaluation in patients with chronic obstructive pulmonary dis. ease is needed (Galka & Rebuck 1985); although thert: is a close similarity in the pharmacokinetics of almitrine in patients with this disease and in healthy volunteers (Bromel et al. 1983; Campbell et at 1983), The average bioavailabitily after oral administration is 70%. In spite of the high protein binding of almitrine (99%), the volume of distri­bution is high at 14 L/ kg. Most of the administered dose is metabolised and total clearance averages 15 L/h (0.22 L/h/kg). Terminal half-life is long and values ranging from 30 to 60h have been reponed after single dose administration when plasma was collected for 72 hours. There is a trend to longer half-life when measured at the end of a period of maintenance administration.

2.4 Cardiovascular Drugs and Diureties

2.4.1 Digoxin Several reviews on the pharmacokinetics of dig­

oxin have been published previously in the Journal (Aronson 1980; lsalo 1977; Mooradian 1988), and readers are referred to these for further informa­tion.

The use of digitalis in patients with pulmonary hean disease has been a longstanding controversy but, in certain clinical conditions, digitalis treat­ment was proven to be effective (Mathur et al. 1981). However, a high incidence of digitalis tox­icity has been reported in such patients without clear pharmacodynamic or pharmacokinetic ex­planations. Du Souich et al. (1985) studied the in­fluence ofhypoxaemia and respiratory acidosis on the plasma kinetics and tissue distribution of dig­oxin in the conscious dog.. Plasma digoxin concen­tmtions are lower in dogs with hypoxia and res­pimtory acidosis, the result of an increase in both clearance (average 45%) and steady-state volume of distribution (Vu) [36%1, while the half-life re­mains unchanged. As a consequence of the in­creased V u. the ratio of digoxin concentrations in

elm, Pho.rmaroklnl'f. 19 (6) /990

tissue and plasma increased by 15% in the liver and to a lesser extent in the renal cortex and len ventricle. These experimental data led the authors to assume that hypoxaemia combined with hyper­capnia changes the distribution pattern of digoxin owing to changes in the binding characteristics of digoxin to the rtaptors. Further studies are needed to extrapolate these data to patients with respira· tory failure.

2.4.2 Diuretics

Furosemide A critical review of furosemide pharmacokin·

etics has recently been published by Hammarlund· Udenaes and Benet (1989). In healthy volunteers. mean total clearance ranged between 5.8 and 11.6 Llh, renal clearance is reponed as being 4.7 lIh and Vu averaged 0.11 to 0.13 L/ kg. Most studies show a terminal half-life of 45 to 92 minutes (0.7 to 1.5h); absolute bioavailability ranged from 43 to 71%. The rate-limiting step after oral administra· tion is most probably the absorption process. About 14% of the available dose is excreted as furosemide glucuronide after both intravenous and oral doses of furosemide; this metabolite has been shown to be very sensitive to both light and pH, which ex­plains discrepancies in the literature regarding how much glucuronide metabolite is formed.

Perez et al. (1979, 1980) studied the pharmaco­kinetics of furosemide in patients with acute pul­monary oedema and reported half-lives ranging from 3.4 to 19.8h (mean 7h) in II of 16 patients with a mean volume of distribution of 0.39 ± 0.24 Lfkg, considerably higher than in healthy volun­teers. However, as pointed out by Hammarlund­Udenaes and Benet (1989), the analytical proce­dures used may be inappropriate. The bioavaila­bility of furosemide in 6 patients with chronic res­piratory failure was reponed to be 41 ± 10'Ib (Ogata et a!. 1985); this is in the range of data from healthy volunteers listed by Hammarlund·Udenaes and Benet (1989). In the study of Ogata et al. (1985), the amount of furosemide gJucuronidated was found to be higher in patients than in controls (21 and 7.3%, respectively). The reasons for such en-

Pharmacoklllellcs III Respirator) Disorders

haneed metabolism are unclear. as Babini and Du Souieh ( 1986) have shown that in rabbits with hy­poxaemia. hypercapnia a nd respiratory acidosis, nonrenal clearance of furosemide was unchanged compared with controls.

