Pharmacokinetics PDF

PHARMACOKINETICS -Decided by therapeutic objective like desire for rapid onset,long Pharmacokinetics- is the term treatment,Restriction of quantitative measurement of delivery to a local site drug:...

PHARMACOKINETICS -Decided by therapeutic objective like desire for rapid onset,long Pharmacokinetics- is the term treatment,Restriction of quantitative measurement of delivery to a local site drug: Major Routes are absorption-First, absorption from enteral,parenteral,and topical the site of administration permits entry of the drug (either directly or indirectly) into plasma. distribution-Second, the drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids. metabolism-Third, the drug may be biotransformed by metabolism by the liver or other tissues. elimination/Excretion-Finally, the drug and its metabolites are eliminated from the body in urine, bile, or feces. -It includes the rate processes for drug movement into the body, within the body, and out of the body. Pharmacodynamics-is what the drug does to the human body and its adverse effects ROUTE OF DRUG ADMINISTRATION -Is Determined by the properties of the drug like water and lipid solubility  -Advantageous for drugs with short half-lives A. Enteral -(administering a drug by mouth) -the safest and most common, Example: Morphine with 2-4 Hrs convenient, and economical Half-life and administered 6 times method of drug administration. daily only needs 2 tablets when 1.Oral ER tablets are used -easily self-administered, and toxicities and/or overdose of oral 2.Sublingual/Buccal drugs may be overcome with -Buccal is similar to sublingual antidotes such as activated -has several advantages,including charcoal ease of administration, rapid -the most complicated, and the absorption, bypass of the harsh low gastric pH inactivates some gastrointestinal (GI) environment, drugs. and avoidance of firstpass metabolism a.Enteric-coated preparations -Placement under the tongue -are chemically enveloped allows a drug to diffuse into the protecting the drug from stomach capillary network and enter the acid, delivering it instead to the systemic circulation directly. less acidic intestine, where the coating dissolves and releases the B.Parenteral drug -Useful for acid unstable drugs like -Introduces drug directly to the Omeprazole systemic circulation -Useful Stomach irritating drugs -Used for drugs poorly absorbed in like aspirin the GI tract example:Heparin -Drugs unstable in GI tract b.Extended release preparations example:Insulin (Abbreviated ER or XR) -Used in unavailability of oral route -Has special coating for slower example: Unconscious Patient absorption and prolonged duration -Used in circumstances requiring of action rapid onset of action -Highest bioavailability and not 2.Intramuscular (IM) subjected to First-pass -Can be aqueous solutions metabolism -specialized depot preparations, -irreversible,may cause pain, which are absorbed slowly. Depot fear,local tissue damage,and preparations often consist of a infections. suspension of the drug in a nonaqueous vehicle such as 1.Intravenous (IV) polyethylene glycol. -the most common parenteral -Drugs dissolution slowly providing route sustained release example -useful for drugs that are not haloperidol and absorbed orally, such as medroxyprogesterone the neuromuscular blocker rocuronium. 3.Subcutaneous (SC) -When injected as a bolus, the full -SC injection minimizes the risks amount of drug is delivered to the of hemolysis or thrombosis systemic circulation almost associated with IV injection immediately -may provide constant, slow, and -administered as an IV infusion, sustained effects. the drug is infused over a longer -should not be used with drugs period of time, resulting in lower that cause tissue irritation because peak plasma concentrations and it might lead to severe pain and an increased duration of necrosis circulating drug levels. -Examples are Insulin and Heparin C.Others 3.Topical 1.Inhalations -used when a local effect of the -provide rapid delivery of a drug drug is desired. across the large surface area of -example-clotrimazole is a cream the mucous membranes of the applied directly to the skin for the respiratory tract and pulmonary treatment of fungal infections. epithelium -Drug effects are almost as rapid 4.Transdermal as those with IV bolus. -achieves systemic effects by -effective application of drugs to the skin, and convenient for patients with usually via a transdermal patch respiratory disorders such as -rate of absorption can vary Asthma and COPD markedly,depending on the 2 types of