Pharmacokinetics 2023 PDF

Pharmacology (Membrane and receptor module) Session 8 Lecture 8.1 Pharmacokinetics Assist. Prof.: dr. Zina hasan sahib phd. Pharmacology and therapeutics 1  Key learning outcomes Completion and revision of this lect...

Pharmacology (Membrane and receptor module) Session 8 Lecture 8.1 Pharmacokinetics Assist. Prof.: dr. Zina hasan sahib phd. Pharmacology and therapeutics 1  Key learning outcomes Completion and revision of this lectures should make you achieve the followings Understand the important concepts of pharmacokinetics in clinical settings have a knowledge about how to recognize the main routes of drug administration in the human body Understand the main factors influencing both drug absorption and distribution, can recognize and apply the equations related to bioavailability and volume of distribution Understand the main factors influencing drug metabolism and excretion, can recognize the equations used for drug half life and clearance Understand the difference between linear and nonlinear kinetics Understand how steady state therapeutic plasma concentrations (Cpss) are reached and how loading doses are used to get to Cpss more rapidly  Pharmacokinetics Pharmacokinetics briefly refers to the study of administration, distribution, metabolism and excretion (ADME) Clinical pharmacokinetics refers to application of the principles and concepts of pharmacokinetics to get safe and effective therapeutic management in an individual patient.  Pharmacokinetics Pharmaceutical process Drug formulation (solid or liquid) Site of administration 1) Local route 2) Systemic route (enteral and parenteral) Site of Administration 5 ROUTES OF DRUG ADMINISTRATION  Route of administration A bit more details! Enteral route: it is a simplest route in which drugs are administered by mouth (oral)  Advantages: self-administered convenient, painless and no infection  Drawbacks: oral drugs are exposed to harsh acidic and basic environments in stomach and duodenum respectively, first pass metabolism, require gastrointestinal absorption  Therefore drugs get slowly to the site of action  Route of administration Parenteral route: it is a route in which drugs are administered directly into the systemic circulation, cerebrospinal fluid and other vascularized tissues  Advantages: rapidly go to the site of pharmacological action, high bioavailability, no first pass metabolism and GIT effects  Drawbacks: increase risk of infection, require a health care professional to be administered and increase risk of toxicity 9 ADME  Absorption Absorption: different components are considered after oral drug administration, these include Absorption rate Bioavailability First pass metabolism  Determinants of drug absorption Solubility Concentration gradients Surface area and vascularity (large surface area and vascularity → better absorption)  Absorption Bioavailability (f) It is a fraction of drug that reaches the systemic circulation ranging from 0 to 100 %, f=1 Bioavailability = quantity of drug reaching systemic circulation/ quantity of drug administered It is affected by route of administration, the chemical form of drug and patient specific factors such as GI and hepatic transporters and enzymes Intravenous doses have 100 % bioavailability  Absorption First pass effect Bioavailability Mouth Oral drugs are affected by first First pass pass effect Some drugs get into the portal systemic Portal circulation circulation circulation and distribute into the liver This affects bioavailability as drugs will be exposed to rapid GIT metabolism Example lidocaine, propranolol, opiates glyceryl trinitrate  Distribution It is defined as a distribution of drug molecules from systemic circulation into organs and tissues Three factors affect distribution 1. Organ blood flow 2. Plasma protein binding 3. Molecular size  Plasma Proteins I. Many drugs bind to plasma proteins. II. It is the free level of drug that exerts an effect, not the total. Protein binding actions can also occur This is important if: A. The drug is highly bound to albumin (>90%) B. The drug has a small volume of distribution C. The drug has a low therapeutic index E.g. Warfarin, tolbutamide 16 Object Drug Precipitant Drug Warfarin Sulphonamides, aspirin, phenytoin Tolbutamide Sulphonamides, aspirin Phenytoin Valproate 18  Volume of distribution (Vd) It is a volume of fluid that is required to contain the total amount of absorbed drug molecules in the body where C is the concentration of drug in plasma at time zero Vd idea What would see if Vd is low or high?  