Pharmacokinetics (4 Lecture) PDF

PHARMACOKINETICS(4 lecture) 3rd year lecture Department of pharmacology Dr. Noor A. Abdullah 2024 1  learning objectives -Short note about pharmacokinetics -Enlist different processes involved in the passage of the drug through membra...

PHARMACOKINETICS(4 lecture) 3rd year lecture Department of pharmacology Dr. Noor A. Abdullah 2024 1  learning objectives -Short note about pharmacokinetics -Enlist different processes involved in the passage of the drug through membranes. Define the individual pharmacokinetic processes: Absorption -Distribution -Metabolism -Excretion -Explain the factors that affect the absorption and distribution of the drugs 2 Pharmacokinetics It is the movement of a drug over time through the body. (what the body does to the drug after being taken)- in other words the behavior of drugs inside the body: -Absorption -Distribution ADME -Metabolism -Excretion Therefore, its concerned with the time course (the rate) at which drug molecules cross cell membranes to enter the body. 3  ADME 4 I. Absorption: is the transfer of a drug from its site of administration to the bloodstream. 5 Mechanism of entrance drug inside the body Drug passage across cell membrane Cell membranes are essentially bilayers of lipid molecules with islands of proteins in between. its strongly Hydrophobic therefore, lipid-soluble substances can diffuse easily. Water soluble substances of small molecular size may filter through water- filled channels between some epithelial and endothelial cells e.g. jejunum and proximal renal tubules. 6 Mechanisms of passage of drugs across cell membrane 1. Passive diffusion (the most important) - move passively from an area of high concentration to one of low conc. -The rate is concentration dependent. Cellular energy is not required 7 Factors affect passive diffusion 1-the concentration gradient 2-molecular size 3-lipid solubility 4- degree of ionization of the drug. Lipid or water solubility is influenced by: -structural properties of the drug molecules -environmental pH. 8  Absorption & Ionization Non-ionised drug More lipid soluble drug Diffuse across cell membranes more easily 9 Drugs are classified according to their ionization in response to environmental pH A. Those that their ionization is dependent on the environmental pH (unionized=lipid soluble, ionized=water soluble) B. Those that are unionized whatever the environmental pH (unionize d lipid-soluble, non-polar compounds) C. Those that are ionized whatever the environmental pH (ionized, water soluble, polar compounds) 10 A. Drugs ionized according to environmental pH The extent to which a molecule has a tendency to ionize is given by the dissociation (ionization) constant, usually expressed as the pKa (i.e. negative logarithm of the Ka) - Acidic drugs in an acidic environment become: unionized, lipid soluble, easily diffusible. - Acidic drugs in an alkaline environment become: ionized, water soluble, non-diffusible. 11 PKa is the pH at which 50% of the drug is ionized i.e. when aspirin pKa is 3.5, this means that at pH 3.5, 50% of aspirin is ionized Gut pH varies: stomach 1.5, upper intestine 6.8, lower intestine 7.6, and pH inside the body 7.4. Therefore, aspirin in stomach (acid in acid medium): un-ionized, lipid soluble, diffuse easily into gastric epithelial cells. Inside epithelial cells, pH is 7.4, aspirin becomes ionized, less diffusible, and localize there (ion trapping)(this is one mechanism for aspirin-induced gastric injury) 12 B. Drugs that are unionized whatever the environmental pH Example: steroids (e.g. Prednisolone), chloramphenicol - Unaffected by environmental pH - Lipid soluble (non-polar compounds) - Diffuse readily across tissues (good oral absorption) 13  c-Drugs that are permanently ionized drugs whatever the environmental pH Water-soluble (polar) - Limited capacity to cross membranes, poor GIT absorption, usually given parenterally -Does not cross the placenta; useful in pregnancy (heparin ) They are either: negatively charged (acidic, e.g. heparin), or Positively charged (basic, e.g. ipratropium, tubocurarine, suxamethonium) 14 -One of the following characteristics of unionized drugs whatever the environmental pH is true: a. It’s water soluble b. It has good oral absorption c. Heparin is an example d. It’s usually given parenterally e. It can not cross the placenta 15 2. Carrier- mediated transport Active transport: drugs are capable to move against concentration gradient - require cellular energy. - rapid diffusion. - high degree of specificity. -subjected to saturation and can be inhibited by other compounds, and are important for some drugs with structural similarity for endogenous molecules. Examples: Levodopa across blood brain barrier (BBB) secretion of many weak organic acids and bases through renal tubules and biliary ducts e.g. penicillin, probenecid and uric acid are actively transported in renal tubules 16 3-Facilitated diffusion Occurs by the carrier proteins. Net flux of drug molecules is from the high concentration to low concentration. No energy is required, saturable Can inhibited by molecules competed for these carriers. 