أسئلة الخامسة فارما PPPM (قبل التعديل)

• Journey of drug inside body = Effect of the body on drug
• Starting from absorption till complete elimination
• Includes absorption, distribution, metabolism, and excretion

Absorption

• Passage of drug from the site of administration to plasma
• Routes of administration include oral, rectal, sublingual, local, inhalation, and injections

Mechanisms of Absorption

Simple Diffusion

• Occurs according to concentration gradient
• Passive, requires no energy
• Drug must be lipophilic

Carrier-Mediated Transport

• Involves specialized carrier molecules
• May be passive (according to concentration gradient)
• May be active (against concentration gradient, requires energy)

Pinocytosis

• Invagination of part of cell membrane traps drug molecule inside a small vesicle
• The vesicle is then released inside the cell
• Used for large molecules such as hormones

Factors Affecting Drug Absorption

Molecular Size

• Small molecules are absorbed more efficiently than large molecules

Dose

• Absorption increases with increasing dose, up to a limit

Drug Formulations

• Absorption rate: Sustained-release (SR) tablets < suspensions < powders

Drug Combination

• Example: Vitamin C increases absorption of iron

Lipid Solubility (Drug Ionization = pKa)

• Lipid solubility is the most important factor

Local Effects of the Drug

• Example: Drugs producing vasoconstriction decrease their own absorption

Route of Administration

• IV route is the fastest
• Rectal route is the slowest

Integrity of the Absorbing Surface

• May increase or decrease absorption

Local Blood Flow

• Ischemia decreases absorption

Specific Factors

• Apoferritin system for iron
• Intrinsic factor for Vitamin B12
• HCl for aspirin

First Pass Metabolism

• Metabolism at the site of absorption decreases drug concentration

Theory of pKa = Lipid Solubility = Drug Ionization = Dissolution Constant

• p = inverse log
• Ka = association/dissociation constant

Definition

• pH at which 50% of the drug is ionized (non-absorbed)
• 50% of the drug is non-ionized (absorbed)

Principles

• Ionized drugs (water-soluble, polar, charged) are poorly absorbed
• Unionized drugs (fat-soluble, non-polar, non-charged) are more lipid-soluble and rapidly absorbed
• Acidic drugs (aspirin): Ionized in basic media and less ionized in acidic media, more absorbed in the stomach and less in the intestine
• Basic drugs (amphetamine, local anesthetics): Ionized in acidic media and less ionized in basic media, more absorbed in the intestine and less in the stomach
• Drugs move better in a medium that's more like them and poorly in a medium that's the opposite
• When the pH of media is equal to the pKa drug, the ratio of unionized to ionized molecules is 1:1
• With every unit change in pH of the media, the unionized to ionized ratio changes 10-fold

Clinical significance of pKa:

• Understanding absorption and excretion of weak acids e.g. Aspirin
• Aspirin is an acidic drug with a pKa = 3.5

Aspirin pH levels

• pH of the stomach is 1.5
• pH of the intestine is 6.5 in the upper intestine and 7.5 in the lower intestine
• pH of blood and body organs (stomach cells and renal tubular cells) is 7.4
• pH of urine is 4.6 to 8.2
• pH of tubular cells is 7.4

Aspirin in the Stomach

• When aspirin is placed in the stomach (acidic environment), it is more unionized than ionized, leading to better absorption

Aspirin in the Intestine

• When aspirin is placed in the intestine (basic environment), it is more ionized than ionized, leading to less absorption

When Aspirin Inside Wall of Stomach Body pH

• Ion trapping of aspirin occurs when aspirin enters the stomach wall, the pH is 7.4 inside, causing aspirin to be more ionized inside cells and less diffuses outside them causing cells to burn and produce gastric ulcers
• When aspirin is in the blood, it is metabolized to salicylic acid with pKa = 3, and as the pH of blood is 7.4, aspirin is more ionized and remains in the blood

Aspirin in Urinary Tract in Acidic Urine

• Less ionized and may be reabsorbed

Aspirin Inside Tubular Cells

• 2nd ion trapping leads to damage of renal tubules

Weak Bases

• Opposite to aspirin
• E.g. Amphetamine (pKa = 9.9)

Treating Drug Toxicity based on pKa

• Alkalinization of urine increases the drug ionization in the urine, preventing its re-absorption and promoting its excretion
• Acidification of urine increases drug ionization in the urine, preventing its re-absorption and promotes its excretion

Knowing the Site of Drug Trap (Ion Trap)

• Acidic drugs get trapped in the stomach wall (pH = 7.4) after absorption, may cause ulcer, given after eating
• Acidic drugs get trapped in nephron wall (pH = 7.4) after reabsorption from urine, may cause kidney injury. Alkalinization of urine helps excretion
• Alkaline drugs get trapped in milk and tumors as they are more unionized in plasma (pH = 7.4), can cross to milk or tumor (pH = 6.5 - 7) and drug becomes ionized and trapped in milk or tumor
• Take drug after lactation and alkalinization of blood increase ion trapping (bad for baby, good to kill tumor)

