Pharmacokinetics 1 Final PDF

PHARMACOKINETICS LAWRENCE MICAH-AMUAH 1 OBJECTIVES By the end on the lecture, you should be able to 1. Understand the general concept of Pharmacokinetics 2. Appreciate the concept of Clinical Pharmacokinetics 3. Understand the four aspects of pharmacokinetics (absor...

PHARMACOKINETICS LAWRENCE MICAH-AMUAH 1 OBJECTIVES By the end on the lecture, you should be able to 1. Understand the general concept of Pharmacokinetics 2. Appreciate the concept of Clinical Pharmacokinetics 3. Understand the four aspects of pharmacokinetics (absorption, distribution, metabolism and excretion) 4. Discuss the relevance of the four aspects of pharmacokinetics to professional nursing practice 5. Employ the pharmacokinetic properties of drugs to improve benefits as well as minimize risks of drugs 2 3 PHARMACOKINETICS Pharmacokinetics is the study of what happens to a drug from the time it enters the body until the parent drug and all metabolites have left the body. The action of the body on drugs. This includes the processes of ✓Absorption ✓Distribution and localization in tissues ✓Biotransformation (metabolism) and ✓Excretion. Can also be defined as: The process of drug movement in the body with the ultimate aim of achieving drug action. The four processes are absorption, distribution, metabolism (or biotransformation), and excretion (or elimination) The four pharmacokinetic processes, acting in concert, determine the concentration of a drug at its sites of action. 4 CLINICAL PHARMACOKINETICS Clinical Pharmacokinetics is the application of pharmacokinetic methods to ensure patients are treated safely and effectively. The essence of Clinical Pharmacokinetics is to employ the benefits of pharmacokinetic properties to ensure a faster (rate) and better (extent) drug concentrations needed at the active site of drug action for prompt and better therapeutic outcome. It also seeks to minimize any treatment failure as well as adverse effects of medicines in patients 5 Clinical Pharmacokinetics All drugs must meet certain minimal requirements in terms of concentration to achieve clinical effectiveness. A successful drug must be able to cross the physiologic barriers that limit the access of foreign substances to the body. Drug absorption may occur by a number of mechanisms that are designed either to exploit or to breach these barriers After absorption, the drug uses distribution systems within the body, such as the blood and lymphatic vessels, to reach its target organ in an appropriate concentration. The drug’s ability to access its target is also limited by several processes within the patient. These processes fall broadly into two categories: ✓Metabolism; the body inactivates the drug through enzymatic degradation (Primarily in the liver) and ✓Excretion; in which the drug is eliminated from the body (primarily by the kidneys through urine and liver through faeces) 6 7 BENEFITS OF PHARMACOKINETICS Pharmacokinetic principles have facilitated 1. The development of rational drug therapy 2. Understanding drug action and metabolism 3. Understanding of concentration-effect relationship 4. The establishment of dosage regimens and adjustments 8 WHY IS PHARMACOKINETICS SO IMPORTANT TO THE NURSE By applying knowledge of pharmacokinetics to drug therapy, we can help maximize beneficial effects and minimize harm (adverse effects). It helps the nurse to understand the reasons behind selection of route, dosage, and dosing schedule. Knowledge in pharmacokinetics help to manipulate the various passages to enhance therapeutic effect, thereby promoting patient satisfaction. You will be less likely to commit medication errors than will the nurse who, through lack of this knowledge, administers medications by blindly following prescribers’ orders. Knowledge of pharmacokinetics can increase job satisfaction. 