Inhalations physical characteristics of the skin ​ Oral Inhalations at the site of application, as well examples:Albuterol,Corticosterois as the lipid solubility of the drug. ,such as fluticasone -most often used for the sustained ​ Nasal Inhalations delivery of drugs Examples:oxymetazoline, and - examples are antianginal drug corticosteroids, such as nitroglycerin, the antiemetic mometasone furoate and scopolamine, Desmopressin -nicotine transdermal patches are used to facilitate smoking 2.Intrathecal/Intraventricular cessation. -When local, rapid effects are needed, it is necessary to introduce drugs directly into the cerebrospinal fluid. -example:intrathecal amphotericin B is used in treating cryptococcal meningitis 5.Rectal -50% of the drainage of the rectal region bypasses the portal circulation -the biotransformation of drugs by the liver is minimized with rectal administration -prevents destruction of the drug in the GI environment. -useful if the drug induces vomiting when given orally, if the patient is already vomiting, or if the patient is unconscious. -[Note: The rectal route is commonly used to administer antiemetic agents.] -Rectal absorption is often erratic and incomplete -many drugs irritate the rectal mucosa.  3.Nasal Spray for allergies (e.g. fluticasone nasal spray) EXTRAVASCULAR -Topical administration of a drug ADMINISTRATION can produce therapeutic effects INCLUDE while minimizing systemic Oral toxicity due to lower systemic Sublingual exposure, but some topical Buccal formulations are designed to Intramuscular deliver a systemic dose (e.g. Subcutaneous Duragesic Patch). Transdermal -The extent of topical absorption is Inhaled affected by many factors, including Topical the presence of open wounds on Ocular the skin (increased absorption) Intraocular and the amount of drug applied Intrathecal Rectal 2.Drugs intended for systemic effects -are generally administered to EXTRAVASCULAR facilitate absorption to the circulatory system. ADMINISTRATION Examples of drugs intended for -Drugs administered systemic effects: extravascularly can 1.Oral tablets for seasonal be divided into two categories allergies (e.g. loratadine) 1.Drugs intended for local effects 2.Suppositories for fever -are often applied topically where (e.g. acetaminophen) the drug effect is 3.Sublingual tablets for angina needed. (e.g. nitroglycerin SL) Examples: -Some percentage of a drug 1.Eye drops for glaucoma intended for systemic effect will (e.g.latanoprost) move from the site of 2.Dermal preparations for administration into the psoriasis (e.g. coal tar prep) systemic circulation. ABSORPTION -Drugs with a high lipid solubility -When a drug is administered (e.g. diazepam, fentanyl) readily intravascularly, it directly enters dissolve in membrane the blood either intravenously or phospholipids and rapidly diffuse intraarterially. across cellular membranes. -When a drug enters the systemic -Only the smallest molecules like circulation (bloodstream) and water, carbon dioxide, and oxygen absorption is not necessary. can freely diffuse across cell -If the drug is administered membranes. extravascularly, drug absorption ​ Weak acid drugs occurs as the drug moves from the -LUNA in stomach site of administration to -HIPE in Small Intestine the systemic circulation. ​ Weak base drugs -HIPE in stomach -LUNA in small intestine 2.Facilitate diffusion -It does not require energy, Mechanism of absorption can be saturated, and may 1.Passive diffusion be inhibited by compounds -Most common that compete for the carrier. -Follows Fick’s Law of diffusion -Agents can enter the cell through -Non-energy requiring specialized transmembrane carrier -The drug moves from proteins that facilitate the passage a region of high concentration to of large molecules from an area of one of lower concentration. high concentration to an area of -Passive diffusion does low concentration. not involve a carrier, is not -Moves along the concentration saturable, and shows a low Gradient structural specificity. -Polar and charged molecules, -Water-soluble via aqueous such as carbohydrates, amino channels or pores and acids, nucleosides, and ions, lipid-soluble drugs Move from high cross the plasma membrane. concentration to low concentration. 