Pharmacology Lecture 5: Pharmaco-kinetics PDF

Pharmacology Pharmaco-Kinetics LECTURE (5) Pharmaco-kinetics (1) DR. El-Sawy 0  Pharmacology...

Pharmacology Pharmaco-Kinetics LECTURE (5) Pharmaco-kinetics (1) DR. El-Sawy 0  Pharmacology Pharmaco-Kinetics Definition :  Journey of drug inside body = Effect of the body on drug. (Starting from absorption till complete elimination). ‫تأثري اجلسم عيل ادلواء‬ Include: DR. El-Sawy 1  Pharmacology Pharmaco-Kinetics ‫الامتصاص‬ Definition: Passage of drug from the site of administration to plasma. Routes of administration Mechanisms of absorption:  According to conc. gradient. Simple diffusion  Passive (no energy)  The drug must be lipophylic.  By specialized carrier molecules Carrier-mediated  May be: transport a. Passive according to conc. Gradient b. Active against conc. Gradient by energy  Invagination of part of cell membrane and trapping drug molecule inside a small vesicle, which is then released Pinocytosis inside the cell.  e.g. large molecules as hormones. DR. El-Sawy 2  Pharmacology Pharmaco-Kinetics Factors affecting drug absorption : 1. olecular size: ‫حجم‬  Small molecules are absorbed than large molecules. 2. ose:  Absorption increases with increasing dose (up to limit). 3. rug formulations:  Sustained-release (SR) tablets > suspensions & powders Factor related to drug : 4. rug combination:  e.g. vit C : ↑ absorption of iron. 5. ipid solubility (drug ionization = pKa)  The most important. 6. ocal effects of the drug:  e.g. drugs producing VC : ↓ their own absorption. 1. Route of administration:  IV route is the fastest  Rectal route is the slowest. 2. Integrity of the absorbing surface:  May ↑ or ↓ absorption. 3. Local blood flow: Factor related to absorbing  Ischemia ↓ absorption. surface : 4. Specific factors:  Apoferritin system for iron  Intrinsic factor for Vit.B12  HCl for aspirin 5. First pass metabolism:  metabolism at site of absorption →↓drug conc. DR. El-Sawy 3  Pharmacology Pharmaco-Kinetics 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 & Less ionized in an acidic media. More absorbed in stomach & less in intestine, Basic drugs (Amphetamine & local anasthetics) : Ionized in acidic media & Less ionized in a basic media. More absorbed in intestine & less in stomach, ‫ادلواء بيتحرك افضل يف الوسط اليل زيه‬ ‫واسوا يف الوسط اليل عكسه‬  When pH of media is equal to pKa of drug, ratio of ionization (unionized to ionized molecules) is 1:1 DR. El-Sawy 4  Pharmacology Pharmaco-Kinetics  With every unit change in pH of media, unionized to ionized ratio changes 10 folds as following: ↑ 1:100 100 % ionized 100:1 100 % union ↑ 1:10 10/90 10:1 90/10 1:1 50 % / 50 % 1:1 50/50 ↓ 10:1 90/10 1:10 10/90 ↓ 100:1 100 % union 1:100 100 % ionized DR. El-Sawy 5  Pharmacology Pharmaco-Kinetics Clinical significance of pKa - Understanding absorption & excretion of weak acids e.g. Aspirin  Acid in acid When aspirin is  So aspirin is more unionized than ionized put in stomach More absorbable in the stomach.  Acid in base When aspirin is  So aspirin is more ionized than unionized put in intestine Less absorbable in the intestine.  Ion trapping of aspirin  When aspirin entered inside stomach wall, pH is 7.4 inside, So When aspirin that aspirin will be more ionized inside cells and less diffuse inside wall of outside them → cells will burn → gastric ulcer. stomach  When aspirin is in the blood → aspirin is metabolized to (body pH) salicylic acid with pKa = 3 & as pH of blood is 7.4 → aspirin is more ionized & remain in the blood When aspirin in urinary tract  less ionized & may be reabsorbed in acidic urine When aspirin inside tubular  2nd ion trapping → damage of renal tubules cells DR. El-Sawy 6  Pharmacology Pharmaco-Kinetics Understanding absorption & excretion of weak base:  e.g. Amphetamine (pKa = 9.9) →  Opposite to aspirin Treating drug toxicity based on pKa : Toxicity with acidic drugs Toxicity with basic drugs Aspirin Ephedrine  TTT by alkalinization of urine by  TTT by acidification of urine by Na bicarbinate: ammonia : ↑drug ionization in the urine → ↑drug ionization in the urine → prevents its reabsorption and prevents its reabsorption and promotes its excretion promotes its excretion Knowing the site of drug trap (ion trap) :  Trapped in stomach wall (pH = 7.4) after absorption, may cause ulcer, given after eating. Acidic drug  Trapped in nephron wall (pH 7.4) after reabsorption from urine, may cause kidney injury, alkalinization of urine helps excretion.  Trapped in milk & tumors as more unionized in plasma (pH = 7.4), can cross to milk or tumor (pH = 6.5 - 7) & drug become Alkaline drugs ionized & trapped in milk or tumor.  