9  What do I need to know before I administer a drug? How do I give the drug? Is it going to be absorbed and to what extent? Where does it go to after absorption? How long does it stay in the body to work? How often do I have to give it and why? How does it leave the body? 10 PASSAGE OF DRUGS ACROSS MEMBRANES All four phases of pharmacokinetics—absorption, distribution, metabolism, and excretion—involve drug movement across membranes Drugs must cross membranes to enter the blood from their site of administration. Once in the blood, drugs must cross membranes to leave the vascular system and reach their sites of action. In addition, drugs must cross membranes to undergo metabolism and excretion. Therefore, the factors that determine the passage of drugs across biologic membranes have a profound influence on all aspects of pharmacokinetics. Biologic membranes are composed of layers of individual cells very close to one another such that drugs must usually pass through cells, rather than between them, to cross the membrane. The membrane structure consists of a double layer of molecules known as phospholipids 11 12 PASSAGE OF DRUGS ACROSS MEMBRANES The three most important ways by which drugs cross cell membranes are: (1) passage through channels or pores, (2) passage with the aid of a transport system, and (3) direct penetration of the membrane itself. Of the three, direct penetration of the membrane is most common. Very few drugs cross membranes via channels or pores Reason Only the smallest of compounds (e.g., potassium or sodium) can pass through these channels, and then only if the channel is the right one because channels in membranes are extremely small and specific 13 PASSAGE OF DRUGS ACROSS MEMBRANES Passive transfer i) Simple diffusion ii) Filtration iii) Facilitated diffusion Specialized transport i) Active transport ii) Non-specific drug transporters like P-glycoprotein iii) Phagocytosis & Pinocytosis (Endocytosis and Exocytosis) 14 15 PASSIVE DIFFUSION The most common mechanism of absorption for drugs Process can be explained through the FICK LAW OF DIFFUSION “Drug molecule moves according to the concentration gradient from a higher drug concentration to a lower concentration until equilibrium is reached” Diffusion rate is directly proportional to ✓Concentration ✓Molecule’s lipid solubility, size and degree of ionization ✓Area of absorptive surface (favours drug absorption in the small intestines) 16 CARRIER MEDIATED MEMBRANE TRANSPORT Numerous specialized carrier-mediated membrane transport systems are present in the body to transport ions, nutrients and drugs, esp. in the intestines. Such systems include ✓Active Transport ✓Facilitated Diffusion 17 ACTIVE TRANSPORT Energy consuming system essential for GI absorption, renal excretion and biliary excretion of many drugs It is an energy requiring process. Energy usually derived from ATP Movement of molecules (drugs) AGAINST concentration gradient – from low to high Involves carrier molecules Carrier molecule binds to a drug to form a COMPLEX. The complex facilitates the transportation of the drug across the membrane and then de-associates on the other side Carrier molecule may be highly specific to the drug molecule Drugs sharing similar structures can compete with each other for absorption site Binding sites may be saturated if drug concentration is very high, after which the dose increase does not affect the rate of absorption 18 FACILITATED DIFFUSION Not energy requiring. Employs specific TRANSMEMBRANE INTEGRAL PROTEINS Movement of molecules is ALONG concentration gradient Movement process is similar to that of Active transport 19 20 PINOCYTOSIS and PHAGOCYTOSIS Fluid or particles are engulfed by a cell Cell membrane invaginates, encloses the fluid particles, then fuses again, forming a VESICLE Vesicle later detaches and moves to the interior of the cell Energy expenditure is required Pinocytosis plays a small role in drug transport, EXCEPT for protein drugs. 21 22 Comparison of Movement across barriers 23 ANY QUESTIONS SO FAR? 24 ABSORPTION This is the entry of drugs into the blood via the biological membrane from the site or route of administration It is the movement of drug into circulation from the site and route of administration for distribution into tissues The rate and total amount of drug absorbed is dependent upon many factors. After a drug is administered in any form or route, it must reach the site of action and remain there for a particular period, so as to yield the desired effect. During their way to the site of action, drug molecules have to cross one or more membranous barriers, which are lipoidal in nature, and having different sizes or pores. Areas in the body from which absorption can take place include; the GIT either orally or rectally, mucous membranes, the skin, lungs, muscle or subcutaneous tissues. The rate of absorption determines how soon effect of drug will begin. The amount of absorption helps