Pharmacokinetic (Absorption, distribution, metabolism and elimination)

must read the bold points

what happens when you eat a pill ?

Pharmacokinetics: 

describe drug absorption, distribution, metbolism and elimination 

Routes of drug administration: 

1) Omeprazole are acid unstable, enteric-coated preparation.

2) Aspirin have irritating effects on stomach, enteric-coated preparation 

3) t1/2 of Morphine is 2-4 hours, oral morphine need 6 times in 24hrs, need extended release 

preparation 

4) nitroglycerein is sublingual 

5) Atracurium, neuromuscular blocker, i/v administered, not absorbed orally 

6) I/V bolus: full amount of a drug is delivered to the systemic circulation almost immediately

7) I/V infusion: full amount of drug administered slowly during a long time 

8)Depot preparation: suspension of drug in a non-aqueous vehicle such as polyethylene glycol 

e.g Erythromycin, haloperidol(anti-psychotic/neuroleptic),medroxyprogesterone(contraceptive) 

9) sub-cutaneous: Epinephrine ,Lidocaine , insulin etc. 

10) Epinephrine act as local vasoconstrictor and decrease the removal of lidocaine 

11) oral inhalation: bronchodilator albuterol, corticosteroid fluticasone

12) nasal inhalation: nasal decongestant oxymetazoline, desmopressin used in diabetes

insipidus, salmon calcitonin a peptide hormone used in osteoporosis 

13) Intrathecal/Intraventricular: Amphotericin Bintrathecal, 

14) topical: clotrimazole cream antifungal 

15)transdermal: Bypass the first pass effect –EX. Anti-anginal Nitroglycerin, Anti-emetic 

Scopolamine, Nicotine patches for smoking cessation 

16)Rectal: partially bypass the first pass effect of liver---e.g anti-emetic 

ABSORPTION OF DRUGS

Absorption : transfer of drug from its site of administration to the bloodstream via one of 

several mechanisms 

1)Passive Diffusion: higher conc. To lower----no carrier, not saturable, show a low structural 

specificity—water soluble drugs pass through pores/aqueous channels 

2)Facilitated Diffusion: through specialized transmembrane carrier protein for large molecules 

High to low conc.----don’t require energy, can be saturated, 

3) Active Transport: Low to high conc.---energy require, carrier proteins, saturated, 

competitively inhibited by another organisms 

4)Endocytosis: engulfment of drug by the cell memb. & transport into the celle.g vitB12 

5)Exocytosis: cell transport the substance out of the cell by vesicle formation 

 e.g nor-epinephrine 

6)factors affecting the Abs.----PH,blood flow, total surface area, contact time, p-glycoprotein 

7)uncharged weak acid & base ,pass through memb. Easily than strong acid and base 

8) pKa=measure of strength of acid/base—higher pKa more basic---pH<pKa HA & BH+ dominate 

& pass through memb easily 

9) increase blood flow, total surface area, contact time increase abs. 

10)p-glycoprotein =multidrug trans-memb transporter protein transporting various molecules 

Decrease drug abs. in areas of high expression

BIOAVAILABILTY

1)Bioavailabilty= fraction of administered drug that reaches systemic circulation

2)Bioavailability=AUC oral/AUC injected x 100 

3)factors affecting bioavailability: first pass effect, solubility, nature of drug , chemical 

instability 

4)first pass effect decrease the bioavailability 

5) very hydrophilic drug-poor abs.-poor bioavailability-----extreme hydrophobic-poor abs.& 

bioavailbility 

6)for a drug to absorb –largely hydrophobic with some solubility in aqueous soln. 

7)Bioequivalence=two related drug preparations having comparable bioavailability and similar 

time to achieve peak blood conc. 

8)Therapeutic equivalence=two similar drugs are therapeutically equivalent if they are 

pharmaceutically equivalent with similar clinical & safety profile 

DRUG DISTRIBUTION 

1) DRUG distribution=drug reversibly leaves the blood stream and enters the 

interstitium(extracellular fluid) and then the tissues. 