17 4-Endocytosis :The drug molecule holds on the cell membrane and then surrounded with plasma membrane and inserted into the cell within small vesicles Large polar molecules such as peptides. - Small polar substances such as vitamin B12 and iron combine with special proteins (intrinsic factor or transferrin) and the complexes enter the cell by this mechanism. 18 5-Filtration plays a minor role in drug transfer except for glomerular filtration. It occurs through water (aqueous) channels allowing passage of water soluble substances 19 Q-Active transport is characterized by one of the following: a. It does not require energy b. Its slower than passive diffusion c. The transport occur mainly through water pores d. It can move against concentration gradient e. Its occurs in renal tubules only 20 The order of the pharmacokinetic processes :Rate of processes Rate of (PK) Rate of(PK) constant directly in respective proportion to to drug conc. drug conc. 21 The order of the pharmacokinetic processes : First order processes A constant fraction (proportion, percentage) of the drug is processed per unit time e.g. 50% of the dose is metabolized per hour 22 In first order kinetics: The rate of the pharmacokinetic process of a drug is directly proportional to the amount of the drug administered or to its concentration in the blood (high at high concentration, low at low concentration). The plasma half-life (t1/2) (which is the time for any plasma concentration to fall by 50%) is always the same (constant) When different therapeutic doses are given. The majority of drugs follow first-order kinetics, but in overdose, their kinetic processes may get saturated. 23 Zero-order processes A constant amount of the drug is processed per unit time e.g. 10 mg of the dose is metabolized per hour. In zero-order (saturation) kinetics, the process may become easily saturated e.g. limited amount of metabolizing enzymes A small increase in the dose can result in a steep and disproportionate increase in plasma concentration. Examples of drugs following zero-order kinetics in metabolism: Phenytoin, theophylline, ethanol and also aspirin in high therapeutic doses, Zero-order absorption applies to iron, also to depot formulation and to drug implants e.g. antipsychotics and sex hormones. 24 Zero-order processes 25  First order kinetics Zero order kinetics Other names Linear kinetics Non-linear, saturation Definition Fixed fraction (proportion), Fixed amount, a change of a change of 10% per hour 10 mg per hour 1000 →900 →810 → 730.. 1000 →990 →980→970,.. Half life Constant; does not change Varies; increase with with changing dose increasing the dose Drug example Paracetamol, ampicillin,…. Phenytoin, theophylline, ethanol Predictability Plasma concentration of Plasma concentration the drug can be predicted cannot be predicted and TDM is necessary Practical example 300mg dose produces The same increase from 12mg/l concentration in 300mg to 400mg may plasma, an increase of increase plasma dose to 400mg results in concentration from 12mg/l 16mg/l (proportional) to more than 30mg/l 26 Plasma half-life and steady state concentration Plasma elimination half life Is the time taken for any plasma concentration to fall by half of its original value. It is constant if elimination follows first order kinetics Half-life can be used: 1-to determine the dosing frequency if drug effect is directly related to plasma concentration. 2- calculate the time taken to reach a steady state. 3- calculate the time for the decline in plasma concentration after dosing ceases. 4- calculate the clearance and volume of distribution. 27 The steady state concentration When a drug is given at a constant rate, the time to reach a steady state depends on the drug half-life and is practically reached after five half-lives. In a steady state: The rate of administration is equal to the rate of elimination and the plasma concentration will be at a plateau Any increase or decrease in drug dosing, the new steady state is reached after five half-lives. 