Spironolactone This aldosterone antagonist is extensively bio­

transformed into many metabolites which rapidly appear in the plasma after drug intake. Several have an timineralocortieoid activity, in particular can­renone (Overdiek et al. 1985). Pharmacokinetic studies arc scarce and most report the parameters of canrenone only. In volun teers the mean half-life of this agent is 23h (Ho et al. I 984a): lillie is known abou t its pharmacokinetics in disease sta tes. Platt et al. (1984) havc shown that in 10 elderly female patients with multi morbidity, concentrations were twice as high as those measured in a group of younger, healthy female volunteers: this increase was unrelated to renal function. It should be noted that 8 patients had compensated heart failure and about half had emphysematous bronchitis or pneu­monia. Whether the impai red pharmacokinetics of caorenone could be related to the cardiopulmonary conditions remai ns to be investigated. In another group of elderly patients. Ho et at (1984b) found that concentrations after single or multiple doses of spironolactone were lower than in young sub­jects.

2.5 Benzodiazepines

Infusions of several benzodiazepines are used for sedation in patients under mechanical venti­lation in intensive care units. including diazepam (the oldest), lorazepam, flunitrazepam (available in sonle cou ntries only) and Ihe newest, midazolam. They are used either alone or in combinalion wilh an opioid. The phannacokinetic paramelers and t he factors infl uencing the pharmacokinetics of Ihese drugs in crit ically ill patients have recently been reviewed by Bodenham et at (1988). Midazolam offers Ihe a dvantage of having a s hort half-life (2.5h); its volume o f distribution is large (0,8 10

1.5 L/ kg) and its total clearance is high (0,35 to

481

0.54 L/h/ kg). Occasionally, wide variations In

awakening time have been observed in surgical patients, and associated with longer half-lives (Byan el at 1984: Byrne el a1. 1984). Since the n larger series of patients have been studied. Dundee et at. (1986) studied the half-life of midazolam in a large population of patients undergoing surgical opera­tion and found that 6% of these had prolonged half­lives (8 to 22h): they suggested thai a sllbpopula­tion of poor metabolisers could exist. Th is as­sumption was not verified in a sample of 168 sur­gical palienls (Kassai et at. 1988), of whom only 3 patients exhibited prolonged half-lives and the AUe ratio of cr-hydroxy-midazolam (the major metab­olile) 10 midazolam displayed a unimodal distri­bution.

Two subsequent studies appear 10 indicate that most patien ts under mechanical ventilation exhibit longer half·lives. Maitre et al. (1989) and Oldenhof et al. (1988) have reported mean half- lives of Ilh in patients recovering rrom cardiac surgery or in a general intensive care unit. respecti"ely. Both stud­ies show large interindividual variat ion in clear­ance and volume of distribution data, which are summarised in table VI. It appears that in the study of Maitre et a1. (1989) the longer half·life was caused by decreased clearance. whereas variations in both clearance and distribut ion were noticed by Old­enhofct a1. (1988). In the latter study, thc ratio of midazolam to cr-hydroxy.midazolam glucuronide at the end of infusion varied widely from 0.033 to 15.6, wh ich indicates differences in the accum u­lation profi le as well as impairment of metabolism. It is worth noti ng that the liver is not the only site of metabol ism fo r midazolam, as Park et al. ( 1989) have shown that metabol ism docs occur during the anhepatic period of liver transplantat ion: o n the other hand, impaired perfusion of metabolising or­gans during a period of septic shock leads to Ihe inhibition of midazolam metabolism (Shelly et a1. 1987). These studies show thai many facto rs are involved, which could explain the variabililY in Ihe pharmacokinetics of this drug in patients under mechanical ventilation. Maitre el a1. (J 989) have shown that in their patients, cardiac outpul was stable and in Ihe normal range (the clearance of

48' Cfln. Pharmacokinl'l. /9 (6) {990

T.ble VI. F'harmacokioetie parameters of midazolam In patients under mechanical ventilation; comparison willi surgical patlellt$

Reference """ (1'10. 01 patients)

$!,Irgle,' patlen" (IndUC:lion 01 ."..,111."8' Dundee at al. (1986)" 0.3 mg{kg over 20 sec

tn - 106)

(n _ 9)

KasSll I at al. (1988)C 0.1 to 0.2 mg/kg over 2 min

'. '"I

3.3 :!: 0.15 (0.8-6.6f (8-22)1>

"" '"I CL 'LI'I

v. (l./kg)

In • 168) 2.9 :t 1.1 In • 3)

