Pharmacokinetics PDF

Pharmacokinetics N E H A L M. R A M A DA N. M. B. B. C H , M S C , P H D , MD Associate professor of clinical pharmacology Clinical pharmacology department, faculty of me dic ine , Mansoura univ e rsity, Eg y pt 9.24.XX  NEHAL M. R...

Pharmacokinetics N E H A L M. R A M A DA N. M. B. B. C H , M S C , P H D , MD Associate professor of clinical pharmacology Clinical pharmacology department, faculty of me dic ine , Mansoura univ e rsity, Eg y pt 9.24.XX  NEHAL M. RAMADAN. M.B.B.CH, MSC, PHD, MD E-mail: [email protected] [email protected] Tel: +2 01113397935 Learning objectives: By the end of this lecture, the student will be able to: Lecture outline:  Pharmacology The study of the actions , mechanisms , uses and adverse e f fe c t s o f d r u g s. A drug is any natural o r synthetic substance that al te r s the physi o l o gical state of a living organism. Drugs are used for the prevention, treatment and diagnosis of disease 5  Adverse T h e r e i s a l w ay s a risk of effects a d v e r s e e f fe c t s a s s o c i a t e d with the use of any drug Desired effects The physician should assess the balance of desired a n d a d v e r s e e f fe c t s w h e n deciding which drug to prescribe. 6  Pharmacology Pharmacology can be divided into two disciplines → P h ar m aco k i n e t i cs a n d P h a r m a co d y n a m i cs 7 A. T h e d r u g m u s t t r a v e rs e m e m b ra n e s t o r e a ch t h e sy st emi c c i r cul at i on ( Ab so rption ). D. T h e d r u g i s t h en d i st ri b ut ed i n s p e ci fic o r gan s a n d t i ssu es ( D istrib utio n). M. T h e d r u g o f t e n u n d e r g o e s e n z y ma t i c a l t e ra t i o n o f t h e c h e m i c a l s t r u c t u re o f t h e c o mp o u nd , l e a d i n g t o f o rma ti o n o f a m e t ab ol i t e ( o r m e t ab o li t es) ( Metabo lism). E. T h e d r u g a n d i t s m e t a bo l i tes a r e u l t imately r e mov ed f ro m t h e b o dy b y a v a r i e t y o f p r o c e s s e s ( E xc ret i o n ). 8 P h ar m ac o ki n et i c s i s the b ra n ch o f p h a rmaco l og y s t u d yi n g t h e m o v em e n t a n d d i s p o s i t i o n o f d rugs within an d b y t h e b o d y a n d i n cl u des: A. D r ug a b sorpt ion D. D i s t ri b u t i o n M. M et abo lism E. E x c r et i o n 9 Drug absorption 10  DRUG ABSORPTION Def: passage of drug molecules from the site of administration to the systemic circulation. The process of drug absorption applies to all routes of administration, except for the topical route (drugs are applied directly on the target tissue) and intravenous route (the drug is injected directly into the blood). Drug absorption requires the drug to cross one or more layers of plasma membranes. 11 Factors affecting absorption of drugs Factors related to the drug Factors related to the absorbing surface ▪ Molecular size: ▪ Route of administration Small molecules are absorbed >> large IM route is faster while oral route. molecules. ▪ Dose and concentration of the drug ▪ Integrity of the absorbing surface Absorption increases with increasing the dose (up to limit) ▪ Lipid solubility ▪ Vascularity at the site of absorption Ionization of the drug (pKa or ionization Ischemia ↓ absorption constant) 12  The pKa and drug ionization Most drugs are weak acids or bases that exist in both ionized and nonionized forms. Only nonionized form (nonpolar) of the drug is lipid soluble → cross biological membranes. Ionized form (polar) of the drug is non-lipid soluble (water soluble) → does not cross biological membranes. At any given pH, the ratio between the two forms determines the rate of drug absorption. 