Take drug after lactation & alkalinization of blood increase ion trapping (bad for baby, good to kill tumor) DR. El-Sawy 7  Pharmacology Pharmaco-Kinetics 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 & inflammation makes tissue acidic & increase ionization of local anesthetics & decrease penetration. DR. El-Sawy 8  Pharmacology Pharmaco-Kinetics  Fraction of unchanged drug reaching systemic circulation following administration by any route in comparison to Def administered dose (total amount given / plasma concentration).  The bioavailability of drugs given IV is 100%.  Bioavailability of other routes measured by: Examples  Determine duration & effectiveness of drug administered by different formulations at different routes especially for the following drugs: Importance 1. Digoxin 4. Prednisolone 2. Phenytoin 5. Chloramphenicol. 3. Warfarin  Factors affecting absorption. Factors  First-pass metabolism for oral route. DR. El-Sawy 9  Pharmacology Pharmaco-Kinetics ‫التوزيع‬ Definition:  Transport of drug from site of administration to all body tissues through circulation Sites of drug distribution: Plasma Extracellular water Intracellular Water 3 liter 9 liter 29 liter DR. El-Sawy 10  Pharmacology Pharmaco-Kinetics  The apparent volume of water into which the drug is Def distributed in the body after distribution equilibrium = time needed for drug distribution allover body. 1- Lipid solubility is low. 1- Lipid solubility is high. 2. large drug size 2. Small drug size Factors 3- There is a high degree of 3- There is a low degree of affecting plasma protein binding. plasma protein binding. 4- There is low level of tissue 4- There is high level of tissue binding. binding. Total amount of drug in body (L) Plasma conc. of drug after distribution equilibrium  e.g. → Vd for Digoxin is 6 L/kg (total = 420 L), what is meaning of this? Calculation Each 1 kg of tissue takes a concentration of drug equal to the 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. Or Each 1L plasma takes 1/6 of conc of digoxin in 1kg tissue  So, If we want to distribute digoxin equally between all body tissues (70 kg) and plasma, we need an imaginary volume of plasma = 6 × 70 = 420 liters. DR. El-Sawy 11  Pharmacology Pharmaco-Kinetics  Determination of site of drug distribution : Drug is confined to the blood Can be removed by dialysis. Drug is restricted to ECF. Drug is distributed throughout all body water. significance Drug bind extensively to tissue protein Cannot be removed by dialysis.  Calculation of total amount of drug in body By single measurement of plasma concentration.  Calculation of drug clearance = Vd x Kel  Calculation of loading dose (total drug amount) = Vd × plasma conc. DR. El-Sawy 12  Pharmacology Pharmaco-Kinetics  Most drugs bind to plasma proteins: Bound form is inactive Free unbound part is active  Bound form is released slowly with the gradual ↓ in plasma concentration of the drug 1. Albumin:  most important plasma protein binds mainly to acidic drugs, & some basic drugs 2. Other plasma proteins:  Globulin, Glycoproteins, binds mainly basic drugs.  Binding does not prevent the drug from reaching its site of Advantages action but only retards the rate of drug action → ↑duration of drug in the blood → good for prophylaxis  bound form is not effective  drug interaction, if give other drug with affinity to plasma proteins. ↑ with drugs have high plasma protein bound (e.g. 99% for warfarin) Disadvantages  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. DR. El-Sawy 13  Pharmacology Pharmaco-Kinetics Clinical significance 1. They can cross the BBB and exert CNS effects. 2. Stored in body fats for a long time e.g. vit A is stored in fat cells of liver for 6 months. 3. Rapid elimination of drug to fat by Redistribution Redistribution  Strong lipophylic drugs (thiopental) when injected i.v. goes into 2 phases :  Drug is distributed into blood-rich  Drug leaves blood-rich organs organs  Redistributed finally into body fats Brain resulting in abrupt termination of liver. drug effect. Notes Second phase of drug distribution into less vascular tissue occurs after an initial distribution phase into highly vascular organs. Thiopental is an ultra-short acting anesthetic (~ 15 min) although t 1/2 is 3- 6 hours :  Following i.v. injection of thiopental, it rapidly distributes in the brain and produces anesthesia (phase 1).  After 15 min, it leaves brain (terminating its effect) and redistributes in body fats and does not return to the brain again (phase 2).  We can make thiopental a long-acting by repeated injection to saturate fats & stop redistribution DR. El-Sawy 14  Pharmacology Pharmaco-Kinetics  Some drugs selectively accumulate in certain organs.  They leave plasma rapidly : so that have short plasma half life (t1/2) & supposed to be taken multiple times per day. They may be taken once daily or more due to selective accumulation in organs that prolong biological half life (tissue half life). Carbimazole used to ttt hyperthyroidism, it has short t1/2 (3-6 hrs), but has selective accumulation in thyroid gland, so that used once daily. DR. El-Sawy 15