3.Active transport -Energy dependent -active transport is driven -Vitamin B12 is transported across by the hydrolysis of the gut wall by endocytosis adenosine triphosphate. -whereas certain -It is capable of moving neurotransmitters (for drugs against a example,norepinephrine) are concentration gradient, stored in intracellular vesicles in from a region of low the nerve terminal and released by drug concentration to exocytosis. one of higher drug ​ Phagocytosis-Cell eating concentration. Large drug molecules -Calcium moves between cells ​ Pinocytosis- Cell drinking with the use of ATP energy. Liquids, small molecules ADEK,Griseofulvin FACTORS AFFECTING B. Carrier – Mediated Transport ABSORPTION -Specificity is one of this transports feature since the Carriers recognize special 1.Effect of pH on drug absorption molecules -for a weak acid, the uncharged, -Subject to Competiton protonated HA can permeate -Saturable through membranes, and A− -Displays Michaelis-Menten kinetic cannot. -For a weak base, the uncharged 4.Endocyctosis form B penetrates through the cell -Involves engulfment of a drug by membrane, but the protonated the cell membrane and form BH+ does not. transport into the cell by -the effective concentration of the pinching off the drug-filled permeable form of each drug at its vesicle. absorption site is determined by -Exocytosis is the the relative concentrations of the reverse of endocytosis. charged and uncharged forms. 2.Blood flow to the absorption site 5.Expression of P-glycoprotein -intestines receive much more -a transmembrane transporter blood flow than the stomach, so protein responsible for absorption from the intestine transporting various molecules, is favored over the stomach. including drugs, across cell -Shock severely reduces blood membranes flow to cutaneous tissues, thereby -expressed in tissues throughout minimizing absorption from SC the body, including the administration. liver, kidneys, placenta, intestines, and brain capillaries, 3.Total surface area available for -Is involved in transportation of absorption drugs from tissues to blood. -surface rich in brush borders -transporting many drugs out of containing microvilli, the intestine cells,is associated with multidrug has a surface area about resistance 1000-fold that of the stomach, making absorption of the drug Dosage Form Dissolution and across the intestine more efficient. Drug Solubility 4.Contact time at the absorption DISSOLUTION surface -When an oral dosage form is -drug moving through the GI tract ingested,it begins to dissolve in very quickly, as can happen with the GI tract and the active severe diarrhea, will lead to drug ingredient is released from the being not well absorbed. dosage form (typically a -anything that delays the compressed tablet or a capsule). transport of the drug from the -Most immediate-release stomach to the intestine delays formulations dissolve and get the rate of absorption of the drug. absorbed rapidly, but some can be destroyed in the gut (primarily by hydrolysis, o lysis with water) making them less available for absorption. -Drug formulations have been - generally lipophilic, or lipid developed with a protective loving. coating to limit drug degradation in -Poor systemic absorption the acidic medium of the stomach ​ Freely soluble drugs but permit dissolution in the basic -generally hydrophilic, or medium of the intestine. water-loving. -Examples of drugs with these -Good systemic absorption protective coatings -As a drug moves through the GI include enteric-coated tract, only dissolved drug is formulations such as absorbed into the bloodstream. Dulcolax and Entocort EC. -If a drug has poor absorption,Its particle size is usually decreased BIOAVAILABILITY in order to increase it's surface area. -Micronized:Are drugs with very small particle size that it's diameter is measured in Micrometer but it can also be measure now in nanometers -Drugs with poor absorption like progesterone and fenofibrate formulations are Micronized. It's rate of dissolution is described by Noyes-Whitney equation -the drug that is released -The extent to which a drug is from the dosage form can be absorbed into the systemic dissolved in GI fluids. circulation. -The rate and extent to which the -can be calculated using the area drug dissolves depends on the under the plasma concentration drug’s solubility. time curve or AUC(represents the ​ Poorly soluble drugs total exposure of drug). -the percentage of a drug Factors affecting absorbed from the extravascular bioavailability (e.g. oral) relative to intravascular administration (e.g. IV). a.First-pass metabolism -affected by absorption, -a degradation that Occurs dissolution, route of administration With orally administered drugs and other factors. -In contrast to IV administration, -is reported as a percentage from which confers 100% bioavailability, 0 to 100%. orally administered drugs often ​ Good absorption=High