Patient. und.r mechllnlcal vanlWal10n

Oklennof at al. (l988f 0.05100.10 mg/kgfh (intensive care patients)

MMra a t al. (1989) (recovery from cardiac surgery)

II Values given life mean :t SEM. b Rangoe. c Values given are mean :t SD.

over 22 to 326h In • 17)

(n - 5) (n _ 12)

15 mgfh for 4h

(n . 12)

7.4-9 ,8-10.2

1.4-40

(mean 11)

" 4,5 4.9-40

Mean 10.6 5.3 :t I .S (2.5·8.2)l'

18 % 5 (11-28)1>

0.7-4.6

1.3 :t 0.4 (0.6-1.9)1>

Abbreviations; MAT - mean residence time: Vso _ volume 01 distribution at steady-state; for other atlbraviatior1s. see lable n.

midazolam depends on both hepatic blood flow and intrinsic clearance). Besides pharmacokinetic var­iability. Oldenhof et al. (1988) have noticed that a wide range of midazolam concentrations are as­sociated with adequate sedation, and similarly that concentrations of the drug at the moment ofawak­ening are highly variable.

Aunitrazepam is another benzodiazepine that is used in some countries as a sedative in intensive care units. As with midazolam. great interindiv­idual variability in awakening time has been ob­served after the end of the infusion. At the end of an infusion a t a rate of I m&lh fo r 2 or 3 days. half-lives in 6 patients under mechanical ventila­tion were well above those measured after a IOmg bolus intravenous injection in 6 other patients (52 ± 38 liS 15 ± 5h). This difference was attributed to changes in volume of distribution at high doses rather than to impaired clearance (Taburet et al. 1989).

In neonatal intensive care units, diazepam is

often used as the sedative of choice. The slower clearance of diazepam in the premature and full term neonate is due to reduced hydroxylation and subsequent conjugation processes while demethy­lating activities are less impaired. (Morselli et at 1980). This could lead to high plasma concentra­tions of diazepam and nordiazepam. In unrespon­sive neonates, drug monitoring of diazepam and nordiazepam could help the cli nician to differen­tiate between poor clinical condition and drug ov­erdosing.

2.6 Anti-Infectious Agents

2.6.1 Antjmicrobial Drugs There is a lack of information about overall

pharmacokinetic impairment in patients with res­piratory disease. except in patients with cystic fi­brosis. This field has been recently reviewed by De Groot and Smith (1987). It appears that patients with cystic fibrosis have a lower Cmax, a smaller

Pharma,O"In<:IICS In Resplrlllor) Disorders

AUC and a shorter elimination half-life than non­cystic fibrosis patients. These modifications are the conseq uence of larger volume of distribution and increased total body clearance due to increased renal elimination and/or induction of drug metab­olism as recently shown for fleroxacin (Mimeault et at. 1990). De GroOl and Smith (1987) have pro­posed the administration of larger doses of most antibiotics more frequently in these patients. pointing out that there is a lack of information on the ideal sputum concentration to be reached. Du Souich et at. (1978) had already mentioned that the effects of respiratory disease on the efficacy of most long term antibiotic use are likely to be minimal since therapeUlic indices are wide. The exception to these general rules appears to be the aminogly­cosides. which have a narrow therapeutic range. Patient variables which influence serum concen­trations are listed by Wenk et at. (1984), and in­clude decreased renal function. age. lean body mass. obesity. haematocril. fever. major burns and in­teractions with fJ-Iactam antibiotics. Special men­tion should be made of hypoxaem ia in neonates. which has been found to lengthen the half·life of amikacin (Myers et at. 1977). It should be remem· bered (sec section 1.4.2) that decreased renal blood flow is to be expected in patients under mechanical ventilation. which leads to enhanced concentra· tions of those antibiotics eliminated exclusively through the kidney. This underlines the need for therapeutic drug monitoring of aminoglycosides (Zaske 1986).

To decrease the toxicity of the aminoglycosides and to enhance efficacy, short term endotracheal administration of these drugs has been effective. Aerosolised aminoglycosides did not appear to be as effective as endotracheal admin istration (Hoi· zapfel et al. 1989; Smi th & Lefrock 1983).

