Assignment on

Effects of Diseases on Drug Metabolism.

Sumitted by,

Md. Azamu Shahiullah Prottoy

ID - 11146018

Overall, there are a large number of factors that can influence drug metabolism, either by

increasing clearance to cause drug failure, or by preventing clearance to lead to toxicity. In the

real world, it is often impossible to delineate the different conflicting factors which result in net

changes in drug clearance which cause a drug to fall out of, or climb above, the therapeutic

window. It may only be possible clinically in many cases to try to change what appears to be the

major cause to bring about a resolution of the situation to restore curative and non-toxic drug

levels.

Non Hepatic

Drug metabolism in thyroid disease

Thyroid dysfunction can influence the physiological disposition of drugs. Depending on the

pharmacokinetic properties of the individual drug, changes in the rate of metabolism ranging

from profound to moderate or negligible have been observed. Since renal function is also

influenced by thyroid disease, changes in renal elimination of drugs which are excreted in the

urine mainly as unchanged drugs have to be considered as another reason for altered drugs

disposition in thyroid disease. In patients with thyrotoxicosis lower, and in patients with

myxoedema, higher, digitalis plasma levels have been observed. The altered disposition of

cardiac glycosides in thyroid dysfunction can be attributed to changes in renal elimination and

metabolism. These findings may be the kinetic correlate for the clinical observation that larger

than the usual dose of digitalis is required in thyrotoxic patients and lower in hypothyroid

patients. Antipyrene half-lives are very much shortened during hyperthyroidism and prolonged

appreciably during hypothyroidism. The alterations in the disposition of these drugs seen during

thyroid dysfunction can be ascribed to changes in its rate of metabolism which is controlled by

the levels of circulating thyroid hormones. N-demethylation of aminopyrine is depressed both in

hyper- and hypothyroid patients as compared with euthyroid subjects. Changes in the half-life of

this drug were observed only during hypothyroidism. The physiological disposition of the

antithyroid drug propylthiouracil is not changed during thyrotoxicosis. A decrease in plasma

half-life of methimazole is however, observed during hyperthyroidism, whereas in hypothyroid

patients half-life is increased. The few data available so far do not allow general prediction of

how thyroid disease could alter drug metabolism in man.

Thyroid hormone regulates the metabolism of drugs by the hepatic cytochrome p450 enzyme.

Examples of drugs with a metabolism that decreases in hypothyroidism are antiseizure

medications, digoxin and narcotics. In addition, the effect of warfarin therapy may change

because of alteration of the turnover of serum clotting factors. Thus the dose requirements of

these medications may change as a result of T4 treatment.

Obviously renal disease has a marked effect on drug clearance, and impairment in renal function

is detected by the measurement of creatinine clearance, which gives an accurate estimate of the

glomerular filtration rate (GFR).

Effects of Renal diseases on Drug Metabolism

If the drug has a narrow therapeutic index, creatinine clearance is poor and the major route of

clearance of that drug is renal rather than hepatic, then drug dosage must be reduced. Many

antibiotics (aminoglycosides, betalactams) as well as atenolol (mentioned earlier), methotrexate

cimetidine and metformin are some of the agents primarily cleared renally. With drugs that

undergo extensive hepatic clearance, the metabolites must be eliminated through the urine,

although their accumulation is not usually such as problem as most drug Phase II metabolites are

effectively prevented by their water solubility from exerting much therapeutic effect.

Abnormal drug metabolism in chronic pancreatitis. Treatment with antioxidants. 

 Functional and morphological changes in hepatocytes, indicating induction of the drug

metabolizing enzymes and free radical-mediated damage, were found in 4 patients with

idiopathic chronic pancreatitis. The possibility that reflux of abnormal bile (rich in lipid

peroxidation and other products generated through hepatic metabolism of xenobiotics) into the

pancreatic duct may initiate pancreatic damage was negated when bile duct ligation and bile

diversion did not abolish attacks of pancreatitis in 3 cases, although the evidence of reflux was

indisputable in 1 of them who also had a pancreatoduodenectomy. Pancreatic acinar cells from

that patient showed extensive microvesiculation, as did hepatocytes from each case. These

observations suggest that pancreatic and liver damage in chronic pancreatitis proceed

independently but by the same mechanism-heightened, but unmitigated, oxidative detoxification

of xenobiotics by cytochromes P450. Therefore, although bile reflux is not a prerequisite, it

could compound injury in the head of the gland. Antioxidants were prescribed to the 3 cases

mentioned and, from the outset, to a fourth patient who showed the same liver changes. This

unconventional approach has held attacks at bay during a follow-up period of 5 yr. 