determine how intense effects will be. 25 ABSORPTION Most drugs are absorbed into the surface area of the small intestine through the action of the extensive mucosal villi. If the villi are decreased in number because of disease or the removal of small intestines, absorption and drug effect is reduced. Protein–based drugs such as insulin and growth hormones, are destroyed in the intestines by digestive enzymes. The three major processes for drug absorption through the gastrointestinal membranes are ✓passive absorption ✓active absorption and ✓pinocytosis. Passive absorption occurs mostly by diffusion (movement from higher concentration to lower concentration). With diffusion, the drug does not need energy to move across the membrane. 26 ABSORPTION Active absorption requires a carrier such as an enzyme or protein to move the drug against a concentration gradient. Energy is needed for active absorption. Pinocytosis: the process by which cells carry drug across their membrane by engulfing the drug particles The GI membranes is composed mostly of lipid (fat) and protein, so drugs that are lipid soluble pass rapidly through the GI membrane. Water soluble drugs need a carrier, either enzyme or protein, to pass through the membrane. Large particles pass through the cell membrane if they are nonionized (no positive or negative charge). Weak acid drugs, such as aspirin, are less ionized in the stomach, and they pass through the stomach lining easily and rapidly. HCl acid destroys such drugs, such penicillin G, therefore a large oral dosage of penicillin is needed to offset the partial loss. Penicillin G is therefore not given as an oral formulation. 27 ABSORPTION Drugs that are lipid soluble and nonionized are absorbed faster than water –soluble and ionized drugs. Therefore to enhance absorption, some drugs are ingested orally as Prodrugs. Eg. Cefuroxime Axetil Drug absorption is affected by blood flow, pain, stress, fasting, food, and pH. Poor circulation resulting from shock, vasoconstrictor drugs, or disease hampers absorption. Pain, stress, and foods that are solid, hot (spicy) and fatty can slow gastric emptying time, so the drug remains longer in the stomach. Exercise can increase more blood to the peripheral muscles, thereby decreasing blood circulation to the GI tract. 28 PRODRUGS Prodrug is a compound with little or no pharmacological activity that metabolizes inside the body and converts into a pharmacologically active drug compound. Prodrugs are designed to overcome pharmaceutical, pharmacokinetic, and/or pharmacodynamic challenges. Prodrugs can be utilized for a variety of purposes including: ✓Improvement of the bioavailability ✓Decreasing drug toxicity ✓Facilitating administration of the drug ✓improve patient acceptability (unpleasant taste or odour) ✓Delivering the drug to specific cells 29 PRODRUGS Some drugs have accidentally been found to be prodrugs Eg. Isoniazid, metronidazole whiles others have been manufactured as such eg. Valacyclovir, Cefuroxime axetil For the activation of prodrugs, they have to be transformed by drug- metabolizing enzymes The biotransformation or activation of a prodrug may occur prior, during, and after absorption, or at specific target sites within the body. When prodrugs enter the body, chemical reactions or enzymes activate them. These common enzymes are Cytochrome P450 enzymes 30 Egs. Of Prodrugs Omeprazole Methyldopa Tramadol Cefuroxime Axetil Codeine Prednisone Metronidazole Azathioprine Clopidogrel Enalapril Levodopa 31 ABSORPTION Drugs given IM can be absorbed faster in muscles that have more blood vessels, such as the deltoid, than those that have fewer blood vessels, such as the gluteal. Subcutaneous tissue has fewer blood vessels, so absorption is slower in such tissue. FIND OUT VARIOUS SITES FOR IM AND SC ADMINISTRATION 32 ORAL ABSORPTION – FIRST PASS EFFECT Drugs do not go directly into the systemic circulation following oral absorption but pass from the intestinal lumen to the liver via the portal vein. In the liver, some drugs may be metabolized to an inactive form, which may then be excreted, thus reducing the amount of active drug. Some drugs do not undergo metabolism at all in the liver, and others may be metabolized to the drug metabolite, which may be equally or more active than the original drug. The process in which the drug passes to the liver first is called FIRST PASS EFFECT 33 FIRST