Pharmacokinetics PDF

PRINCIPLES OF PHARMACOKINETICS Block 1.2 - TL Dr. Girish Meravanige College of Medicine, KFU PRINCIPLES OF PHARMACOKINETICS Block 1.2 - TL Dr. Girish Meravanige College of Medicine, KFU ...

PRINCIPLES OF PHARMACOKINETICS Block 1.2 - TL Dr. Girish Meravanige College of Medicine, KFU PRINCIPLES OF PHARMACOKINETICS Block 1.2 - TL Dr. Girish Meravanige College of Medicine, KFU  Bound drugs: - are not available for distribution (because the plasma proteins Plasma Protein Binding (PPB) have a lot of molecular weight and size, so the drug is unable to penetrate through the biological membrane and will be again con ned to the vascular compartment). - cannot undergo metabolism in the body or elimination through I t refe rs to t h e d e g re e t o w h i c h the kidney. - do not interact with the receptor and do not produce any d r u g s b i n d to p l a s m a p ro te i n s biological effects. ( P P ) p r i m a r i l y a l b u m i n & ⍺ 1 Free drugs: a c i d g l yc o p ro te i n. T h i s b i n d i n g -pass through the biological membrane easily. a f fe c t s t h e p h a r m a c o k i n et i c s -can undergo metabolism and elimination. -can produce biological effects. and pharmacodynamics of d r u g s The binding depends on the type of the drug whether it’s weakly acidic or weakly basic. Acidic drugs have strong af nity toward albumin protein. Basic drugs have strong af nity toward alpha 1 acid glycoprotein. Acidic drugs - a l b u m i n ( ex. N SA I D ’s ) Basic drugs- ⍺1-acid g l yc o p ro te i n ( ex. P ro p ra n o l o l )  Temporary reservoir sites means not permanent storage sites. It depends on the plasma Plasma Protein Binding (PPB) concentration if the concentration of the drug declines or decreases, it will be gradually dissociate Pharmacological/ Clinical significance: and release into the circulation that it is going to prolong the duration of action of the drug. P ro l o n g s t h e d r u g ava i l a b i l i t y & d u rat i o n o f a c t i o n ( ‘ te m p o ra r y re s e r vo i r s i te s ’ ) D i st r i b u t i o n : B o u n d d r u g s a re re st r i c te d to t h e va s c u l a r co m p a r t m e nt , w h i l e u n b o u n d d i st r i b u te to t i s s u e s M eta b o l i s m : O n l y u n b o u n d d r u g s a re m e ta b o l i ze d E xc ret i o n : B o u n d d r u g s a re l e s s a c c e s s i b l e to re n a l exc re t i o n Unbound drugs=Free drugs Re c e p to r i nte ra c t i o n : O n l y u n b o u n d d r u g s i nte ra c t w i t h ta rge t re c e p to rs The bound drugs which are not undergoing distribution nor metabolism nor elimination from the kidney means they have not been ltered from the membrane, they will gradually dissociate then once it undergo metabolism it will be eliminated.  If the drug is more extensively binding to the plasma protein the free drug concentration is going to be decreased Plasma Protein Binding (PPB)…Cont’d (only the free drug can produce a pharmacological effect) since there is a decrease in the free drug concentration the drug ef cacy will be affected. D r u g ef f i c a c y : P P B a ffe c t s d r u g co n c e nt rat i o n a t t h e s i te o f a c t i o n D o s i n g a d j u st m e nt s : N e c e s s a r y i n co n d i t i o n s a l te r i n g P P B, s u c h a s re n a l o r h e p at i c i m p a i r m e nt , i nfe c t i o n s , inflammation or malnutrition. Tox i c i t y : D r u g tox i c i t y r i s k i n c re a s e d w i t h h i g h l y b o u n d d r u g s i n p at i e nt s w i t h a l te re d P P B. Ex:D r u acute g d renal i s p failure l ora c e m hepatic e nt i nte ra c t i o n s : cirrhosis. In such conditions, there is a possibility of decrease in the plasma albumin (hypoalbuminemia).  Sis abound Albumin l i cbyy lweakly ate acidic s - To l bIfuyoutaadjust drugs. m ithed esame : H y pfreeodrug dose, g l yconcentration ce m i a is going to be increased which can lead to toxicity (the dose has to be reduced).  