Pharmacokinetics II Lecture Notes PDF

Pharmacokinteics II Dr.Leila Alblowi Lecture Objectives: 01 Understand the factors that influence drug biotransformation 02 Identify the excretion process Identify disease conditions and their effects on the rate and extent of drug 03 metabolism and excretion. Factors Affect Drug bio...

Pharmacokinteics II Dr.Leila Alblowi Lecture Objectives: 01 Understand the factors that influence drug biotransformation 02 Identify the excretion process Identify disease conditions and their effects on the rate and extent of drug 03 metabolism and excretion. Factors Affect Drug biotransformation 1. Entry into the liver 2. Enzyme induction 3. Enzyme inhibition 4. Genetic factors (Race and Ethnicity) 5. Age 6. Gender 7. Diseases 1. Entry into the liver 1. Plasma protein binding 2. Hepatic transporters 3. Conditions that reduce the hepatic blood flow 1. Entry into the liver (Plasma protein binding ) Plasma protein binding can Examples of plasma significantly reduce the rate of uptake and metabolism of Albumin protein the drug by the liver, e.g., 1. ✓Uremia reduce the binding α1-acid capacity of albumin !! glycoprotein 2. ✓Inflammation and stress increase the plasma conc. Of α1-acid glycoprotein ? 1. Entry into the liver (Hepatic transporters ) Hepatic transporters can significantly influence the uptake of drugs by the liver The metabolism of pravastatin, (treatment of hypercholesterolemia) is dependent on the transporter OATP1B1, which transport the drug into hepatocytes Drug uptake into hepatocytes via OARP1B1 is thought to be the rate-limiting step in the clearance of pravastatin 1. Entry into the liver (Conditions that reduce the hepatic blood flow) Cirrhosis and cardiac insufficiency may significantly -------the metabolism 2. Enzyme Induction Microsomal CYP450 drug metabolizing enzymes can be enhanced by certain drugs Enzyme induction speeds up the metabolism of the inducing drug itself and other drugs metabolized by the microsomal enzymes Example of enzyme inducer:Cigarette smoke. Drugs such as: Phenobarbital, Phenytoin, Carbamazepine 2. Enzyme Induction Clinical important of microsomal enzyme induction: 1- Drug-Drug interactions: Therapeutic failure of some drugs due to reduce duration of action Failure of oral contraceptives in pt. taking rifampicin Interactions between tobacco smoke and medications have been identified due to induction of hepatic cytochrome P450 enzymes. 2. Enzyme Induction Clinical important of microsomal enzyme induction:( cont...) 2- Toxicity: Enhance the drug toxicity, e.g., a pt. treated with rifampicin is likely to develop hepatotoxicity with paracetamol because a higher amount of the toxic intermediate metabolites of paracetamol is formed due to enzyme induction 2. Enzyme Induction Clinical important of microsomal enzyme induction:( cont...) 3-Tolerance: e.g., in case of carbamazepine since it induces its own metabolism 3. Enzyme inhibition Some drugs inhibit microsomal enzyme activity Ketoconazole (antifungal drug) , competitively inhibit the metabolism of some co- administrated drugs Enzyme inhibition by drugs results in several drug- drug interactions 3. Enzyme inhibition Example of enzyme inhibitors: Grapefruit Drugs such as: Ketoconazole, Omeprazole Omeprazole is a potent inhibitor of three of the CYP isozymes responsible for warfarin metabolism If the two drugs taken together plasma conc. of warfarin ↑ leads to greater inhibition of coagulation and risk of haemorrhage and other serious bleeding reactions 4. Genetic Factors Genetic polymorphisms involve: Minor (i.e. single nucleotide polymorphisms *SNPs*) Major (i.e. gene deletions or duplications) Changes in the nucleotide sequences of a gene encoding a drug metabolizing enzyme Genetic polymorphism in both phase I and phase II enzymes exist that result in altered efficacy of drug therapy or adverse drug reaction Population is divided into: “Ultrarapid metabolizers” “Poor metabolizers” 4. Genetic Factors Genetic polymorphisms in drug-metabolizing enzymes may cause: 1. Reduction in systemic clearance and potential for accumulation 2. Altered metabolite profiles and the production of active or toxic metabolites 3. Altered drug-drug interactions 4. Alteration in therapeutic effects of a drug 4. Genetic Factors Pharmacogenomics and personalized medicine Pharmacogenomics: is the study of genetic variations that influence individual response to drugs Enzymes involved in drug metabolism and the proteins that determine cellular drug responses (receptors) are encoded by genes. These genes can exhibit genetic variations, leading to differences in expression, activity levels, and functions of the enzymes and proteins. 4. Genetic Factors Pharmacogenomics and personalized medicine Knowing whether a patient carries any variations may help health care professionals individualize drug therapy that will: Decrease the number of adverse drug reactions Increase the effectiveness of drugs Pharmacogenomics has been characterized as “getting the right Dose of the right Drug to the right Patient at the right Time” 4. Genetic Factors Pharmacogenomics and personalized medicine Codeine : Is a prodrug with analgesic properties due primarily to its conversion into morphine Conversion to morphine is mediated by the cytochrome P450 enzyme CYP2D6 Poor CYP2D6 metabolizers obtain no pain relief from codeine It is estimated that 5–10% of Caucasians are CYP2D6 poor metabolizers 4. Genetic Factors Pharmacogenomics and personalized medicine Ultrarapid CYP2D6 metabolizer experiences an enhanced