PASS EFFECT This is the term used for the hepatic metabolism of a pharmacological agent when it is absorbed from the gut and delivered to the liver via the portal circulation. This is the metabolism of the drug BEFORE it reaches the systemic circulation The greater the first-pass effect, the less the DRUG will reach the systemic circulation when it is administered orally Drugs extensively metabolized by first-pass effect are not suitable for oral administration e.g. Glyceryl trinitrate (Nitroglycerine) 34 35 Oral Absorption Drug absorption after oral administration has two (2) components: The Rate of Absorption Bioavailability of the drug. 36 THE RATE OF ABSORPTION The rate of absorption is partially controlled by the physicochemical characteristics of the drug. – Particle size, lipid solubility, ionization, partition co-efficient This could be modified by formulation to enhance or slow the rate of absorption. Reduction in the rate of absorption can lead to a smoother concentration-time profile with a lower potential for concentration-dependent adverse effects. E.g. Slow K It may even allow less frequent dosing e.g. Nifedipine GITS (extended release Nifedipine) 37 BIOAVAILABILITY Defined as the fraction of administered dose of a drug that reaches systemic circulation In can also be seen as the extent at which the active moiety of a medicine is delivered from the pharmaceutical form and becomes available in the systemic circulation. Bioavailability is expressed as the FRACTION or PERCENTAGE of administered drug that gains access to the systemic circulation in a chemically unchanged form. Bioavailability can be calculated for the various dosage forms as well as routes of administration 38 BIOAVAILABILITY CALCULATION Bioavailability is calculated as the fraction of the concentration of the drug in plasma after a given route of administration to the concentration of the drug in plasma after intravenous route administration. Bioavailability (F) = Concentration in plasma after route of Admi (AUCr) Concentration in plasma after IV Admi (AUCiv) % Bioavailability = Concentration in plasma after route of Admi (AUCr) x 100% Concentration in plasma after IV Admi (AUCiv) Or it can be calculated as the fraction of the amount of the drug in plasma after a given route of administration to the amount of the drug administered. Bioavailability (F) = Amount of drug in plasma after route of Admi Amount of drug administered % Bioavailability = Amount of drug in plasma after route of Admi x 100% Amount of drug administered 39 Example 1. Aspirin 300mg is administered orally and after some few hours 75mg is found in plasma. Calculate the percentage bioavailability. Ans: % Bioavailability = Amount in plasma after oral admi x 100% Amount of drug administered = 75 mg x100% 300 mg = 25% NB: the amount administered orally (300 mg) is what would be obtained if the drug was administered IV 40 BIOAVAILABILITY Bioavailability ranges from 0 to1 or 0 to 100 %. First-pass effect reduces the bioavailability of the drug to less than 100%. Many drugs administered by mouth have a bioavailability of less than 100%, whereas drugs administered by the intravenous route are 100% bioavailable. If two drug products have the same bioavailability and same concentration of active ingredient, they are said to be bioequivalent (e.g., a brand-name drug and the same generic drug) 41 Bioavailability Factors that alter bioavailability include; The drug form (tablet, capsule, sustained-release, liquid, transdermal patch, rectal suppository, inhalation) ✓Route of administration (oral, rectal, topical, parenteral), ✓GI mucosa and motility ✓Food and other drugs ✓Changes in liver metabolism caused by liver dysfunction or inadequate hepatic blood flow. A decrease in liver function or a decrease in hepatic blood flow can increase the bioavailability of a drug, but only if the drug is metabolized by the liver. Less drug is destroyed by hepatic metabolism in the presence of liver disorder. With some oral drugs, rapid absorption increases the bioavailability of the drug and can cause an increase the drug concentration and Drug toxicity may result. Slow absorption can limit the bioavailability of the drug, thus causing a decrease in drug serum concentration. 