Increase or Decrease Drug Action E.G. Local Anesthetics

• Local anesthetics are weak bases
• Addition of bicarbonate to the anesthetic solution maintains the anesthetic in the non-ionized state and increases penetration
• Tissue Infection and inflammation make tissue acidic and increase ionization of local anesthetics, and decrease penetration

DEF (Fraction of Drug)

• Fraction of unchanged drug reaching systemic circulation following administration by any route in comparison to administered dose (total amount given / plasma concentration)

Bioavailability

• The bioavailability of drugs given IV is 100%
• Bioavailability of other routes measured by IV dose

Bioavailability formula

• Oral bioavailability = (Area under the curve (AUC) oral) / (Area under the curve (AUC) IV)

Importance

• Determine duration and effectiveness of a drug that's administered by different formulations at different routes, especially for drugs like Digoxin, Phenytoin, Warfarin, Prednisolone and Chloramphenicol

Factors

• Factors affecting absorption
• First-pass metabolism for oral route

Definition of Distribution

• Transport of drug from the site of administration to all body tissues through circulation
• Sites of drug distribution include plasma (3L), extracellular water (9L), and intracellular water (29L)
• Vd more than 41 liters indicates the drug moves to tissues

Volume of distribution Vd

Definition

• Is the apparent volume of water into which the drug is distributed in the body after distribution equilibrium
• Time is needed for distribution all over the body

Factors Affecting

Small Vd occurs when:

• Lipid solubility is low
• Large drug size
• There is a high degree of plasma protein binding
• There is a low level of tissue binding

Large Vd occurs when:

• Lipid solubility is high
• Ssmall drug size
• There is a low degree of plasma protein binding
• There is a high level of tissue binding

Formula for Vd

• Calculation of volume of distribution: Total amount of drug in body, divided by plasma conc. of drug after distribution equilibrium (L)

Distribution facts

• If Vd calculated for 1 KG, Total Vd = Vd x 70 kg (the large Vd = the more tissue distribution) For example Vd for Digoxin is 6 L/kg (total = 420 L)
• Each 1 kg of tissue takes a concentration of the drug as equals to concentration of drug in 6 L of plasma, or each 1 kg of tissue takes 6 fold, the conc of Digoxin in 1 L of plasma
• If it's needed to distribute Digoxin equally between all body tissues (70 kg) and plasma, than an imaginary volume of plasma would be: 6 x 70 = 420 liters

Significance of distribution

Determination of Site of Drug Distribution

A total Vd < 5L:

• The drug remains confined to the blood
• It can be removed by dialysis

Total Vd < 15 L:

• The drug is restricted to ECF

Total Vd 15 - 41 L:

• The drug is distributed throughout all body water

Total Vd > 41L:

• The drug binds extensively to tissue protein
• It cannot be removed by dialysis

Further calculations

• Calculation of total amount of drug in body, using single measurement of plasma concentration
• Calculation of drug clearance = Vd x Kel
• Calculation of loading dose (total drug amount) = Vd × plasma conc.

Binding of Drugs to Plasma Proteins

• Most drugs bind to plasma proteins
• Bound form is inactive
• Free unbound part is active

Further info

• Bound form is released slowly with the gradual decrease in the plasma concentration of the drug
• Albumin is the most important plasma protein, binding mainly to acidic drugs and some basic drugs
• Globulin and Glycoproteins, binds mainly basic drugs

Advantages of plasma binding

• Binding does not prevent the drug from reaching its site of action but only retards the rate of drug action increasing the duration of drug in the blood

Disadvantages of plasma binding

• Bound form is not effective
• Drug interaction (if given with another drug)
• Change in binding:(e.g. hypoalbuminemia, pregnancy, renal failure, etc.)
• Plasma protein binding will be altered so that the free part of the drug will ⬆or⬇leading to serious toxicity or under-response

Binding of Drugs to Fats

• They can cross the BBB and exert CNS effects
• Stored in body fats for a long time, e.g, vit A is stored in fat cells of the liver for 6 months
• Rapid elimination of the drug to fat by Redistribution, Strong lipophilic drugs (thiopental) when injected iv goes into 2 phases :
• Drug is distributed into blood-rich organs (brain, heart, liver)
• Drug leaves blood-rich organs, is redistributed finally into body fats, resulting in abrupt termination of drug effect

Note

• The second phase of the drug distribution into less vascularized tissue occurs after the initial distribution phase into highly vascular organs
• e.g. thiopental is an ultra-short acting anesthetic (~15 min) although t 1/2 is 3-6 hours

Selective Accumulation of Drugs and Tissue Half Life

• Selective accumulation in a drug can occur
• They leave plasma rapidly so that they have short plaza half life (t1/2) and supposed to be taken multiple times per day
• They may be taken once daily or more because selective accumulation in organs and prolong half life
• e.g. Carbimazole is used to treat hyperthyroidism, it's used to treat t1/2 (3-6hrs), and has selective accumulation in the gland so that the daily dose is low