analgesic effect because codeine is quickly converted into morphine. Patients who carry this variations are at risk for opioid toxicity, which includes moderate to severe CNS depression (extreme sleepiness, confusion or shallow breathing) The prevalence of the CYP2D6 ultra-rapid metabolizer phenotype has been most common in: Ethiopian and Saudi Arabians The use of codeine in nursing mothers who are CYP2D6 ultra-rapid metabolizers achieve “higher-than expected levels of morphine in breast milk and potentially dangerously high serum morphine levels in their breastfed infants” 5. Age Many reactions of biotransformation are slowed in both young children and the elderly Neonates are capable of performing many oxidative reactions at birth. However, they cannot carry out all oxidative reactions immediately. The drug-metabolizing enzyme systems develop and mature: ✓ Gradually over the first two weeks of life. ✓ Continue to mature throughout childhood. 5. Age Neonatal jaundice : is a deficiency of the bilirubin-conjugating enzyme UGT. It occur especially in premature infants Lead to relative inability to conjugate bilirubin in the liver with glucuronic acid (UGT facilitate excretion of bilirubin) Development of hyperbilirubinemia Neonatal jaundice is problematic because neonates have both underdeveloped enzyme activity and an immature blood-brain barrier (BBB). Unconjugated bilirubin is water-insoluble and lipophilic, It bind readily to the neonatal brain and causing significant damage to the CNS This condition is known as bilirubin encephalopathy 5. Age Neonatal jaundice Neonatal hyperbilirubinemia can be treated with: 1. Phototherapy with 450-nm light, which converts circulating bilirubin to an isomer that is more rapidly excreted 2. Administration of phenobarbital which powerfully up-regulates the expression of the enzyme UGT and thereby reduces serum levels of unconjugated bilirubin 5. Age Gray baby syndrome: is a deficiency of the conjugating enzyme in infants Chloramphenicol is an antibiotics for treatment of Haemophilius influenzae infections in infants Excretion of this drug requires an oxidative transformation followed by a conjugation reaction The oxidation metabolite of chloramphenicol is toxic; if this metabolite fails to undergo conjugation, it can build up in the plasma and may reach toxic concentration Neonates will experience shock and circulatory collapse, leading to cyanosis that gives the syndrome its name 5. Age In elderly individuals: a general decline in metabolic capacity is observed, which requires careful drug prescription. The decline in metabolic capacity in the elderly is attributed to: 1. --------- in liver mass 2. --------- hepatic blood flow 3. ---------possibly hepatic enzyme activity. 6. Gender Evidence suggests there are gender differences in drug metabolism. The mechanisms behind these differences are not well understood. Studies report that women have decreased oxidation of ethanol, estrogens, benzodiazepines, and salicylates compared to men. These differences may be related to androgenic hormone levels 7. Diseases Many disease states can affect the rate and extent of drug metabolism in the body: 1. Liver diseases significantly compromise drug metabolism e.g.: Hepatitis, cirrhosis, liver cancer. 2. Cardiac disease: blood flow is compromised in cardiac disease ,so the drug delivery to the liver will decrease, the rate of metabolism of many drugs, such as the antiarrythmic lidocaine and the opioid morphine, is dependent on drug delivery to the liver via the bloodstream ↓ Blood Flow → Potential toxic levels of such drugs 3. Endocrine diseases such as, hypothyroidism may slow biotransformation of certain drugs; hyperthyroidism tends to have opposite effect Excretion Most drugs and drug metabolites Renal excretion is the most common are eliminated from the body mechanism of drug excretion, and it relies on the hydrophilic character of a through: drug or metabolite. ✓Renal excretion Only a relatively small number of drugs are excreted in: ✓Biliary excretion ✓ Lung: Respiration ✓ Intestines: Fecal and biliary excretion ✓ Sweat gland: Sweat ✓ Salivary gland: Saliva ✓ Mammary gland: Milk Excretion Three processes involved in the elimination of drugs through kidneys are: 1. Glomerular filtration 2. Passive tubular reabsorption 3. Active tubular secretion Excretion Renal excretion is the primary method for clearing many drugs For example: Examples include: Vancomycin In individuals with normal kidney ,Atenolol and Ampicillin function, the typical dosing interval for vancomycin is 12 hours These drugs can accumulate to toxic In severe kidney disease: Therapeutic levels in: levels of the drug may persist for 7 Patients with compromised renal days after a single intravenous dose. function. Elderly patients, who often have some degree of renal impairment. Excretion Factors Affect Renal Excretion Blood flow PH An increased rate of urine output tends - Renal reabsorption is limited primarily to: by pH trapping -Dilute the drug concentration in the - Drug reabsorption in the tubule can be tubule enhanced or inhibited by chemical adjustment of the urinary pH -Decrease the amount of time during which facilitated diffusion can occur Excretion For example: Aspirin is a weak acid that is excreted by the kidney. Aspirin overdose is treated by: 1. Administering sodium bicarbonate to --------the urine (and thus trap aspirin in the tubule) 2. ---------the urine flow rate (and thus diluting the tubular concentration of the drug) → Result in faster elimination of the drug