Iwith Similarly n dpatients o m ethat t hhave a csome i n -kindWa r fa r iornin: ammations. of infections H e m oInr such r h aconditions ge weakly basic drugs are used. The alpha 1 acid lipoprotein levels are going to rise (the dose has to be increased) otherwise if you use the same dose the patient will not have any effect because most of the drug is going to bind to the plasma proteins and results in less free drug.  drug-drug interaction or a drug displacement reaction is called drug displacement. Ex: a diabetic patient is taking a Tolbutamide (an oral hypoglycemic drug to control the blood sugar level) he's also taking a Salicylates (an aspirin-like drug for controlling pain). Both are weakly acidic drugs and both are competing to bind to the plasma albumin, whichever has a higher af nity to bind to that albumin is going to bind and the one which is already bound is going to be displaced from its site. In this case, Salicylate has a higher af nity than Tolbutamide, so it’s going to displace the Tolbutamide from the plasma albumin. As a result, the free drug concentration of Tolbutamide is going to increase and the patient will suffer from hypoglycemic symptoms. Ex: a patient is taking Warfarin (an oral anti-coagulant drug) he’s also taking Indomethacin (a non-steroidal in ammatory drug). Both are weakly acidic drugs competing for the albumin. Indomethacin has a higher af nity than Warfarin, so it’s going to displace the binding of warfarin. As a result, the free drug concentration of Warfarin is going to increase and the patient will suffer from unnecessary bleeding.  Physiological Barriers Blood brain barrier Placental barrier  The blood brain barrier is a barrier existing between the brain and the peripheral blood circulation composed of tight endothelial cells, the end foot process of astrocytes, and the basement membrane. It prevents the entry of harmful substances into the brain like a toxins or pathogens and regulates nutrients, hormones, and neurotransmitters. The difference between typical capillaries and blood brain capillaries: Peripheral / Typical capillaries : They are composed of endothelial cells that have loose junctions between them. Blood brain capillaries: They have tight junction between its endothelial cells which will help in preventing the entry of harmful Substances from the blood circulation to the brain. (The only substances which can easily cross are the lipid soluble and unionized molecules). * Remember: the function of the blood brain barrier is sometimes disrupted in cases of brain infections like in meningitis or encephalitis. Also if the patient had any head trauma or head injuries. Ex: in normal conditions when an antibiotic like penicillin is administered it will not pass the blood brain barrier. However, when administered in cases of brain infection or in ammation like meningitis or any effective condition these antibiotics like penicillin will easily diffuse the blood brain barrier and enter the brain. The placental barrier is a barrier between the mother and the fetus composed of chorionic villi, trophoblastic cells, and a basement membrane under endothelial cells. It prevents the entry of harmful substances into the fetus, protects the fetus from therapeutic effects, and regulates the entry of gases, nutrients, and all the substances to the fetus. * In comparison to the blood brain barrier the placental barrier is ineffective in preventing all potentially harmful compounds from reaching the fetus. As a result, gynecologists will tend to avoid prescribing some medications to prevent harmful effects on the baby. lipid soluble drugs and the unionized molecules can easily pass through. However, drugs which are highly polar or more water soluble or have large molecular weight and size (like heparin and penicillin) are unable to pass through.  Apparent Volume of Distribution (aVd) “Hypothetical volume of body fluid into Drugs with low volume of distribution: which a drug is uniformly distributed at a Drugs that are highly bound to plasma concentration equal to that in plasma” proteins have less volume of distribution. Because proteins which have a large molecular weight and size or highly polar or undergo a high degree of ionization are unable to aVd = Dose/Concentration (plasma) penetrate the basement membrane and remain E.g. = 50mg/ 0.1mg = 500ml con ned to the vascular compartment. Anti-coagulation drug Drugs with high volume of distribution: Drugs that are distributed to the total body  Low aVd E. g. Wa rfa rin(8L) water as well as extensively binding to the  H ig h aVd E. g. Chlo