undergo first-pass metabolism. bioavailability -If the drug is rapidly metabolized -​ >70% in the liver or gut wall during this ​ Poor absorption=Low initial passage, the amount of bioavailability unchanged drug entering the -​ 90%) and serum albumin is low greater than that to the skeletal ( 7 mg/L. Phenytoin theophylline Phenylbutazone voriconazole Ethanol ​ Km-the rate of metabolism is half maximal is defined as the Michaelis-Menten constant -At concentrations above the Km, the rate of metabolism becomes mixed (first-order and zero-order) -at even higher concetrations relative to the  Km, the rate of metabolsim A. Renal elimination of a drug becomes zero-order -Elimination of drugs via the (e.g. Vmax). kidneys into urine ​ Vmax-is the maximum rate of metabolism 1. Glomerular filtration -Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. EXCRETION -the process of irreversible 2.Proximal tubular secretion removal of drugs from the body. -Drugs that were not transferred -occur through the kidney (urine), into the glomerular filtrate leave liver (bile), gut (feces), lungs the glomeruli through efferent (exhaled air), and skin (sweat). arterioles, which divide to form a -The primary route of excretion for capillary plexus surrounding the most drugs is the nephric lumen in the proximal kidney (renal excretion). tubule. -P-glycoprotein (P-gp) -Secretion primarily occurs in the efflux pumps play a role in proximal tubules by two absorption and excretion energy-requiring active transport of many drugs. systems: ​ one for anions (for example, DRUG CLEARANCE BY deprotonated forms of weak THE KIDNEY acids) ​ one for cations (for example, -Drugs must be sufficiently polar to protonated forms of weak be eliminated from the body. bases) -the most important being -These transport systems shows elimination through the kidney into low specificity and can transport the urine. many compounds. Thus, -Patients with renal competition between drugs for dysfunction may be unable to these carriers can occur within excrete drugs and are at risk for each transport system. drug accumulation and adverse effects. [Note: Premature infants and -To minimize this reabsorption, neonates have an incompletely drugs are modified primarily in the developed tubular secretory liver into more polar substances mechanism and, thus, may retain via phase I and phase II reactions certain drugs in the glomerular (described above). filtrate.] VII. CLEARANCE BY OTHER 3. Distal tubular reabsorption ROUTES -As a drug moves toward the distal -Drug clearance may occur vvia convoluted tubule, its intestines, bile, lungs, and breast concentration increases and milk, among others. exceeds that of the perivascular -drugs that are secreted directly space. into the intestines or into bile are -weak acids can be eliminated by eliminated in the feces. alkalinization of the urine, -The lungs are primarily involved whereas elimination of weak in the elimination of bases may be increased by anesthetic gases for acidification of the urine.This example:isoflurane process is called “ion trapping.” -Elimination of drugs in breast example: milk may expose the a patient presenting with breast-feeding infant to phenobarbital (weak acid) medications and/or metabolites overdose can be given being taken by the mother and is a bicarbonate, which alkalinizes the potential source of undesirable urine and keeps the drug ionized, side effects to the infant. thereby decreasing its -Total body clearance and reabsorption. drug half-life are important 4.Role of drug metabolism measures of drug clearance that -Most drugs are lipid soluble and, are used to optimize drug therapy without chemical modification, and minimize toxicity. would diffuse out of the tubular lumen when the drug concentration in the filtrate becomes greater than that in the perivascular space. A. Total body clearance VIII. DESIGN AND -The total body (systemic) OPTIMIZATION clearance, CLtotal, is the sum of OF DOSAGE REGIMEN all clearances from the -initiate drug therapy, the clinician drug-metabolizing and must select the appropriate route drug-eliminating organs. of administration, dosage, and -Total clearance is calculated dosing interval. using the following equation: -regimen depends on various patient and drug factors, including how rapidly therapeutic levels of a drug must be achieved. -The regimen is then further refined, or optimized, to maximize B. Clinical situations resulting in benefit and minimize adverse changes in drug half-life effects. -patient having abnormality that alters the half-life of a drug, A. Continuous