42  Bioavailability Principle For drugs taken by routes other than the IV route, the extent of absorption and the bioavailability must be understood in order to determine what dose will induce the desired therapeutic effect. It will also explain why the same dose may cause a therapeutic effect by one route but a toxic or no effect by another. 43 Bioavailability Bioavailability depends on a number of physico-chemical & clinical factors. It may be altered: ✓By low solubility of the drug ✓If drug is destroyed by the acid in the stomach (e.g. X’Pen). ✓By the presence of food in the G.I.T. ✓Co-administration with other drugs. e.g. Cations in antacids (Mg, Al) and Heavy metals (Fe, Zn) can reduce the absorption of quinolones (e.g. Ciprofloxacin) and tetracyclines by binding them in the gut. 44 Bioavailability For drugs that are susceptible to extensive first pass metabolism, a substantial portion or almost all the drug could be metabolized in the liver before it reaches the site of action. E.g. nitroglycerin Drugs with very low lipid solubility such as strong acids: pKa ≤ 3 or strong bases pKa ≥ 10 (e.g. suxamethonium); are fully ionized in the GIT, may not be absorbed when administered orally. [administer parenterally] Other highly polar molecules such as amino glycosides (e.g. Gentamycin) and vancomycin are also poorly absorbed from the G.I. (Very low oral bioavailability). These drugs are usually formulated as injections. 45 Rectal drug Absorption Lower rectum – middle and inferior rectal vein drain into inferior vena cava and by-pass liver. This route by-passes first-pass metabolism As a suppository is moved upward in the rectum, it gains access to superior hemorrhoidal (rectal) vein which drains into the portal vein of the liver. This is more likely to lead to first pass effect This gives it a MIXED FIRST PASS EFFECT 46 Clinical Relevance of Drug Absorption The rate of absorption determines how soon effects will begin. The amount of absorption helps determine how intense effects will be. The nurse should be conversant with the various routes of administration and their respective likely time for onset as well as extent of action. This will help the nurse in; 1. Employing the benefits of certain drug-food drug-drug interactions for benefit of enhanced absorption 2. Minimizing drug interactions that leads to loss of therapeutic effect 3. Monitoring for efficacy (effectiveness) 4. Effective Patient counselling 5. Clinical discussions with other healthcare professionals on the best option of therapy to maximize bioavailability 47 Practical Examples Administration of Oral Ciprofloxacin and Antacids, Iron preparations (Blood tonics), Milk or Egg Administration of Oral Doxycycline and Zincovit IV vrs IM for Ceftriaxone Administration of Oral Methyldopa and Iron preparations Patients with history of gastrectomy or enterectomy and drug absorption Co-administration of oral Iron formulations and Vitamin C oral 48  ROUTES OF DRUG ADMINISTRATION (cont.) - Time until effect- Intravenous 30-60 seconds Intraosseous 30-60 seconds Endotracheal 2-3 minutes Inhalation 2-3 minutes Sublingual 3-5 minutes Intramuscular 10-20 minutes Subcutaneous 15-30 minutes Rectal 5-30 minutes Ingestion(oral) 30-90 minutes Transdermal (topical) variable (minutes to hours) 49 DISTRIBUTION This is the process by which the drug becomes available to body fluids and body tissues. Drug distribution is influenced by blood flow, its affinity to the tissue, and protein-binding effect. Areas of rapid distribution include the heart, liver, kidneys, and brain. Areas of slower distribution include muscle, skin, and fat. Once a drug enters the bloodstream (circulation), it is distributed throughout the body As drugs are distributed in the plasma, many are bound to varying degrees (percentages) with protein (primarily albumin). Drugs that are greater than 89% bound to protein are known as highly protein – bound drugs. Drugs that are 61% to 89% bound to protein are moderately highly protein- bound. Drugs that are30% to 60% bound to proteins are moderately protein – bound, and Drugs that are less than 30% bound to protein are low protein – bound drugs. 