13  The pKa and drug ionization The pKa of a drug → the pH at which 50% of the drug is ionized and 50% is non-ionized 14  The pKa and drug ionization Clinical significance of pKa 1. Site of drug absorption from the GIT: e.g., Aspirin is a weak acid (pKa = 3.5), it becomes Nonionized and more absorbable in the stomach (pH = 1.5) Ionized and less absorbable in the intestine (PH = 8) 2. Drug excretion by the kidney: Aspirin toxicity (weak acid) can be treated by alkalinization of urine → aspirin becomes more ionized and less reabsorbable. Amphetamine toxicity (weak base) can be treated by acidification of urine → amphetamine becomes more ionized and less reabsorbable. 15  Bioavailability Def: the fraction of the administered dose of a drug that reaches the systemic circulation. An intravenously administered drug has 100% bioavailability. The oral bioavailability of a drug = 𝒕𝒐𝒕𝒂𝒍 𝒂𝒎𝒐𝒖𝒏𝒕 𝒐𝒇 𝒅𝒓𝒖𝒈 𝒓𝒆𝒂𝒄𝒉𝒊𝒏𝒈 𝒄𝒊𝒓𝒄𝒖𝒍𝒂𝒕𝒊𝒐𝒏 𝑨𝑼𝑪 𝒂𝒇𝒕𝒆𝒓 𝒐𝒓𝒂𝒍 𝒂𝒅𝒎𝒊𝒏𝒔𝒕𝒆𝒓𝒂𝒕𝒊𝒐𝒏 × 100 𝒕𝒐𝒕𝒂𝒍 𝒂𝒎𝒐𝒖𝒏𝒕 𝒐𝒇 𝒅𝒓𝒖𝒈 𝒓𝒆𝒂𝒄𝒉𝒊𝒏𝒈 𝒄𝒊𝒓𝒄𝒖𝒍𝒂𝒕𝒊𝒐𝒏 𝑨𝑼𝑪 𝒂𝒇𝒕𝒆𝒓 𝑰𝑽 𝒊𝒏𝒋𝒆𝒄𝒕𝒊𝒐𝒏 The bioavailability of drugs administered via any other route can be determined in the same manner What is meant by: oral bioavailability of drug X is 20%? 16 Drug distribution 17  Apparent volume of distribution (V d ) Drugs are distributed to organs and tissues via the circulation, diffusing from the blood to the interstitial fluid and into the cells. Apparent volume of distribution (Vd) Def: The apparent volume of water into which the drug has distributed in the body after distribution equilibrium. Vd (L) = The dose of the drug given intravenously Plasma drug concentration after distribution equilibrium Sites of drug distribution: Plasma (3 L) Extracellular fluid (15 L) The total volume of body fluid → 40 L. 18  Calculate 200 mg of drug X is given intravenously to a 70 kg man and plasma samples are attained at several times after injection. After distribution equilibrium, the drug plasma concentration was found to be 2 mg/L. Which of the following compartments does this drug appear to be primarily found in? a. In the blood b. Extracellular fluid c. Total body water The dose of the drug given intravenously Vd (L) = Plasma drug concentration after distribution equilibrium 𝟐𝟎𝟎 𝒎𝒈 Vd of drug X = 𝟐 𝒎𝒈/𝑳 = 100 L 19  Apparent volume of distribution (V d ) Clinical significance: 1. Determination of the site of distribution of the drug A Vd = 5L → the drug is retained within the vascular compartment → it is easily removed from the body by dialysis Vd > 40 L → the drug binds to tissue proteins → can not be removed by dialysis because of extensive tissue binding. 2. Determination of the Loading dose of drug: Loading dose (LD) = 𝑽𝒅 × 𝒕𝒂𝒓𝒈𝒆𝒕 𝒑𝒍𝒂𝒔𝒎𝒂 𝒄𝒐𝒏𝒄𝒆𝒏𝒕𝒓𝒂𝒕𝒊𝒐𝒏 (𝑪𝒑) 20  Q Which compartment does this drug appear to be primarily found in: The anticoagulant warfarin → its Vd of approximately 8 L Ethanol → its Vd of approximately 40 L For theophylline, the estimated Vd in an adult weighing 70 kg is 35 L. calculate the loading dose required to achieve a desired Cp of 15 mg/L? 21  Factors affecting drug distribution 1. Molecular size of the drug Extremely large molecules are retained in plasma e.g., the anticoagulant heparin. 2. Lipid Solubility Polar and ionized molecules can not penetrate blood-brain barrier 3. Plasma Protein Binding Most drugs bind reversibly to plasma proteins, primarily albumin. The extent of plasma protein binding differs greatly between drugs from 20 000 daltons → it will not be filtered through glomeruli. 2. Active Tubular Secretion Some drugs undergo active tubular secretion by transport proteins located in renal tubules. 3. Passive Tubular Reabsorption The amount of drug undergoes reabsorption from the renal tubules back into the circulation depends on the lipid solubility of the drug. Polar (ionized; water soluble; lipid insoluble) drugs or metabolites are NOT reabsorbed → rapidly excreted in urine 35  Renal clearance of drugs 3. Passive Tubular Reabsorption The degree of drug ionization and rate of renal excretion is depending on the drug pKa and the pH of the renal tubular fluid (urine). 