infusion regimens adjustment in dosage is required. -consist of a single dose of a drug, -Patients who may have an for example, a sleepinducing increase in drug half-life include agent, such as zolpidem. those with -More commonly, drugs are 1) diminished renal or hepatic continually administered, either as blood flow example:cardiogenic an IV infusion or in oral fixed-dose/ shock, heart failure, or fixed-time interval regimens (for hemorrhage example:one tablet every 4 hours 2) decreased ability to extract drug -Steady-state concentration is from plasma, for example, in renal reached when the rate of drug disease elimination is equal to the rate of 3) decreased metabolism, for drug administration, such that the example, when a concomitant plasma and tissue levels remain drug inhibits metabolism or in relatively constant. hepatic insufficiency, as with cirrhosis. 1. Plasma concentration of a drug b. Time required to reach the following IV infusion steady-state drug concentration -With continuous IV infusion, the -concentration of a drug rises from rate of drug entry into the body is zero at the start of the infusion to constant. its ultimate steady-state level, Css -continuous IV infusion, the -The sole determinant of the rate plasma concentration of a drug that a drug achieves steady rises until a steady state (rate of state is the half-life (t1/2) of the drug elimination equals rate of drug, drug administration) is reached B. Fixed-dose/fixed-time regimens a. Influence of the rate of infusion -Fixed-dose/fixed-time regimens on steady-state concentration Administration of a drug by fixed -The steady-state plasma doses rather than by continuous concentration (Css) is directly infusion is often more convenient. proportional to the infusion rate. -fixed doses of IV or oral -example, if the infusion rate is medications given at fixed doubled, the Css is doubled intervals result in time-dependent -Css is inversely proportional to fluctuations in the circulating level the clearance of the drug. Thus, of drug any factor that decreases clearance, such as liver or kidney 1. Multiple IV injections disease, increases the Css of an -When a drug is given repeatedly infused drug at regular intervals, the plasma -Factors that increase clearance, concentration increases until a such as increased metabolism, steady state is reached decrease the Css a. Effect of dosing frequency -With repeated administration at regular intervals, the plasma concentration of a drug oscillates about a mean. Using smaller doses at shorter intervals reduces the amplitude of fluctuations in drug concentration. 2. Multiple oral administrations concentration in plasma (Cp), -Most drugs that are administered clearance (CL) of the drug from on an outpatient basis are oral the systemic circulation, and the medications taken at a specific fraction (F) absorbed dose one, two, or three times daily. (bioavailability): -In contrast to IV injection, orally administered drugs may be absorbed slowly, and the plasma concentration of the drug is influenced by both the rate of absorption and the rate of 2.Loading dose: Sometimes rapid elimination obtainment of desired plasma levels is needed (for example, in C. Optimization of dose serious infections or arrhythmias). -The goal of drug therapy is to Therefore, a “loading dose” of achieve and maintain drug is administered to achieve concentrations within a therapeutic the response window while minimizing desired plasma level rapidly, toxicity and/or side effects. With followed by a maintenance dose to careful titration, most drugs can maintain the steady stateIn achieve this goal. general, the loading dose can be calculated as 1. Maintenance dose: Drugs are generally administered to maintain a Css within the therapeutic window. It takes four to five half-lives for a drug to achieve Css. -The dosing rate can be 3. Dose adjustment determined by knowing the target -The amount of a drug administered for a given condition is estimated based on an “average patient.” overlooking interpatient variability in pharmacokinetic parameters such as clearance and Vd -optimize therapy for a given patient.Monitoring drug therapy and correlating it with clinical benefits provides another tool to individualize therapy -Vd can be used to calculate the amount of drug needed to achieve a desired plasma concentration. example: assume a heart failure patient is not well controlled due to inadequate plasma levels of digoxin. Suppose the concentration of digoxin in the plasma is C1 and the desired target concentration is C2, a higher concentration.