Pharmacokinetics (Lec. I) PDF

Pharmacokinetics (lec.I )  Pharmacokinetics: refers to what the body does to a drug, whereas pharmacodynamics describes what the drug does to the body  Four pharmacokinetic properties determine the onset, intensity, route of administration,...

Pharmacokinetics (lec.I )  Pharmacokinetics: refers to what the body does to a drug, whereas pharmacodynamics describes what the drug does to the body  Four pharmacokinetic properties determine the onset, intensity, route of administration, dose, frequency, and duration of treatment. Pharmacokinetic properties Mca Absorption: from the site of administration into plasma. ADME Distribution: → the interstitial and intracellular fluids. metabolism eliminatin is Metabolism: by the liver or other tissues. & U ↳ L distrubtion absorption Elimination: in urine, bile, or feces. Pharmacokinetic properties → (ADME) 1. Absorption: from the site of administration into plasma. * 2. Distribution: the drug leaves the blood stream & distribute into the interstitial and intracellular - fluids. 3. Metabolism: the drug may be biotransformed through metabolism by - the liver or other tissues. edetoxify 4. Elimination: the drug & its metabolites are eliminated from the body in urine, bile, or feces.  1.Absorption  Absorption is the transfer of a drug from (the site of administration → the bloodstream).  The rate and extent of absorption depend on: I. the environment where the drug is absorbed II. chemical properties of the drug III. and the route of administration (which influences bioavailability).  Routes of administration other than intravenous may result in partial absorption and lower bioavailability. the first-pass effect by pass IV injection delivers the drug directly to the blood →completely absorbed 100% bioavailability * Other routes → partial absorption and lower bioavailability.  Routes of Drug Administration Mechanisms of absorption of drugs from the GI tract 1. Passive diffusion  99% drugs are absorbed by this mechanism  the drug moves from high conc. to low conc. < Law ofdiffusion (  It does not involve a carrier , no energy is required & is not saturable , shows low structural specificity.  Water-soluble drugs penetrate through aqueous channels, - whereas lipid-soluble drugs readily move across the - membrane lipid bilayers. water soluble - no carrier i oa needhunt Lipid > need soluble - carrier in ↓ blood pass directly to inside of all 2. Facilitated diffusion  Drugs can enter the cell through transmembrane carrier proteins that facilitate the passage of such large molecules.  Carrier proteins undergo conformational changes, allowing the passage of drugs or endogenous molecules into the interior of cells.  It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier. 3. Active transport  It also involves specific carrier proteins that span the membrane.  Energy dependent: driven by the hydrolysis of ATP (adenosine triphosphate).  It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher drug concentration.  The process shows saturation kinetics for the carrier.  Active transport systems are selective and may be competitively inhibited by other co-transported substances. 4. Endocytosis and exocytosis  Endocytosis is used to transport drugs of large size across the - - cell membrane.  It involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle. -  Exocytosis is the reverse of endocytosis. -  Vitamin B12 is transported by endocytosis, whereas neurotransmitters (norepinephrine) are released from the nerve terminal by exocytosis.  Factors influencing absorption P _B A T_ P Surface P- Ph Blood flow Time area glycoprotein 1. Effect of pH on drug absorption Lipid solubility Ionization pKa of drug and PH of media  Most drugs are either weak acids or weak bases.  Acidic drugs (HA) release a proton (H+ ), causing a charged anion (A− ) to form: weak acid HA ↔ H⁺+ A⁻  Weak bases (BH+) can also release an H+. However, the protonated form of basic drugs is usually charged, and loss of a proton produces the uncharged base (B): weak base BH⁺ ↔ H⁺ + B  A drug passes through membranes more readily if it is uncharged  Thus, for a weak acid, the uncharged, protonated HA can permeate through membranes, and A− cannot. uncharged  For a weak base, the uncharged form B penetrates through the cell membrane, but the protonated form BH+ does not.  Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms.   The ratio between the two forms is, in turn, determined by the pH at the site of absorption and by the strength of the weak acid or base, which is represented by the ionization constant, pKa. Note: The pKa is a measure of the strength of the interaction of a compound with a proton.  The lower the pKa of a drug, the more acidic it is.  Conversely, the higher the pKa , the more basic is the drug.  Distribution equilibrium is achieved when the permeable form of a drug achieves an equal concentration in all body water spaces. Solubility : I. lipid soluble drug cross easily through the cell membrane(diffuse into lipid bilayers). II. Water soluble drug cannot cross the lipid membrane.  Lipid soluble HA - nonionized s nonpolar H+ + A-/gionized polarwater Ionization HA : - able I. (Non ionized = non polar = non charged drug = Lipid - soluble)→ cross the membrane. + HA-H A + II. (Ionized = polar = charged) drug has a charge → attract water (water shell) → become as water soluble → not cross the membrane. Ionization depends on pKa of the drug and PH of the media. ( for a drug to be absorbed it must be of the same nature to the media of absorption ) → e.g. acidic drug in basic environment → ionized → not cross , also basic drug in acidic environment → ionized → not cross. the drug determine what part of OIT Absorb - pKa : is the PH at which half of the drug is in its ionized form and half isn’t ( 50% ionized : not absorbed & 50 % non-ionized : absorbed ) , a neutral point , the ionization constant. The lower the pKa of a drug, the more acidic it is. Conversely, & the higher the pKa , the more basic is the drug. E.g aspirin (acetylsalicylic acid) pKa = 3.5. So aspirin is an acidic drug , in the stomach (PH=1.5) → (99 % absorbed). While aspirin in the small intestine( PH=8.5) → (1 % absorbed).  Therefore aspirin in PH media lower than 3.5 → ↑ absorption , while in PH more than 3.5 even if acidic such as (4 , 5, 6)→↓ absorption.  That is why aspirin mainly affect gastric mucosa (peptic ulcer) →1- absorption is ↑ in acidic PH=1.5 and 2- aspirin trapping in the gastric epithelium PH=7.4 inside the gastric cells → ionization → not cross to the blood → trapped inside the cells → peptic ulcer. In practice the clinical significance of pKa is : 1. To know the site of absorption. - 2. To treat drug toxicity: e.g. asprin pKa=1.5 in urine PH=5.2 - →↑ reabsorption→↑toxicity, so use an alkalinizing agents (sodium bicarbonate)→↑ionization →elimination , and vice versa in basic drug toxicity. 3. In breast feeding: PH of plasma 7.4 → if alkaline drug is - used → good absorption → pass into the breast milk PH=7 →ionized →cannot pass→trapped→ affect the baby. * ↳ thus some drugs Can't be taken by mother nursing  intestine - ** Stomach - 2. Blood flow  The intestines receive much more blood flow than does the stomach, so absorption from the intestine is more.  [Note: Shock severely reduces blood flow to cutaneous tissues, thereby minimizing absorption from SC Subcutaneous administration.]  3. Total surface area available for absorption ↑P The intestine has a surface area about 1000-fold that of the ↳stomach, making absorption of the drug across the intestine more efficient. 4. Contact time more slow - ↑ absorption  In severe diarrhea, a drug moves through the GI tract very quickly→ not well absorbed.  Conversely, the presence of food in the stomach dilutes the drug and slows gastric emptying → absorbed slowly. thus , some drug should be taken after meals 5. P-glycoprotein  is a transmembrane transporter protein responsible for - transporting various molecules, including drugs, from - tissues to blood.  It is expressed in the liver, kidneys, placenta, intestines, and - - brain capillaries. -  That is, it “pumps” drugs out of cells. Thus, in areas of high expression, P-glycoprotein reduces drug absorption.  It is also associated with multidrug resistance.