50 DISTRIBUTION Only drug molecules that are not bound to plasma proteins can freely distribute to extravascular tissue (outside the blood vessels) to reach their site of action. If a drug is bound to plasma proteins, the drug-protein complex is generally too large to pass through the walls of blood capillaries into tissues The portion of the drug that is bound is inactive because it is not available to receptors, and the portion that remains unbound is free, active drug. Only free drugs ( drugs not bound to protein) are active and can cause a pharmacologic response. As the free drug in circulation decreases, more bound drug is released from the protein to maintain the balance of free drug. 51 Drug Plasma Protein binding and its effect on distribution 52 DISTRIBUTION When two protein-bound drugs are given concurrently, they compete for protien-binding sites, thus causing more free drug to be released into the circulation. Drug accumulation and possible drug toxicity can result in this situation. Protein binding may thus lead to an unpredictable drug response called a drug-drug interaction. Also, a low protein level decreases the number of protein-binding sites and can cause an increase in the amount of free drug in the plasma. Drug overdose may then result. Certain conditions that cause low albumin levels, such as extensive burns and malnourished states, renal diseases and liver diseases result in a larger fraction of free (unbound and active) drug. This can raise the risk for drug toxicity. 53 DISTRIBUTION Some drug dose is prescribed according to the percentage in which the drug binds to protein. With some health conditions that result in a low serum protein, excess free or unbound drug goes to nonspecific tissues binding sites until needed and excess free drug in the circulation would not occur. Some drugs bind with a specific protein component such as albumin or globulin. Most anticonvulsants bind primarily to albumin. Some basic drugs such as anti-arrhythmics ( lidocaine, quinidine) bind mostly to globulins. Clients with liver or kidney disease or who are malnourished may have an abnormally low serum albumin level. This results in fewer protein-binding sites, which in turn, leads to excess free drug and eventually to drug toxicity. The elderly are more likely to have hypoalbuminemia. 54 DISTRIBUTION The patient’s plasma protein and albumin levels should be checked because a decrease in plasma protein (albumin) decreases protein- binding sites, permitting more free drug in the circulation. E.g is dosing of phenytoin in hypoalbuminaemia Depending on the drug, the result could be life-threatening. Checking the protein-binding percentage of all drugs administered to a client is important to avoid possible drug toxicity. Abscesses, exudates, body glands, and tumours hinder drug distribution. Antibiotics do not distribute well at abscess and exudates sites. In addition, some drugs accumulate in particular tissues, such as fat, bone, liver, eyes and muscle. 55 Volume of Distribution A theoretical volume, called the volume of distribution, is sometimes used to describe the various areas in which drugs may be distributed. 1. These areas, or compartments, may be the Blood (intravascular space) 2. total body water 3. body fat or 4. other body tissues and organs. Typically a drug that is highly water-soluble (hydrophilic) will have a smaller volume of distribution and high blood concentrations. In contrast, fat-soluble drugs (lipophilic) have a larger volume of distribution and low blood concentrations. There are some sites in the body that have poor penetration and hence poor distribution of drugs. These sites typically either have a poor blood supply (e.g., bone) or have physiologic barriers that make it difficult for drugs to pass through (e.g., the brain due to the blood-brain barrier). 56 METABOLISM This is also referred to as biotransformation. It involves the biochemical alteration of a drug into an inactive metabolite, a more soluble compound, a more potent active metabolite (as in the conversion of an inactive prodrug to its active form). Metabolism is the next step after absorption and distribution. The organ most responsible for the metabolism of drugs is the liver. Other metabolic tissues include skeletal muscle, kidneys, lungs, plasma, and intestinal mucosa. Hepatic metabolism involves the activity of a very large class of enzymes known as Cytochrome P-450 enzymes (or simply P-450 ENZYMES), also known as microsomal enzymes. These enzymes control a variety of reactions that aid in the metabolism of medications 57  Drug molecules that are the metabolic targets of specific enzymes are said to be substrates for those enzymes. Specific P-450 enzymes are identified by standardized number and letter designations. E.gs. 1A2, 3A4, 2C9, 2C19, 3D6, 2E1 Find common drugs that are metabolized by these iso- enzymes of the Cyt P-450 enzyme system. 