أسئلة الـ Pharmacokinetics (Very Hard)

Pharmacokinetics

• It is the journey of a drug inside the body and its effect.
• Includes absorption, distribution, metabolism, and excretion.
• It discusses how the body affects the drug

Absorption

• It is the passage of a drug from the site of administration to the plasma
• Routes of administration include oral, rectal, sublingual, local, inhalation, and injections.

Mechanisms of drug absorption

Simple Diffusion

• Drugs move according to the concentration gradient from high to low concentration.
• It is a Passive process, as it requires no energy.
• The drug must be lipophilic to pass through the lipid membrane.

Carrier-Mediated Transport

• Achieved by specialized carrier molecules.
• Can be passive, moving according to the concentration gradient.
• Can be active, moving against the concentration gradient using energy.

Pinocytosis

• Part of the cell membrane invaginates and traps the drug molecule.
• The trapped drug molecule inside a vesicle is then released inside the cell.
• Large molecules such as hormones use this mechanism.

Factors Affecting Drug Absorption

Factor related to drugs

• Molecular size: Smaller drug molecules are absorbed better than larger ones.
• Dose: Absorption increases with increasing dose, up to a limit.
• Drug formulations: Absorption rates vary as sustained-release tablets < suspensions < powders
• Drug Combination: Certain drugs affect the absorption of others. Example: Vitamin C increases iron absorption.
• Lipid Solubility: Lipid solubility is most important factor as described by (drug ionization = pKa)
• Local effects of the drug: Some drugs affect their own absorption. Example: drugs producing vasoconstriction decrease their own absorption.

Factor related to absorbing surface

• Route of administration: IV route is the fastest, and rectal route is the slowest.
• Integrity of the absorbing surface: The absorbing surface or decrease in absorption
• Local blood flow: Ischemia decreases absorption.
• Specific factors that affect drug absorption include:
  • Apoferritin enhances iron absorption
  • The intrinsic factor is needed for Vitamin B12 absorption
  • HCl is needed for aspirin absorption.
• First-pass metabolism: Metabolism at the absorption site decreases the concentration of the drug.

Relationship Between Lipid Solubility and Drug Ionization

• Theory of pKa = Lipid solubility = Drug ionization = Dissolution constant
• Definition: pKa is the pH at which 50% of the drug is ionized (non-absorbed), and 50% is non-ionized (absorbed).
• Principles:
  • Ionized drugs, which are water-soluble, polar, and charged, are poorly absorbed.
  • Unionized drugs, which are fat-soluble, non-polar, and non-charged, are more lipid-soluble and rapidly absorbed.
  • For acidic drugs like aspirin
    • They are more ionized in basic media and less ionized in acidic media.
    • More absorbed in the stomach, less in the intestine.
  • For basic drugs such as amphetamine and local anesthetics
    • They are more ionized in acidic media and less ionized in basic media.
    • More absorbed in the intestine, less in the stomach.
• Key principle: Drugs move better in a similar environment and worse in an opposite environment.
• When the pH of the media equals the pKa of the drug, the ratio of ionization or unionization is 1:1.
• With every unit change in pH of the media ionized to unionized ratio changes 10 folds
  • Acidic drug in pH medium with unionized ionized ratio
    • ↑pH 2 unit shows a 1:100 ratio and is 100 % ionized.
    • ↑pH 1 unit shows a 1:10 ratio with 10/90 ionized
    • pH = pKa shows a1:1 ratio, with 50%/50% ionized
    • ↓ pH 1 unit shows a 10:1 ratio with 90/10 ionized
    • ↓ pH 2 unit shows a 100:1 ratio and is 100 % union
• Basic drugs in pH medium with unionized ionized ratio
  • ↑pH 2 unit shows a 100:1 unit and is 100 % union
  • ↑pH 1 unit shows a 10:1 ration with 90/10 ionized
  • pH = pKa shows a1:1 ratio, with 50%/50% ionized
  • ↓ pH 1 unit shows a 1:10 ratio with 10/90 ionized
  • ↓ pH 2 unit shows a 1:100 with 100% ionized