28 example; the time required to reach a steady state concentration for dobutamine (t1/2 is 2 minutes) is 10 minutes, and for digoxin (half life is 36 hours) is 7.5 days (here, a loading dose is required to reach SS state quickly). Half-life varies in the population over a range of values but a single average half life is given for clarity, examples: Adenosine < 2 seconds Paracetamol 2hours Dobutamine 2 minutes Diazepam 41 hour Benzylpenicillin 31 minutes Piroxicam 45 hours Plasma concentration can be measured for therapeutic purposes (Therapeutic Drug Monitoring, TDM) if the drug effect is related to drug concentration at receptors in the tissues (drugs that can be easily under- or overdose) 29 A drug with a half-life of 10 hours is administered by continuous intravenous infusion. Which of the following best approximates the time for the drug to reach steady state? A. 10 hours. B. 20 hours. C. 33 hours. D. 70 hours. E. 50 hours 30 Individual Pharmacokinetic processes 1-Absorption Absorption from GIT *Small intestine is the main site of absorption of drugs. *Stomach does not play a major role in absorbing drugs (small surface area, rapid gastric emptying), even with acidic drugs; the onset of absorption occurs in stomach, but the main part of the dose is absorbed in the small intestine. *The colon is also capable of absorbing drugs particularly slow- release formulations (SR) 31 Buccal absorption is rapid for lipid-soluble drugs; blood flow is abundant, entry into systemic circulation avoiding first pass Metabolism. 32 Enterohepatic circulation Bile salts are conserved about 8 times a day. A number of drugs form conjugates with glucuronic acid and are excreted in bile. Glucuronides are polar (ionized) and are not absorbed, but the parent drugs are released by being hydrolyzed by intestinal enzymes and bacteria. Recycling helps to sustain plasma concentration and increase duration of action. Examples: sulindac, ethinylestradiol 33 34 Bioavailability (Systemic availability) Systemic availability is the percentage of the administered dose that reaches the systemic circulation intact. In simple terms, bioavailability Is how much of the drug dose is available to produce a biological effect. Bioavailability is useful to: 1. Determine the dose and route of administration e.g. propranolol i.v. 1-10mg, oral 10-320mg (because of FPM); a drug with oral bioavailability of 5% should not be given orally. 2. Compare between different formulations of a drug e.g. sublingual GTN >90%, oral GTN 50%) first pass metabolism (FPM) Hepatic: Beta blockers (e.g. propranolol, metoprolol) Opioids (e.g. morphine, pethidine) Antiarrhythmics (e.g. lignocaine, verapamil) Others (e.g. glyceryl tri-nitrate GTN, imipramine) Gut wall: Estrogens, levodopa, isoprenaline 40 The importance of extensive FPM 1. It is a major source of variations between individuals in response to drugs. A small change in first pass metabolism will have a relatively large effect on systemic availability if the drug is extensively metabolized. 2. If the FPM is over 95% e.g. lignocaine, then the oral route is not suitable. 3. In severe hepatic disease e.g. cirrhosis with both impaired liver cell function and shunting of blood into systemic circulation; FPM is reduced and systemic availability is increased (i.e. exaggerated response to normal doses). 41 The effect of food on drug kinetics 1. Changes in gastric emptying (slower absorption of most drugs) 2. Drug chelation (tetracycline and dietary calcium; iron and tannic acid in tea and coffee). 3. Changes in drug metabolizing enzymes (induction by alcohol, charcoal grilled beef, brussel sprout). 4. Changes in splanchnic blood flow (increased after food), FPM is reduced. 42 Food can decrease bioavailability of certain drugs: Examples Ampicillin (markedly reduced) Erythromycins (except erythromycin estolate) Rifampicin and INH (anti-Tb) Atenolol and captopril 43 Food can increase bioavailability of certain drugs: Examples - propranolol, metoprolol, hydralazine - griseofulvin, nitrofurantoin, mebendazole (particularly by fatty food) - Erythromycin estolate 44 II.Distribution Drug distribution is the process by which a drug leaves the bloodstream and enters the interstitium (extracellular fluid) and/or the cells of the tissues. The extent of distribution depends on: -water/lipid solubility -protein and tissue binding - ability to cross cell membrane passively or actively 45 The volume of distribution (Vd) It is a theoretical (apparent) volume of fluid in which the drug dose appears to distribute with a concentration equal to that in plasma. Dose Vd = ------------- Co Co is the initial plasma concentration, 46 47 48 Vd is small: if the drug remains mostly in plasma e.g. warfarin which is highly protein bound (also tolbutamide, salicylates) Vd is large: if the drug is present mainly in the tissues e.g. digoxin, pethidine, nortriptyline, and chloroquine. 