58 METABOLISM These enzymes target lipid-soluble (non polar) drugs (also known as lipophilic OR ‘fat loving’’), which are typically very difficult to eliminate. This include the majority of medications. Those medications with water-soluble (polar or hydrophilic [‘water loving’]) molecules may be more easily metabolized by simpler chemical reactions such as hydrolysis. 59  Mechanisms of Biotransformation Type of Mechanism Result Biotransformation Oxidation Chemical reactions Increase polarity of Reduction chemical, Hydrolysis making it more water- soluble AND more easily excreted. This often results in a loss of pharmacologic activity. Conjugation (e.g., Combination with Forms a less toxic product glucuronidation, another substance (e.g., with glycination, glucuronide, glycine, less activity. sulfation, sulfate, methyl groups, methylation, alkyl groups) alkylation) 60 METABOLISM Many drugs can inhibit drug-metabolizing enzymes and are called enzyme inhibitors. Decreases in drug metabolism result in the accumulation of the drug and prolongation of the effects of the drug, which can lead to drug toxicity. In contrast, drugs that stimulate drug metabolism are called enzyme inducers. This can decrease pharmacologic effects. This often occurs with the repeated administration of certain drugs that stimulate the formation of new microsomal enzymes. 61 DRUG INDUSERS AND INHIBITORS ENZYME INDUCERS ENZYME INHIBITORS Carbamazepine Omeprazole Griseofulvin Isoniazid Rifampicin Erythromycin Spironolactone Metronidazole Sodium Valproate Ketoconazole Warfarin Chloramphenicol Phenytoin Sulphonamides Phenobarbitone Ritonavir Topiramate Grape fruit 62 EFFECTS OF DRUG INDUCERS AND INHIBITORS The nurse should be aware that the presence of an enzyme inducer or inhibitor in the regimen of a patient calls for evaluation of the therapy. The options to consider may be: Modify (increase or decrease) dose or dosage to reflect safe and effective plasma levels Discontinue one of the drugs in order of therapeutic needs Switch to a different drug that does not have such interactions 63 Egs. Of Clinical Relevance Omeprazole + Clopidogrel Rifampicin + Artemether/Lumefantrine OR Diazepam Phenytoin + Erythromycin Phenobarbitone + Rivaroxaban 64 METABOLISM OR BIOTRANSFORMATION In Summary The liver is the primary site of metabolism. Most drugs are inactivated by hepatic enzymes to inactive metabolites or water-soluble substances for excretion. A large percentage of drugs are lipid soluble; thus, the liver metabolizes the lipid-soluble drug substances to a water – soluble substance for renal excretion. However, some drugs are transformed into active metabolites, causing an increased pharmacologic response e.g. Clopidogrel, Enalapril. Liver diseases, such as cirrhosis and hepatitis, alter drug metabolism by inhibiting the drug-metabolizing enzymes in the liver. When the drug metabolism rate is decreased, excess drug accumulation can occur, which can lead to toxicity. The half-life, symbolized as t1/2, of a drug is the time it takes for half (50%) of the drug concentration to be metabolized or eliminated. 65 METABOLISM OR BIOTRANSFORMATION Metabolism and elimination affect the half-life of a drug. For example, with liver or kidney dysfunction, the half-life of the drug is prolonged and less is metabolized and eliminated. When a drug is taken continually, drug accumulation may occur. A drug goes through several half-lives (about 5 to 6) before more that 90% of the drug is eliminated. Eg. If the patient takes 650mg of Aspirin and the half- life is 3 hours, then it takes 3 hours for the first half-life to eliminate 335mg. And the second half-life (at 6hours) for an additional 162mg to be eliminated, and so on until the sixth half – life (or 18hours), when 10mg of aspirin is left in the body 66 METABOLISM OR BIOTRANSFORMATION A short half – life is considered to be 4-8 hours A long half-life is 24hours or longer. If the drug has a long half-life (such as digoxin: 36hours), it takes several days until the body completely eliminates the drug. BY KNOWING THE HALF-LIFE, the time it takes for the drug to reach a steady state of serum concentration can be calculated. Administration of the drug for three to five half lives saturates the biologic system to the extent that the