Clinical Significance of pKa

Understanding Absorption and Excretion of Weak Acids, e.g., Aspirin

• Aspirin is an acidic drug with a pKa of 3.5
• pH values in different body locations:
  • Stomach: 1.5
  • Upper Intestine: 6.5
  • Lower Intestine: 7.5
  • Blood and Body Organs (stomach cells & renal tubular cells): 7.4
  • Urine: 4.6 to 8.2
  • Tubular Cells: 7.4

Actions of apsirin

• Aspirin in the stomach
  • Acid conditions, making it more unionized than ionized
  • Resulting in better absorption in the stomach
• Aspirin in the intestine
  • Basic conditions, making it more ionized than unionized
  • Resulting in less absorption in the intestine.
• Aspirin inside the stomach wall (body pH) exhibits ion trapping
  • pH inside the cells is 7.4, aspirin becomes more ionized and less able to diffuse out.
  • This can lead to cell damage and gastric ulcers.
• Aspirin in the blood
  • Aspirin is metabolized into salicylic acid with a pKa of 3.
  • At a blood pH of 7.4, it is more ionized and remains in the blood.
• Aspirin in the urinary tract at acidic pH
• It becomes less ionized and may be reabsorbed.
• Aspirin inside tubular cells exhibits 2nd ion trapping → and can damage to renal tubules.

Understanding Absorption & Excretion of Weak Base

• Example: Amphetamine (pKa = 9.9)
• Opposite effects compared to acidic drugs like aspirin.

Treating Drug Toxicity Based on pKA

• Toxicity with Acidic Drugs (Aspirin):
  • Treat by alkalinization of urine:
    • Using sodium bicarbonate to increase drug ionization in the urine
    • Prevents reabsorption and promote excretion.
• Toxicity with Basic Drugs (Ephedrine):
  • Treat with acidification of urine:
    • Using ammonia to increase drug ionization in the urine
    • Prevents reabsorption and promotes excretion.

Drug Trapping Sites (Ion Trap)

Acidic Drugs:

• Trapped in stomach wall after absorption, which may cause ulcers when taken after eating.
• Trapped in the nephron wall after reabsorption from urine, leading to kidney injury. Alkalinization of urine helps excretion. Alkaline Drugs:
• Trapped in milk and tumors due to higher unionization in plasma at pH 7.4
• Can cross into milk & tumor due to pH between 6.5 and 7, become ionized, and get trapped.
• Taking the drug after lactation and alkalizing blood increases trapping, which is harmful to the baby but good for killing tumor cells.

Increasing or Decreasing Drug Action

• Local anesthetics are weak bases.
• Adding bicarbonate to the anesthetic maintains it in a non-ionized state, which increases penetration.
• Tissue infection and inflammation can make tissues acidic, increasing ionization of local anesthetics, and decreasing penetration.

Bioavailability of Drugs

• Fraction of unchanged drug reaching systemic circulation after administration by any route compared to the administered dose
• Intravenous bioavailability is 100% since the entire dose reaches the bloodstream
• Bioavailability measured by:

  • AUC: Area under the curve

AUC oral AUC IV

• Oral bioavailability =
• Importance: Determine effectiveness and duration of a drug at different routes especially for drugs like:
  • Digoxin
  • Phenytoin
  • Warfarin
  • Prednisolone
  • Chloramphenicol
• Factors that affect bioavailability:
  • Absorption
  • First-pass for oral routes

Distribution

• Transport of drug from site of administration to all body tissues through circulation.

Sites Of drug distribution

• Plasma (3 liters)
• Extracellular water (9 liters)
• Intracellular water (29 liters).
• Key Point: a Volume of distribution (Vd) of more than 41 liters means the drug moves to tissues.