2.6.2 Pentamidine The resurgence of Pneumocyslis carinii pneu·

monia in patients suffering from AIDS has led to the increasing use of pentamidine (used as the is· elhionate salt in the US and as the mesylate in France). Adverse effects a re frequent after intra­venous or intramuscular administration. but in

483

patients with AIDS pentamidine causes a lowcr in· cidence of adverse reactions than cotrimoxazole (trimethoprim plus sulfamethoxazole) IGoa & Campoli-Richards 1987). Pentamidine is poorly absorbed from the gastrointestinal tract. which pre· cludes oral administration. After a 2-hour intra· venous infusion (4 mg/kg) in 6 AIDS patients. the pharmacokinetic parameters were as follows: ter· minal half-life 6.4 :!: 1.3h. total clearance 248 :!:

91 L/h and Vss 821 :!: 535L: 2 to 5% of the dose was recovered unchanged in the urine (Conte et al. 1986). This volume of distribution suggests high tissue uptake, which is confirmed by high tissue concentrations (Bernard et at. 1985: Donnelly et al. 1988).

As aerosolised pentamidine was reported to be efficient in both prophylaxis and the treatment of pneumocystosis in animal models (Debs et al. 1987: Girard et al. 1987). clinical trials were designed to evaluate the effectiveness of aerosol therapy (Cork· cry et a1. 1988: Kovacs & Masur 1988). After in­halation. the peak plasma concentration was about 5% of the concentration reached at the end of a 2-hour infusion. indicating that systemic absorption of pentamidine was minimal. Interestingly. the peak plasma concentration following inhalation did not increase with mult iple dosing (Conte & Golden (988). In this study. higher concentrations of pen· tamidine were found in the bronchoalveolar fluid 24 hours after inhala tion than after intravenous therapy (range 29 to 77 \·s 6 to 21 ~g/L). Elimin­ation from the lungs is slow. as pentamidine was detectable in the bronchoalveolar fluid of 3 patients at 33. 69 and [15 days following the completion of 2 weeks of therapy. Montgomery et al. (1988) found similar results with mean concentrations of drug in the bronchoalveolar sediment after pen­tamidi ne 4 mg/kg inhaled or infused: 705 :!: 242 and 8.3 :!: 7.0 ~g/L. respectively. and 23 ± 8 and 2.8 :!: 0.7 ~g/L in the supernatant. Such low plasma concentralions after inhalation explain why very few systemic side effects are reported from the usc of aerosol pentamidine (Conte et at. 1987; Girard et al. 1988; Montgomery et al. 1987). It is worth noting that after nebulisalion, large interindividual variations in plasma concentrations exist as aero-

484

sol depositing and systemic absorption vary widely between subjects. In a recent study Girard et al. (1989) have demonstrated that plasma concentra­tions after a single aerosolisation of pentamidine (base) were much h igher in 8 palients under me­chanical ventilation than in 18 patients breathing spontaneously (emu 216 ± 50 V,f 66 ± 9.1'g/L; AVe from time tero to 48h postdose (AUC0-4a) 207 ± 63 I'S 78 ± 17 J.Cg/L · hI. This underlines the risk of dose-related pentamidine toxici ty in venti­lated palients. The authors have listed the factors which could ex plain such higher absorption: avoid­ance of drug loss by the direct connection o f Ihe nebuliser 10 the ventilat ion system. reduced par­ticle size and facil itation of alveolar depositing, and finally increased uptake through the alveolocapil­lary barrier due to the patient's respiratory failure.

3. Conclusion

The reponed data show that the pharmacoki­netics of drugs administered in patients with mod­erate asthma or chronic obstructive pulmonary disease are no t extensively impaired, although pharmacokinetic impairments have been demon­strated in patients in the acute slage of respiratory disorders, including those under mechanical ven­tilation. Not all of the underlying mechanisms are well understood, and there are discrepancies either between in vilro and ;n V;I'O findings or between results in animals and humans. Changes in tissue distribution and clearance observed in patients with respiratory failure may not be related di~tly 10 biological parameters such as blood gases. Patients under mechanical ventilation may have other or­gan dysfunctions, such as renal or hepatic failure and sepsis syndrome. Mo ntgomery et al. (1985) have reponed that sepsis syndrome, rather than respiratory failure. is the leading cause of death in patients with acu te respiratory disease syndrome. All these disorders could worsen pharmacokinetic drug impairment. Consequently, drugs with a nar­row therapeutic range should be administered cau­tiously in those critically ill patients.

CUn. pnormQ('(}kmi't. 19 (6) 1990

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