 

Hepatic Diseases 

Effects of Liver Disease on Drug Metabolism

Liver disease may have complex effects on drug clearance, biotransformation, and

pharmacokinetics. Pathogenetic factors include alterations in intestinal absorption, plasma

protein binding, hepatic extraction ratio, liver blood flow, portal-systemic shunting, biliary

excretion, enterohepatic circulation, and renal clearance. Sometimes alterations increase levels of

bioavailable drug, causing normal drug doses to have toxic effects. However, levels and effects

for an individual drug are unpredictable and do not correlate well with the type of liver injury, its

severity, or liver function test results. Thus, no general rules are available for modifying drug

dosage in patients with liver disease.

Clinical effects can vary independent of drug bioavailability, especially in chronic liver disease;

eg, cerebral sensitivity to opioids and sedatives is often enhanced in patients with chronic liver

disease. Thus, seemingly small doses of these drugs given to cirrhotic patients may precipitate

encephalopathy. The mechanism of this effect probably involves alterations in cerebral drug

receptors.

Adverse drug reactions do not appear to be more likely in patients with advanced liver disease;

however, such patients may tolerate any hepatic adverse effects of drugs less well. Although the

liver is the main site of drug metabolism, conflicting results have been reported on drug

elimination during liver diseases. Drug metabolism may depend on histological changes in the

liver (acute or chronic hepatitis, cirrhosis) but may also depend on their origin (viral, toxic or

immunological). Drug metabolism is also influenced by the severity of liver dysfunction.

Cytochrome P450 isozymes and conjugation pathways may be differently affected by these

conditions, and specific probe drugs have to be used in order to study the effect of diseases on

each enzyme of drug metabolism. Probe-based assays must be validated during disease, since the

pharmacokinetics of the parent drug and/or of its metabolites may be altered. Because of these

limitations, therapeutic drug monitoring may be the most reliable way to adjust drug dosing at

present.

A number of hepatic diseases have showed effects on drug metabolism. These are

1.Cirrhosis of the liver

2.Alcoholic liver disease

3.Cholestqtic jaundice

4.Liver carcinoma

5.Viral hepatitis

6.Hepatoma

7.Tumor growths in liver

Cirrhosis

Cirrhosis is characterized by

*Increase in number of functional hepatocytes due to

*Replacement of parts of liver by fibrous tissue.

Examples of cirrhosis effects on drug metabolism

1. Oxidative metabolism of Chlordiazepoxide to primary metabolites

Desmethyldiazepoxide is slowered.

2. Elimination half life of Lignocaine, Theophylline, Tolbutamide following N-

Dealkynation is prolonged in cirrhosis patients.

3. Activation of prodrug is affected in cirrhotic patients. For instance, conversion of

prodrug Prednisone to active drug Prednisolone is slowered in cirrhotic condition.

4. Great diminish in degree of increase in drug metabolism is also affected by

cirrhotic condition. Phenobarbiton pretreatment markedly increases in normal patients

whereas the cirrhotic patients has little effects.

There are some others drug metabolism process following Clucuronidation route is not affected.

For instance,

1. Oxazepam

2. Lorazepam

3. Morphine

4. Paracetamol

Jaundice

THE EFFECT OF OBSTRUCTIVE JAUNDICE ON DRUG METABOLISM IN RABBITS 

(Authors - Edwin F. McLuen and James R. Fouts, Department of Pharmacology, College of

Medicine, State University of Iowa, Iowa City, Iowa) 

Obstructive jaundice affects liver microsomal drug metabolism in rough proportion to the degree

of histologically observable cell damage. Livers with mild cellular damage often retain

essentially normal hexobarbital metabolism while other pathways are markedly reduced from

normal levels. Severe cellular damage leads to nearly complete loss of all the drug enzyme

activities studied. 

In vitro, sodium deoxycholate inhibits most drug enzyme activities at about the same final

concentration—50% inhibition at approximately 1 x 10-2 M. The curves of enzyme inhibition

and those of microsomal solubilization (Palade and Siekevitz, 1956) by deoxycholate can almost

be superimposed on one another. This suggests that the two phenomena may be related.

Deoxycholate effects on drug metabolism cannot be reversed by dialysis of the enzyme-bile acid

mixture against distilled water. This too would be consistent with an inhibition-by-destruction

mechanism. 

The prolongation of sleeping times seen when jaundiced and normal rabbits are compared is

compatible with the effects of deoxycholate on the drug enzyme systems in vitro. 

Alcoholic Liver Diseases

It is the replacement of fibrous mass of liver following the death of parenchymal cells.

The stages in the development of effect of ethanol on hepatic drug metabolism can be described

as,

Acute Ethanol Exposure = Chronic Ethanol Exposure (Induction Phase) = Alcoholic

Cirrhosis (Inhibition Phase)

Viral Hepatitis

Viral hepatitis causes the decrease of hepatic drug metabolism. Example, Chlordiazepoxide

clearence is decreased as is the clearence of Mepridine.

Hepatoma

It is actually cancerous growth of liver parenchymal cells. The presence of different parenchymal

cells can decrease the hepatic drug metabolism by 20%.