roquine various tissue proteins in the body like in the muscles, adipose tissue, brain, liver, or heart. (1 5 0 0 0L) Anti-malarial drug  Apparent Volume of Distribution (aVd) Factors Affecting: Molecular size & weight, Lipid-solubility, degree of ionization, plasma protein & extra vascular protein binding, disease In case of an overdose the patient develops toxic effects. states. The drug is going to be distributed extensively: - if it remains in the vascular compartment it can be treated with hemodialysis. - If the drug has been distributed to the tissue proteins removal is not possible. Clinical significance: A medical procedure done to patients who have nonfunctioning - In drug poisoning (hemodialysis) kidneys to lter waste products, excess uids, and electrolytes. - To calculate loading dose (drug): Vd X Desired Cp Where Vd - Volume of distribution Ex: In the case of Chloroquine (an anti-malarial drug) we should start with a loading dose (the single largest Cp - Plasma concentration dose) followed by the maintenance dose In order to saturate the binding sites. Once the binding sites get *Drugs which have a high volume of distribution should always be treated with saturated, only the free drugs are going to be in the the loading dose (start with the single largest dose) that is going to saturate the plasma and produce pharmacological effects. If you use binding sites and achieve the therapeutic concentration of the drug in the plasma. the normal therapeutic dose, there won’t be any free drugs in the plasma in order to produce its effects.  Biotransformation (Drug metabolism) “Enzyme catalyzed chemical transformation of drugs from nonpolar (lipid-soluble) to polar (lipid-insoluble) compounds” so that drug/metabolite is not reabsorbed in renal tubules and are excreted. The main (major) site of biotransformation is the liver, where 90% of drugs undergo metabolism. There are other (minor) sites where selected drugs will undergo metabolism such as the kidneys, intestine , glands or maybe plasma. End result of drug metabolism: 1-Active drug to inactive metabolite 2-Active drug to active metabolite e.g., Diazepam to oxazepam 3-Inactive drug to active metabolite (‘prodrug’) e.g., Levodopa to dopamine levodopa is used for the treatment of Parkinson's disease (de ciency of dopamine in the brain). We cannot use dopamine directly since it’s highly polar and cannot penetrate the blood-brain barrier. Instead, levodopa is used (a lipid soluble drug that can easily pass through the blood-brain barrier and reach the brain) brain enzymes are going to convert levodopa into dopamine. Advantages: site-speci c delivery and improve the duration of action.  Biotransformation (Drug metabolism) Phase I reactions: Convert parent drug into a more polar metabolite by adding (-OH, - SH, -NH2) E.g. Oxidation, reduction, hydrolysis Phase II reactions: Conjugation with endogenous substrate to further increase aqueous solubility. E.g. Glucuronide Phase I reactions (Non-synthetic reactions): The metabolite will be added to either hydroxyl, sulfhydryl, or amino group to make it more polar and water soluble. Once they become more water soluble they can be eliminated directly through the kidney in the form of urine or through the GIT in the form of feces. However, some metabolites will still be in a lipid soluble state and have to undergo phase II biotransformation. Phase II reactions (synthetic reactions): This phase makes sure that the parent drug and the metabolite are transformed into a more water soluble state in order to eliminate them from the body.  Sequential metabolism of a drug An important antibiotic used for various conditions like tuberculosis. E.g. Streptomycin, DRUG Unchanged Neostigmine, Pancuronium Phase I Metabolite Phase II EXCRETION Drugs that are already in a highly water Metabolite soluble state (quaternary ammonium EXCRETION compounds) they don’t need to undergo metabolism in the liver they will be eliminated in an unchanged form EXCRETION through the kidney because they’re already in a water soluble state.  Drug Metabolizing Enzymes: “Cytochrome P-450” (CYP -450) Also called monooxygenases.  What are microsomal enzymes? The main enzymes which are responsible for the metabolism of the majority (75-80%) of the drugs by the CYP450 (Cytochrome P450).  