36 Urine acidification and alkalinization in the treatment of drug overdose (ion trapping) Urine pH can be manipulated to increase excretion of the drug after a drug overdose. The excretion of a weak acid (phenobarbital & aspirin) can be accelerated by alkalinizing the urine (using NaHCO3) The excretion of a weak base (amphetamine) can be accelerated by acidifying the urine (using vit C or NH4Cl) 37 Pe n i ci l l i n G r e n al excr e t i o n P E NI C I L L I N G R E NAL ra t e = 1 2 0 0 m g / m i n C L E AR ANC E = 4 0 0 M L / M I N The Amount of Penicillin G The volume of plasma cleared excreted in urine per min = 1200 from Penicillin G per min = 400 mg mL 38  How to calculate renal clearance (Cl) of a drug Renal excretion rate (mg/min) Renal clearance of dug X (mL/min) = plasma drug concentration (mg/mL) Renal excretion rate of penicillin E.g., Renal clearance of Penicillin G = penicillin G plasma concentration = 1200 mg/min = 400 mL/min 3 mg/mL 39  Calculate What is the renal clearance (Cl) of Drug X if 600 mL of urine was collected in one hour and the concentration of Drug X in the urine was 1 mg/mL and the mid-point plasma concentration was 0.1 mg/mL ? Renal excretion rate (mg/min) Renal Cl of dug X (mL/min) = plasma drug concentration (mg/mL) Renal excretion rate (mg/min) = 𝑼𝒓𝒊𝒏𝒆 𝒇𝒍𝒐𝒘 𝒓𝒂𝒕𝒆 (𝒎𝑳/𝒎𝒊𝒏) × 𝒅𝒓𝒖𝒈 𝑿 𝒖𝒓𝒊𝒏𝒆 𝒄𝒐𝒏𝒄𝒆𝒏𝒕𝒓𝒂𝒕𝒊𝒐𝒏 𝟔𝟎𝟎 Renal excretion rate (mg/min) = × 𝟏 = 10 mg/min 𝟔𝟎 𝟏𝟎 Renal Cl of dug X (mL/min) = 𝟎.𝟏 = 100 ML/min 40 First order kinetics v s Zero order kinetics 41  First order kinetics Zero order kinetics ▪ A constant ratio (%) of drug is eliminated per unit ▪ A constant amount of drug is eliminated per unit time time ▪ The rate of drug elimination (amount of drug ▪ The rate of drug elimination is constant and eliminated per unit time) is proportional to the independent of plasma drug concentration. plasma drug concentration ▪ Half-life (t1/2) is constant (i.e., independent of ▪ Half-life (t1/2) is not costant (i.e., proportional to dose). dose ▪ Drug cumulation is not common → safe ▪ Small increase in dose → produce larger increase in plasma drug concentration → drug cumulation ▪ Non-saturable elimination mechanisms → renal ▪ Saturable elimination mechanisms: transporters or elimination. liver enzymes. 42  Elimination half life (t 1/2 ) The time taken for a drug concentration in plasma to drop by half (50%). Clinical significance of t1/2: 1. Determination of inter-dosage interval → drugs are given every t1/2 2. Determination of the time needed to reach steady state plasma concentration (Cpss) → 5 t1/2. 3. Determination of the time needed for complete drug elimination → 5 t1/2. 43 Elimination half life (t 1/2 ) 44  Steady state plasma concentration (Cpss) Def: the steady level of drug in plasma achieved when rate of drug administration = rate of drug elimination The Cpss is reached after 5 t1/2 45  References https://www.clinicalkey.com/student/content/book/3-s2.0- B978032375898700002X?origin=share&title=Brenner%20and%20Stevens%E2%80%99%20Pharmacology&meta=2023%2C%20Stevens%2C%20Cra ig%20W.%2C%20PhD&img=https%3A%2F%2Fcdn.clinicalkey.com%2Fck-thumbnails%2FC2019001014X%2Fcov200h.gif https://www.clinicalkey.com/student/content/book/3-s2.0- B978032347652200003X?origin=share&title=Brody's%20Human%20Pharmacology&meta=2019%2C%20Hollenberg%2C%20Paul%20F.&img=https %3A%2F%2Fcdn.clinicalkey.com%2Fck-thumbnails%2FC20150057550%2Fcov200h.gif https://www.clinicalkey.com/student/content/book/3-s2.0-B9780702073441000016#hl0000800 https://www.clinicalkey.com/student/content/book/3-s2.0- B9780323068123000018?origin=share&title=Rapid%20Review%20Pharmacology&meta=2010%2C%20Pazdernik%2C%20Thomas%20L.%2C%20Ph D&img=https%3A%2F%2Fcdn.clinicalkey.com%2Fck-thumbnails%2FC20090497538%2Fcov200h.gif https://www.clinicalkey.com/student/content/book/3-s2.0- B978032307445200001X?origin=share&title=Elsevier's%20Integrated%20Review%20Pharmacology&meta=2012%2C%20Kester%2C%20Mark%2C %20PhD&img=https%3A%2F%2Fcdn.clinicalkey.com%2Fck-thumbnails%2FC20090318899%2Fcov200h.gif 46 Thank you