50 51 A 40-year-old male patient was recently diagnosed with an infection involving methicillin-resistant S. aureus. He received 2000 mg of vancomycin as an IV loading dose. The peak plasma concentration of vancomycin was reported to be 28.5 mg/L. The apparent volume of distribution is approximately : Answer???? 52 The significance of the Vd In drug overdose; removal of a drug by hemodialysis is appropriate for drugs with small Vd i.e. a major proportion of the dose is present in plasma. Drug interaction is likely to occur between those with small Vd e.g. displacement from protein binding. Examples Drugs Vd (in L/70kg) Aspirin 5 Atenolol 75 Diazepam 140 Chloroquine 1300 53 The significance of protein binding 1. It is a source of drug interaction. Displacement may be important for drugs which are highly protein bound and at the same time having small Vd e.g. warfarin and NSAIDs; the free fraction of warfarin is increased leading to bleeding. 54 2. In renal and liver failure The free fraction of drugs may increase and therefore, increase in response or toxicity because of hypo-albuminemia and accumulation of endogenous substances that may cause displacement from protein binding sites. 55  Examples of protein binding of drugs Drugs ~ % protein bound Isoniazid, lithium, 0% ethosuximide Atenolol 5% Ampicillin 15% Digoxin 25% Phenobarbitone 50% Propranolol 95% Diazepam 98% Tolbutamide 98% Warfarin 99% Ibuprofen >99% 56 III. Metabolism Only few drugs excreted unchanged Metabolism changes drugs in two major ways: 1. by reducing lipid solubility (increased elimination) 2. by altering biological activity which occurs in 3 possible ways: 57  2. altering biological activity of drug: a. Conversion of pharmacological active to an inactive substances (most drugs) b. Conversion of active to another active substance. This prolongs the duration of action diazepam oxazepam Codeine morphine Amitriptyline nortriptyline 58 3-Conversion of inactive ( a pro-drug) to active levodopa dopamine cyclophosphamide 4-ketocyclophosphamide Sulfasalazine 5-aminosalicylic acid 59 Sites of metabolism Organs: liver (most important) Kidney (vitamin D, insulin) Gut mucosa (isoprenaline, levodopa, estrogen and progesterone Gut flora (sulfasalazine, hepatic conjugates) Lung (serotonin, noradrenaline, prostaglandins,testosterone, isoprenaline) Skin (vitamin D activation, minoxidil, and capsaicin) Intracellular sites microsomal (mostly), mitochondria, cytoplasm, plasma 60 Drug metabolism can occur in two phases: 1: The most important reaction is oxidation by mixed-function Oxidases in the microsomes (the final component of these oxidases is cytochrome P450; mixed means for aliphatic and aromatic Phase 1 metabolism may occur in: a) the endoplasmic reticulum (microsomal) b) cytoplasm: xanthine oxidase, ethanol metabolism c) mitochondria: monoamine oxidase d) plasma: pseudocholinesterase, histaminase N.B. Not all drugs broken down by enzymes e.g. melphalan which undergoes spontaneous hydroxylation to inactive metabolites. 61 Phase II metabolism Drugs +water soluble molecule=water soluble conjugate eliminated by kidney or bile e.g. glucuronides, sulfate and others. Phase II metabolism almost invariably terminates biological activity Examples Glucuronide conjugation: salicylates, paracetamol, morphine Sulfate conjugation: paracetamol, estrogen, steroids. Acetylation e.g. INH, hydralazine (N-acetyltransferase) Glutathione conjugation e.g. halothane, paracetamol overdose. Most drugs undergo both phase I and II reaction; few have no major conjugates e.g. warfarin 62 Enzyme induction Enzyme induction refers to the increase in enzyme amount and activity as a result of exposure to certain chemicals It is accompanied by hypertrophy of liver cell endoplasmic reticulum which contains most drug metabolizing enzymes. Non- microsomal enzymes are not inducible Examples of enzyme inducers: barbiturates, rifampicin, phenytoin, carbamazepine, griseofulvin, smoking, chronic (not acute) alcohol ingestion 63 The importance of enzyme induction 1. It can be responsible for clinically important interactions Examples a. contraceptive failure if potent inducers are taken at the same time b. increased breakdown of vitamin D resulting in osteomalacia and hypocalcemia; and also in megaloblastic anemia due to folate deficiency. c. failure of anticoagulant therapy due to reduction of warfarin level. Enzyme induction =decrease of drugs concentration =failure of drug action 64 2.Tolerance to certain drugs may occur e.g. with antiepileptic drugs which can induce their own metabolism. 