Volume of distribution (Vd) When Vd is low, this means that high % of a drug is bound to plasma proteins When Vd is high, this means that high % of a drug is restricted to the tissues Vd is important in clinical setting to calculate the loading dose  Volume of distribution (Vd) Vd units are expressed as liter (L) or Liter/kg (L/kg) Assuming that average body weight 70 kg, then for example if the Vd = 10 L, then Vd unit in L/kg = 0.142 L/kg L/kg unit should be taken into account in case of some clinical settings like children and patients with certain diseases such as obesity and cancers In these groups, the Vd will be varied so it will affect dosing of drug that reaches to pharmacological levels Objective-5: Describe mechanisms of drug elimination. Drugs are eliminated from the body by: 1) Metabolism (e.g. by liver) 2) Excretion (e.g. by kidney) DRUG ELIMINATION HOW DRUGS ARE ELIMINATED FROM THE BODY: 1- METABOLISM About 90% of drugs metabolism is by the liver to make them ionized and readily excretable by the kidneys So in hepatic or renal dysfunction many drugs clearance will be halved so consider halving drug dose  Metabolism  Conversion of the drugs to more water-soluble compounds to be easily excreted  These compounds (metabolites) have little or no pharmacological effects  In contrast, other drug metabolites have pharmacological activity like Diazepam causing sedative and hypnotic effect with long duration of action  Prodrugs are compounds that are inactive until they expose to metabolic activation  Kinetics of Metabolism A. First order kinetics: metabolism of most medications is catalyzed by enzymes that obey Michaelis Menten kinetics V max [C] Rate of metabolism (V) Km + [C] Km= Michaelis constant (the substrate concentration at half maximal velocity [C]= concentration of drug - In most clinical situations, [C] is much less than Km, then V max [C] Rate of metabolism (V) Km First order Rate of metabolism (V) [C] kinetics  Kinetics of Metabolism B. Zero order kinetics: few medications like aspirin, phenytoin and ethanol in which concentrations greater than Km, then the equation will be V max [C] Rate of metabolism (V) Km + [C] Rate of metabolism (V) V max In this case, the enzyme is saturated Rate of metabolism is constant It does not depend on [C] Constant amount of drug is metabolized per unit of time (zero order kinetics) 29 Comparison 30  Metabolism Biotransformation can be categorized into two phases, Phase I and Phase II Phase I : modification of drug molecules by oxidation, reduction and hydrolysis 1. Microsomal metabolism (cytochrome p450 enzymes)  These enzymes localized in endoplasmic reticulum (ER) of liver , lung, GIT cells  They need for action to molecular oxygen and NADPH  Oxidations comprise hydroxylation and dealkylation  These family of enzymes differ in their AA sequences, substrate specificity and sensitivity to inducers and inhibitors Examples of enzyme inducers and inhibitors Enzyme inducers Substrates (drug affected) Carbamazepine Warfarin Phenobarbital Phenytoin Rifampicin Ibuprofen Cigarettes Celecoxib Enzyme inhibitors Substrates (drug affected) Cimetidine Warfarin Diazepam Spironolactone Digoxin  Metabolism 2. Nonmicrosomal metabolism: Hydrolysis  Addition of a water molecule with subsequent bond breakage  Examples: amidases and estrases  Genetic polymorphisms Monoamine oxidases  metabolism of endogenous amine neurotransmitters  Metabolism of exogenous compounds such as tyramine Alcohol metabolism  Metabolism Phase II: conjugation with endogenous compounds Types of conjugations 1. Glucuronidation Examples: chloramphenicol, morphine 2. Acetylation: Examples: isoniazid, sulphonamides 3. Glutathione conjugation Examples: acetaminophen  Elimination Elimination is a removal of the drug from the body via a variety of processes including  Biotransformation to inactive compound (previously mentioned)  Renal excretion and other routes like skin (sweat), lungs Clinical relevant Note: not all drug will be therapeutically inactive after elimination as some drugs such as proton pump inhibitors , aspirin are therapeutically active for a while after removal by elimination  Elimination  Half life (T1/2): it can be described by the time required to reduce the plasma concentration of a drug to 50% of the initial level. 0.693 × Vd T1/2 Clearance  T1/2 is affected by Vd and clearance (cl)  To simplify the calculations, we can round 0.693 to 0.7  Clearance (CL) It can be defined as a clearance of a medication from the systemic circulation measured by volume/time Why it is clinically important because 1. The CL value is constant over range of concentrations encountered in term of clinical setting 2. Metabolizing enzymes and transporters are unsaturated so the rate of elimination will follow first order kinetics The excretion of drugs by the kidney - Only the free unbound drug is filtered through glomerular tuft. - Drugs can be actively secreted by the tubule (e.g. penicillin). - Urine pH can determine how much of the drug is excreted: ionized drug (water soluble) is excreted in urine and not reabsorbed from renal tubules. - Unionized drug or (lipid soluble) is reabsorbed into circulation - So in case of over dose we can enforce drug excretion by manipulation of urine PH as drugs either weak acids or weak bases.  For weak acids, e.g. aspirin, making the urine alkaline will make the drug ionised, so there will be less tubular absorption because the charged drugs stay in the tubule lumen. weak bases (e.g. amphetamine), where acid urine increases excretion  Steady state It is reached when rate in = rate out It depends on T1/2 of the drug It is independent of number of administration (dosing frequency) and amount of dose, assuming that the drug follows first order elimination It takes about 4-5 half lives to reach  Loading dose (LD) To reach a steady state (Css), it takes about 4-5 half lives (see previous slide) In clinical settings where it needs a higher dose ie. Loading dose to get effective plasma concentrations Vd= volume of distribution F= bioavalibilty The end