Prescribing safe medication for hepatic

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Published on November 27, 2009

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Nearly every medication that is prescribed has its hepato-toxic effect. : Nearly every medication that is prescribed has its hepato-toxic effect. Bruce R.Bacon 2006 Slide 2: PRESCRIBING A SAFE MEDICATION FOR HEPATIC PATIENTS Prof. Dr. Mohamed Emam Consultant Gastroenterology Riyadh National Hospital Professor of Gastroenterology and Hepatology Zagazig University-Egypt 2009 Slide 3: Most drugs undergo extensive metabolism in the liver which therefore represents the central organ for drug elimination. The liver may also become a major determinant of bioavailability after oral administration of a drug. Liver disease may modify the effect of a drug independently of its pharmacokinetics, and may also increase the risk or be the target of adverse drug effects. Slide 4: In contrast to what occurs in renal dysfunction, where rational dose adjustment can be calculated according to creatinine clearance and fraction these is no validated in hepatic patients. Slide 5: Patients with Child’s Class A hepatic dysfunction require minimal manipulation of their medication, although there may be altered pharmacodynamic responses. Patients with Child’s Class C dysfunction require significant alteration in medication, especially if there is accompanying renal impairment. Slide 6: Pharmacotherapy in patients with liver disease consequently raises three major issues. Pharmacokinetics Pharmacodynamics Is there an increased risk of adverse reactions included? Slide 7: Pharmacokinetics : Means What the body does to the drug. Pharmcodynamics : Means what the drugs does to the body or events consequent on interaction of the drug with it’s receptors or wither primary site of action. Slide 8: PHARMACOKINETICS IN LIVER DISEASE From the pharmacokinetic point of view, the physiologic processes that my be primarily altered in liver disease are: Hepatic circulation and blood flow particularly porto-systemic shunting. Intra-hepatic diffusion processes (fibrosis of the space of disse and loss of fenestrate with consequent functional impairment of sinusoidal exchange). Slide 9: Amount of functional liver cell and enzyme mass with consequent changes in metabolic capacity: Biliary execration Body fluid distribution (ascites). Low plasma albumin levels leading to a decrease in plasma protein binding of drugs. Slide 10: Drug distribution. Liver perfusion Intrinsic hepatic drug clearance. Pharmacokinetic alterations in liver disease that will ultimately lead to changes in a drug’s plasma concentration over time may be predicted by integrating physiologic alterations with basic pharmacokinetic principles. Physiologic alterations result mainly from the effect of liver disease on: Slide 11: The extraction ratio (E) : is defined as the fraction of drug in the incoming blood supply of the liver (i.e., portal vein and hepatic artery }that is removed during one passage through the liver: Slide 12: Hepatic Clearance can now be expressed as the product of hepatic blood flow (O) and extraction ratio: CLh = Q* E For example, it the extraction ratio of a drug is 0.1 and the liver blood flow is 1.3L/min. Then 0.13L blood are cleared from the drug per minute by the liver. Slide 13: Further, if the average concentration in the hepatic artery and the portal vein were, for example, 10mg/L, the rate of elimination from blood would be 1.3 mg/min. Like hepatic clearance, the extraction ratio is a measure of the rate of elimination that is independent of concentration, but is also independent of liver blood flow. Slide 14: Therefore it directly reflects the functional metabolic capacity of the liver i.e., the intrinsic hepatic clearance. Hepatic blood flow and clearance: allows a quantification of the impact of a drug’s extraction ratio and therefore its intrinsic hepatic clearance on total hepatic clearance when liver perfusion is altered. Slide 15: In this context it is important to realize that liver disease usually does not decrease metabolic capacity sufficiently to turn a high extraction drug into one with a low extraction ratio. The effect of changes in metabolic capacity, portosystemic shunting, and plasma protein binding for drugs with high and low extractions on the most important parameters. Slide 16: In patients with significant cirrhosis of the liver, hepatic blood flow is reduced. As a result there is an increase in the systemic bioavailability of oral drugs which are usually removed by the liver during first pass metabolism. Hepatic Blood Flow Slide 17: When the clearance of a drug is highly dependent on liver blood flow it is known as a high extraction drug. Many drugs undergo extensive first-pass metabolism, including clomethiazole, lidocaine (lignocaine), morphine and propranolol. Slide 18: In cirrhotic patients, up to 60% of the blood supply reaching the liver in the portal vein may be diverted into collateral vessels. This has a similar effect to the reduction in blood flow through the liver, and leads to increased bio-availability of many