Volume of Distribution (Vd)

• Apparent volume of water into drug is distributed after distribution equilibrium = time Distribution all over the body.
• Total amount of the drug within the body divided by the drug concentration in the plasma
• Equation: (L)Total amount of drug in body/ Plasma conc. of drug after distribution equilibrium
• Calculated as: Total Vd for 1 KG is Vd x 70kg if Large Vd = more tissue distribution
  • If Vd for Digoxin is 6 L/kg (total = 420 L).
  • Each 1 kg of tissue takes concentration drugs in 6 L of plasma.
  • Then Each 1 kg of tissue takes 6-fold the conc of digoxin 1 L of the plasma.
  • Then each 1L plasma takes a 1/6 of digoxin conc in 1 kg of tissue.
• To distribute digoxin equally between all body tissues (70 kg) and plasma, there is a desire for imaginary volume of plasma = 6 * 70 = 420 L

Volume of distribution dependdant of the type

• small Vd occurs when:
  • Lipid solubility is low
  • Large drug size
  • There is a high degree of plasma protein binding.
  • There's a low level of tissue binding.
• Large Vd occurs when:
  • Lipid solubility is high
  • Small drug size
  • There is a low degree of plasma protein binding.
  • There is a high level of tissue binding

Significance of site distribution

• Use determination of site of drug distribution to check if Drug is confined to Blood or can
  be removed by dialysis.

• if a Total Vd < 5L then drug Confined to blood and be removed by dialysis

• if Total Vd < 15 L then the drug restricted to ECF.

• if Total Vd15-41 L the drug distributed Throughout all body water.

• if Total Vd > 41L then drugs bind extensively To the tissue proteins and Cannot be removed by the dialysis

Calculation

• Calculation of total amount of the drug in the body by a single measurement of the - - - - plasma concentration.
• Calculation of drug Clearance = Vd x Kel. Calculation of the loading dose as (total): drug amount= Vd X plasma Concentration

Binding of Drugs to Plasma Proteins

• Most drugs bind to plasma proteins; the bound form is inactive, and the free unbound part is active.
• The bound form is gradually released, the plasma concentration of the drug decreases
• Albumin:
  • Most important plasma protein
• Binds mainly to acidic drugs and some basic drugs.
• Other plasma proteins
  • Globulin and Glycoproteins bind mainly basic drugs.

Advantages of Plasma Binding

• Slows the rate of drug action but not for stopping, the action is better for prophylaxis due to ↑duration after single in the blood.

Disadvantages of plasma binding:

• Is not effective, as a bound form.
• Drug interaction, if given to other drugs to plasma.
• Increases when drugs have High plasma protein bound.
• Change in the binding occurs
• Plasma protein binding gets altered and is so free that the leading causes a serious issue.

Binding of Drugs to Fats

• Clinical Significance

  • Cross the BBB And exerted CNS effects and
  • Stored in the body fats

• In the same way vitamin A stored in fat cells of river For six months until the Rapid elimination of drug to fat by redistribution

• Strong lipophilic drug (thiopental) when injected intravenously goes into two phases

  • The First Phase

• The drug goes into the organs that are the organs and redistributes into the bloodstream -. The process is abrupt termination of the effect of the drug

• • Second phase of drug distribution to the less vascular tissue occurs after an initial distribution, a phase of a highly vascular organ. The effects of anesthetic and other drugs is ultra acting although one over is 3-6 hours

  • After five minutes the liver (terminating its effect) and redistributes in the body’s after and after that.

  • Can make thiopental a longer repeat to saturate fat distribution.

Selective Accumulation of Drugs

• Tissue half-life of certain organs occurs.
  • So leave plasma rapidly:
  • short plasma
  • so that have short plasma and the time is still being taken multiple times per day.
  • Or may be have to get into.
  • They may be taken once daily or more due to selective accumulation in organs prolong duration hours Carbimazole used to treat hyperthyroidism is selective, like is only 3 hours to 6, is selective and used at the thyroid gland or tissue and used once daily.