intake of drug equals the amount metabolized and excreted. Example: Digoxin has a half-life of 36hours with normal renal function. It would take approximately 5days to 1 week {3 to 5 half lives} to reach a steady state for digoxin concentration. Steady state serum concentration is predictive of therapeutic drug effect.67 EVALUATION OF HALF-LIFE Half-life refers to the amount of time it takes for half of a particular sample to react i.e it refers to the time that a particular quantity requires to reduce its initial value to half Most clinically relevant drugs tend to follow first-order pharmacokinetics; thus, their drug-elimination rates are proportional to plasma concentrations A few drugs follow zero-order elimination in which the drug amount decreases by a constant amount over time regardless of initial concentration Half-life elimination is graphically represented with elimination curves that track the amount of a drug in the body over time, 68 Concentration-time curve indicating Half-life evaluation 69 EVALUATION OF HALF-LIFE The Half-life of a drug can be mathematically determined given its predetermined rate constant k. t-half= 0.693/k The rate constant k, can be determined from the equation ln[Ao]/[A]=kt An alternative half-life equation exists that relates half-life to other pharmacokinetic parameters known as the volume of distribution and clearance t-half= 0.693*Vd/CL where Vd is the volume of distribution and CL is clearance 70 EXCRETION, OR ELIMINATION The main route of drug elimination is through the urine. Other routes include bile, faeces, lungs, saliva, sweat, and breastmilk. Free, unbound drugs, water-soluble drugs, and drugs that are unchanged are filtered by the kidneys. Protein-bound drugs cannot be filtered through the kidneys. Once the drug is released from the protein, it is a free drug and eventually is excreted in the urine. The lungs eliminate volatile drug substances and products metabolized to CO2 and H2O. 71 EXCRETION, OR ELIMINATION The urine pH influences drug excretion. Urine pH varies from 4.5 to 8. Acid urine promotes elimination of weak base drugs and Alkaline urine promotes elimination of weak acid drugs. Aspirin, a weak acid is excreted rapidly in alkaline urine. If a person takes an overdose of aspirin, sodium Bicarbonate may be given to change the urine pH to alkaline to help potentiate excretion of the drug. Large quantities of cranberry juice can decrease urine pH, causing an acidic urine, thus inhibiting the elimination of the aspirin. With a kidney disease that results in decreased glomerular filtration rate (GFR) or decreased renal tubular secretion, drug excretion is slowed or impaired. Drug accumulation with possible severe adverse drug reactions can result. A decrease in blood flow to the kidneys can also alter drug excretion. 72 EXCRETION, OR ELIMINATION The most accurate test to determine renal function is Creatinine Clearance (CrCl). Creatinine is a metabolic by product of muscle that is excreted by the kidneys. Creatinine clearance varies with age and gender. Lower values are expected in elderly female clients because of their decreased muscle mass. A decrease in renal GFR results in an increase in serum creatinine level and a decreased in urine creatinine clearance. With renal dysfunction resulting from kidney disorders or in the elderly, drug dosage usually needs to be decreased. In these cases, the creatinine clearance needs to be determined to establish appropriate drug dosage. 73 EXCRETION, OR ELIMINATION When the creatinine clearance is decreased, drug dosage may need to be decreased. Continuous drug dosing according to a prescribed dosing regimen could result in drug toxicity. The creatinine clearance test consist of a 12– or 24- hour urine collection and a blood sample. Normal creatinine clearance is 85 to 135 mL/min. This rate decreases with age, because aging decreases muscle mass and results in a decrease in functioning nephrons. Elderly clients may have a creatinine clearance of 60mL/min. for this reason, drug dosage in the elderly may need to be decreased. 74 ESTIMATION OF RENAL FUNCTION ASSIGNMENT 1. Outline the various methods employed to estimate the renal function of patients 2. Indicate the various formulas used to estimate the renal function (CrCl and eGFR) of patients 3. Discuss the clinical relevance of evaluating the renal function of patients in drug therapy 75 76 77