Common CYP-450 isoenzymes: CYP3A4 most abundant enzyme, CYP2D6, CYP1A2, CYP2C9. these enzymes are mainly seen in the liver and also found in the lungs, brain, intestine, kidney, and placenta. They are expressed in the smooth endoplasmic reticulum. Also, you can expect a CYP gene polymorphism (variation in the genes).  Drug Metabolizing Enzymes: “Cytochrome P-450” (CYP -450) Enzyme induction & inhibition: Clinical implications:  Induction: Increased enzyme  Interindividual variability expression (e.g., rifampicin,  CYP gene polymorphism phenobarbital)  Drug-Drug interactions  Inhibition: Decreased enzyme  Enzyme induction: Rifampicin with activity (e.g., ketaconazole, OCP – Unwanted pregnancy cimetidine, grapefruit juice)  Enzyme inhibition: Cimetidine with Dicumarol - Increases bleeding  By inducing the enzymes the rate of metabolism of the drugs is going to increase. Ex: A female suffering from tuberculosis is taking rifampicin (anti- tubercular drug) to control her infection she is also taking oral These drugs are called contraceptive pills in order to postpone her pregnancy. The outcome potent enzyme inducers. is an unwanted pregnancy. Because rifampicin is a potent enzyme inducer, by inducing the enzyme it has accelerated the metabolism rate of the oral contraceptive. As a result, the drug is not protecting her from becoming pregnant. By inhibiting the enzymes the rate of metabolism of the drugs is going to decrease. Ex: A patient suffering from an acid peptide disease is taking cimetidine to control the acid secretion and is also taking dicoumarol (oral anti-coagulant drug). The outcome is unnecessary bleeding. Because the cimetidine has inhibited the metabolism of dicoumarol which is the undergoing enzyme, by inhibiting the metabolism the dicoumarol duration of action becomes prolonged.  Drug Excretion The drug will be eliminated through the urine or feces once it has been metabolized and turned into a water soluble state. Process of removal of drugs from the systemic circulation into extra corporeal fluids (e.g., urine or bile) Major routes - Biliary or renal The kidney is the most important organ for the elimination of majority of the drugs. Minor routes - lung, skin, breast milk, tears, saliva  Renal Drug - If the kidney is functioning adequately or not is decided Elimination based on the glomerular ltration rate. * If a patient is having a good ltration rate a good amount of drug is going to be eliminated. Factors influencing rate of * If a patient is suffering from renal related issues like diabetes, hypertension, or elderly age the glomerular ltration drug elimination: rate is going to decrease as well as the elimination of drugs leading to accumulation in the body resulting in toxicity. GFR (glomerular ltration rate) - Bound drugs are not going to be ltered through the Plasma protein binding glomerular membrane. Lipid solubility - lipid soluble drugs can easily pass through the membrane. Molecular wt. & size - the smaller the molecular weight and size is the easier it can pH of urine & Ionization pass through the membrane. Renal route of drug elimination occurs through 3 important processes: 1- Glomerular Filtration Drug Excretion 2- Passive tubular reabsorption 3- Active tubular secretion Renal drug excretion Biliary drug excretion Excretion= (Filtration + Secretion) - Reabsorption 1/Glomerular ltration: 3/Active tubular secretion: This process occurs in the glomerular membrane with Active tubular secretion is an energy dependent process the help of the glomerular capillaries and the that occurs with the help of carrier mediated molecules bowman’s capsule. The elimination of the drug is that transfer molecules from the peritubular capillaries into directly proportional to the glomerular ltration rate. the renal tubules. If the ltration rate is good the drugs will be easily * The pH of the urine doesn’t matter. ltered as well as unbound drugs, drugs that have low * Plasma protein bound drugs can be secreted into the molecular weight and size, and lipid soluble drugs can renal tubules. easily pass through the glomerular membrane. * There’s a separate carrier for weakly acidic drugs and a separate carrier for weakly basic drugs (the carrier is non-selective