Metabolism

• Bio-transformation is the process of chemical alteration of drugs in the body
• Primary site of chemical alteration of drugs is the liver. Other organs include the kidneys, lungs, and GIT
• metabolism aims to convert lipid soluble drugs to water soluble:
  • Facilitate drug Excretion (urine, bile, milk, sweet)
  • decrease tissue penetration and renal reabsorption

Biochemical Reactions

Phase 1 reaction

• oxidation
• reduction
• hydrolysis
• If the drug is converted into the water, with one of the reaction does not mean to inter phase 2 metabolites

Phase 2 reaction

• Conjugation
• Coupling of water, with water and insoluble and forming water to form water sugar

Oxidation Reactions

• Most common reaction. Oxygen to drug or is removed from the drug

Principle of Oxidation REACTIONS

• By oxidizing enyzyms or more organs

Enzymes

• are more enzymes liver especially
• 2-microphones sub cellular membrane or vascular
• 3 cytochrome P450 enzymes Cp450) 4 Family of Enzyme.

microsomal liver enzyme inducers and Inhibitors include

Enhancers

• that the rates of the drugs leading to the therapeutic failure or Must of except of acetaminophen and a clinical examples of some include accelerating rate of A graft injection.

Inhibitors

• the rate of some leading to ↑ and clinical Ciprofloxacin or .

Non-Microsomal Oxidation

• Soluble enzymes in cytoplasm mitochondrial.
• Ex: xanthine converts xanthine to uric acid through oxidatives, oxidizes, oxidation by oxidase, oxidizes catecholamines, and serotonin's.

Reduction reactions

• less common than oxidation. types:
• Microsomal.
• Non-microsomal.

Hydrolysis Reactions

• TYPE
• mainly non-microbial bodies

Main Types

types

• non specifc esterss
• Peptidases

NOTE

• if drug is Water is available from the start then metabolism Excretion

Phase 2 Reactions (Conjugation)

Definition:

• Coupling of a drug metabolite transfer to make water and secreted through
  • Types of endogenous reactions
• Glucuronide for a reaction which is one, where the glucuronic is conjucation and is conjured from it. Drugs will be Metabolized
• Glucuronide is conjugated secreted and rapidly in excreted. It may involve bacteria that has a circulation increased, E.g. birth controlling pills
• Glutathione-Using glutathione acid.
• non Microbial reactions Include Acetylation (isoniazide, salicylic acid). Sulffation

First-Pass Metabolism (Pre-Systemic Elimination)

• Metabolism of drugs at admin, site before reaching action.

oral route:

• Gut first-pass metabolism Gastric acidity destroys benzylpenicillin
• Digestive enzymes digest hormones as insulin
• COMT in intestinal mucosa metabolize L-dopa -Hepatic: the first pass metabolized to and lung through inhalation.
• if drug is partial the doses are High drug dose first pass effect if it is partial with a smaller dose . or complete if there were small inhalators and
  • A low does to avoid

Bio Factors Affect Drug Metabolism

genetic factors the vitamins that decreases amino or increases with malnutrition. Other effects may increase or decrease based on extreme malnutrition

• Age- cause hepatic amino acid. -Hepatic- decreased -Hepatic enzymes- Increase and lead to toxicity.

Excretion and Elimination

Clearance as a Channel of Elimination

• The volume of formula for minute and its Rate or concentration in Vd as with T
• Time taken for one out of two of plasma concentrated to drop
• If one of and in one way to glomerus
• if limited. Not exceed than blood filtered rate
• Is greater, then also the rate of blood

Route of elimination

• Kidney, major Route filtered through Active systems tubular the and
• The Biles and then small bowl followed by
• Lungs then the mouth.

Clinical Importance

• Clinical in portance of the kidney route and the way can adjust for the to avoid coming to the right, with the right dose to the
• Elimination half-life
• Definition Time taken 50% to fall in place
• Calculation 0.69 and one

Clinical time

Clinical with a specific can lead to toxic levels depending on it, The drug if or not is to toxicity for long will improve better Determining the dose over the of all levels one can and the drug to make it effective depends on side effects which may vary if it is already that the side effects are caused or may be of . The use of that certain cases a clinical to better know exactly what one has the patient at

steady state conc

The Steady The administration barriers that the that those this equation If the or If is a one with If and occurs to and.

• Steady Conc with the
  • Determine every order and give calculate drug effect
  • Time to observe will the has will

Time needed to observe toxicity

• Zero order will till improvement

Kinetic Eliminatlion

• the alpha from the the followed B is and the of is to and

type kinetic order, elimination

clinical or

• The drug in what can be followed
• first elimination
  • with toxic known