drugs, particularly those which have a high extraction ratio during first pass metabolism. PORTOSYSTEMIC SHUNTING Slide 19: In patients with severe liver disease there can be as little as 30% metabolic capacity of the liver remaining. This is an important consideration for those drugs that are primarily metabolized by the liver. REDUCED HEPATIC CELL MASS Slide 20: Patients with liver disease tend to have low serum albumin due to a reduction in the synthetic capacity of the liver. A reduction in protein binding is important for drugs that are highly protein bound, such as phenytoin or warfarin. The free drug concentration (which is pharmacologically active) will increase, although clearance may also increase correspondingly. REDUCTION IN PROTEIN BINDING Slide 21: Drugs with low and high hepatic extraction ratios only a few drugs have an intermediate extraction ratio Slide 22: Drugs with a high hepatic extraction ratio are generally used at between 10% and 50% of the dose that would be used in the absence of liver disease. All dose modifications should be monitored closely for clinical effects, with therapeutic drug monitoring wherever possible. For low extraction drugs, where elimination of these drugs is not dependent on liver blood flow, dose reductions do not need to be as great. Slide 23: The pharmacodynamic response to various drugs is altered in patients with liver cirrhosis. Patients with cirrhosis are more sensitive to sedative drugs, such as benzodiazepines and opiates, a drugs with the potential to cause sedation should generally be avoided in patients with significant cirrhosis due to the risk of precipitating or masking encephalopathy. Where liver disease has reduced or impaired the production of clotting factors, patients are at increased risk of bleeding. PHARMACODYNAMICS IN LIVER DISEASES Slide 24: Drugs associated with causing haemorrhage or alteationrs in platelet function, such as aspirin, NSAIDs and warfarin, should therefore be avoided. Drugs that are known to affect liver enzymes are best avoided in patients who have deranged liver function tests. Similarly, drugs that alter the concentration of liver enzymes may increase the toxicity of concurrent therapy. For example, rifampicin may increase the hepatotoxicity is isoniazid by increasing the production of hepatotoxicity metabolites of the latter. Slide 25: Not only pharacokinetics but also susceptibility to drugs at the risk of adverse reactions may be altered in patient with liver disease. In contrast to pharmacokinetic changes, this is related to the numerous mechanisms of drugs and therefore not share general common principles. However, the frequent and clinically relevant changes occur in a limited number of drug classes. Slide 26: The pharmacokinetics of loop diuretics are unaltered in liver disease; however, as sodium excretion is decreased in cirrhosis it is not surprising that their natriuretic response may be decreased. Non-selective as well as COX2 selection cyclooxygenase inhibitors (nonsteroidal anti-inflammatory (NSAIDs) reduce the synthesis of renal prostaglandins regulate the maintenance of an adequate glomerular perf perfusion. Slide 27: NSAIDs may therefore precipitate renal failure in patients without ascites. An increased response to vasoconstrictors in cirrhotic patients, who may have a higher risk of developing neutropenia with B-lactam antibiotics and a higher risk of developing nephrotoxicity aminoglycosides in obstructive cholestasis. Slide 28: Common indications and drugs of choice in patients with liver disease N.B : Pain control in hepatic patient is rarely infective and potentially dangerous Slide 33: Common therapeutic problem in liver disease Slide 35: Physicians are often concerned about prescribing potential hepatotoxic drugs to patients with liver disease. Although drugs may potentially be hepatotoxic, and great caution often recommended by the manufacturer when prescribe patients with liver disease. A closer look at the mechanic hepatotoxicity suggests that the risk of hepatotoxicity necessarily higher in patients with pre-existing liver disease fact. HEPATOTOXIC DRUGS IN PRE-EXISTING LIVER DISEASE Slide 36: In nonhepatic pt the incidence of hepato-toxicity is high with most of antituberculosis drugs. Likehood for developing hepato-toxicity may be greater in hepatic pt and may be a life threatening . The first line ATT, remain the drug of choice inspite of the underlying liver disease pt need to be monitored closely. As a general rule avoide Pyrazinamide . The use of Isoniazid should be on invidulized base (avoid in sever liver decompensation) Recommendation of use of antituberculosis therapy in pt who has chronic liver disease Slide 37: Recommendation of ATT in cirrhotic pt Slide 38: Weight the benefits and risks. Choose the most safest and effective drugs. Decide what risk you will accept in order to get the benefits you want. In facing life threatening illness, you may choose to accept more risk in hope to save your pt life. Finally in hepatic patient start medication low and go slow. In conclusion… Slide 39: Dr. MOHAMED EMAM

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