3. Drug toxicity may be more likely e.g. in paracetamol overdose and in patients on rifampicin or INH (hepatotoxicity). 4. Enzyme inducers can alter liver function tests The level of serum bilirubin helps to distinguish the effect of enzyme induction from that of liver disease. 5. Enzyme induction can be used as a therapeutic mean e.g. phenobarbitone can reduce severe hyperbilirubinemia in neonates by stimulation of fetal hepatic glucuronyl transferase. 65 Enzyme inhibition Enzyme inhibition is an important mechanism for drug- drug interaction and can lead to drug accumulation and toxicity particularly with drugs Of low therapeutic index. A. General non-specific inhibition of microsomal enzymes e.g. cimetidine (inhibits metabolism of warfarin, diazepam, propranolol) Other examples: sodium valproate, chloramphenicol, INH, single large dose of ethanol Enzyme inhibition =drugs accumulation =increased side effects + toxicity of drugs 66 30-year old epileptic female patient has been well controlled on carbamazepine tablets; 200mg twice daily. She developed dizziness, diplopia and ataxia following prescription of erythromycin for tonsillitis. Explain. Erythromycin Enzyme Inhibitors so inhibit metabolism of carbamazepine lead to increased side effect of this anti-epileptic drug which is : dizziness, diplopia and ataxia 67 B. Inhibition of specific enzymes could be a mechanism for therapeutic action of drugs e.g. captopril inhibits ACE aspirin inhibits cyclooxygenase selegiline inhibits MAO(B) allopurinol inhibits xanthine oxidase 68 4-Elimination Drugs can be eliminated by the following mechanisms: 1. Metabolism 2. Storage e.g. highly lipid soluble drugs in fat, heavy metals in bone, phenothiazines and chloroquine in melanin-containing tissues 3. Excretion Renal excretion: is the most important route of excretion if the drug is water-soluble and of low molecular weight 69 Three mechanisms for excretion a. Glomerular filtration - remove small molecules less than the size of albumin, therefore drugs binding to plasma proteins slows the filtration rate of drugs. b. Active tubular secretion - requires energy - shows competition and saturation - occurs in the proximal tubules There are two active transport systems For weak acids e.g. penicillin, probenecid, phenobarbitone, aspirin For weak bases e.g. amphetamine, imipramine, chloroquine 70 c. Tubular reabsorption - may be active or passive - the passive is controlled by the pH of the tubular fluid and pKa of the drug. - acids are best eliminated in alkaline urine and bases best in acidurine. Drug clearance: is the volume of the body compartments from which the drug is removed in unit time. Total body clearance of the drug is the sum of the clearances by all routes of elimination (usually hepatic and renal). 71 Elimination in milk Only free (unbound) drug can be excreted in milk according to pH, pKa, and lipid-solubility Milk pH is toward acidic side and, therefore, basic drugs ionize and may accumulate in milk. Examples of drugs contraindicated during breast feeding: chloramphenicol, anticancer drugs, and repeated doses of ergot alkaloids 72 Pulmonary elimination Important for volatile anesthetics and for alcohol (from medico legal aspect)from blood. Fecal elimination Either the drug is not absorbed Passive diffusion Biliary elimination 73 A patient with severe renal impairment, his doctor prescribed for him gentamicin 40 mg three times daily for treatment of urinary tract infection. The nurse, by mistake, gave him an ampoule of 80 mg three times daily. He developed deafness. What is the possible explanation? PK:-polar ,given parenterally IV,IM More than 90% of the parenteral gentamicin are excreted unchanged in the urine accumulation occurs in patients with renal dysfunction, and dose adjustments is required. 74 Which of the following phase II metabolic reactions makes phase I metabolites readily excretable in urine? A. Oxidation. B. Reduction. C. Glucuronidation. D. Hydrolysis. E. Alcohol dehydrogenation 75 76