for the drugs). Ex: A patient is taking penicillin (an antibiotic) and probenecid (a drug for uric acid excretion). Both are 2/Passive tubular reabsorption: weakly acidic drugs competing on the same carrier Once the drug is ltered into the renal tubules 99% of molecule, whichever has a higher af nity is going to bind the ltrate is going to be reabsorbed into the and the other drug will be displaced. In this case, peritubular capillaries. probenecid has a higher af nity and is going to displace the penicillin. Probenecid is going to be secreted into the * The reabsorption process is highly dependent on renal tubules and the penicillin will be reabsorbed. As a the pH of the urine and the degree of ionization. result, probenecid is going to increase the duration of - weakly acidic drugs in acidic urine are in an action and ef cacy of the penicillin. unionized state, resulting in better absorption. Ex: In case of a barbiturate overdose, we can promote elimination by making the urine basic (adding sodium bicarbonate). * Remember: - weakly basic drugs in basic urine are in an unionized - Glomerular ltration and active tubular secretion state, resulting in better absorption. facilitate the excretion of the drug. Ex: In case of a morphine or amphetamine overdose, - Passive tubular reabsorption promotes the reabsorption we can promote elimination by making the urine of the drug (decreases the excretion of the drug). acidic (adding ascorbic acid or vitamin C). Once the drug gets conjugated (transform into a water soluble state) it’s going to be secreted into the bile then released into the intestine, the intestine is going to eliminate it in the form of feces. Enterohepatic circulation: A process where the conjugated drugs reach the intestine and get deconjugated (split) and reabsorbed because of the bacterial enzymes leading to the prolongation of the drugs duration of action. Ex: Ampicillin, Rifampicin, and contraceptive pills.  Plasma half Life (t1/2)  It’s a time taken by the plasma concentration of drug in the body to be reduced by 50% of its original value  Half life determines:  Duration of drug action  To decide appropriate dosing interval  To estimate time required to reach steady state in blood  Drug Clearance (CL)  It refers to the volume of blood In the form of urine or stool. cleared of the drug in unit time.  For drugs with first order kinetics, clearance is constant  Clearance values can provide useful information about the biological fate of a drug *This is important for making the dosing schedule.  Rate and Pattern of Drug Elimination Only a xed amount of drug is eliminated at a unit of time. Rate of drug elimination is Rate of drug elimination is proportional to drug plasma constant & independent of drug concentration plasma concentration E.g., If the concentration of the plasma increases the *The plasma half-life Ethanol The plasma half-life will never be rate of elimination is also going to increase. will remain constant and constant, It will always be a variable If the concentration of the plasma decreases the the patient will not have and the patient may experience rate of elimination is also going to decrease. any undesirable effects. undesirable effects.  Stable The drug in the steady state concentration will not be toxic Steady state Concentration and the drug response effects will be uniform. The steady state is achieved when the rate of inputs (drug administration) and outputs (drug elimination) are equal. Drug rate in = rate out are equal with a dosing interval at every t1/2 (for 51/2 gives 97% ) Pharmacological significance: - Constant amount of drug in the body - Patient will not experience neither acute toxicity nor decline of drug effect. - E.g., Digoxin, theophylline The steady state concentration is important for the category of drugs that have a low margin A xed amount of drug is administered at every half-life until the of safety and therapeutic index. 4th or 5th half-life, then the steady state concentration is reached. ADME - Summary Reference reader: Rang & Dale’s Textbook of Pharmacology  9th Edition- Chapter numbers 9,10 &11, page numbers 117- 151 Reference reader: Rang & Dale’s Textbook of Pharmacology  9th Edition- Chapter numbers 9,10 &11, page numbers 117- 151