2) Depends upon ---blood flow, capillary permeability, binding to plasma proteins and tissues, 

3) volume of distribution due to variation in blood flow,short duration of hypnosis by PROPOFOL 

4)high blood flow with high lipid solubility THIOPENTAL produce anesthesia 

5)capillary permeability determined by= capillary structure & chemical nature of drug 

6)binding to plasma protein decrease distribution 

7)Plasma albumin act as drug reservoir=when the conc. Of drug decreases due to met. The 

bound drug dissociates from the protein 

8)Binding to tissue protein major source of drug & cause local drug toxicity e.g Acrolein, 

metabolite of Cyclophosphamide is toxic to kidney b/c of its accumulation in renal cells 

9)Hydrophobic drug permeate easily increase drug distribution 

10)Volume of distribution= Vd=the fluid volume required to contain the entire drug in the body 

at the same conc. Measured in the plasma 

Vd=amount of drug in the body/Co, CL is first order process allows calculation of Vd

Vd is useful to compare the distribution of drug with volumes of water compartments in the

body

11)Plasma compartment= drug with large mol.wt, cannot cross slit junction , retain in plasma

6% of the body wt. or 4L in 70kg individual e.g Heparin

12)Extracellular fluid=sum of plasma + interstitial fluid=low mol.wt drug , hydrophilic, can cross

slit junction but not lipid memb. 20% of the body wt. or 14L in 70kg individual e.g

Aminoglycoside antibiotics

13)Total body water= low mol.wt & hydrophobic drug, can move slit junction + lipid memb

 60% of the body wt. or 42L in 70kg individual e.g Ethanol

14)Vd is useful parameter for calculating loading dose

15)Increase Vd increase t1/2(half life) if Vd large long half life

DRUG CLEARANCE THROUGH METABOLISM

1)Three mechanism of clearance= 1)Hepatic met. 2)elimination in bile 3) elimination in urine

2)Aspirin in high dose eliminated according to zero order/non-linear PK

3)Clearance =CL=amount of drug cleared from the body per unit of time

CL= 0.693 x Vd/t1/2

4)First order =Michaelis Menten kinetics: V=Vmax(C)/Km+(C)

V=rate of drug met, Km=Michaelis constant, C=conc. Linear kinetics

5)Zero order:non-linear kinetics=V=Vmax(C)/(C), V=Vmax Do not depend on conc

e.g Aspirin, Ethanol, Phenytoin

REACTIONS OF DRUG METABOLISM

1)Phase 1= convert lipophilic into more polar molecules by introducing OH,NH2 etc

Phase 1 with P450 enzymes system(microsomal mixed function oxidases)

2)CYP3A4= FOUND IN INTEstinal mucosa, accounting for first order met. Of chlorpromazine &

clonazepam

3)CYP2D6 show genetic polymorphism e.g some pt. obtain no benefit from Analgesic Codeine

due to lack of CYP2D6 that O-demethylates & activate the drug

4)FDA Black Box warning for Clopidogrel, Pt. who poor metabolizer of CYP2C19 ,do not convert

Clopidogrel(prodrug) to active metabolite, higher incidence of stroke & myocardial infarction

5)Enzyme Inducer=Xenobiotics induce the activity of enzymes results increased metabolism of

drugs decreasing plasma conc. Of drug e.g Phenobarbital,rifampin, carbamazepine

6)Xenobiotics :chemicals not normally produced in the body

7)Carbamazepine self enzyme inducer

8)Rifampin decreases plasma conc. Of HIV Protease inhibitors

9)CYP3A4/5 Inducers= carbamazepine, Dexamethasone, Phenobarbital, Phenytoin, Rifampin

10)CYP Enzyme Inhibitors= some drugs inhibit the enzymes leading to the inhibition of

metabolism of drug leading to the increase conc. Of drug in plasma

Example ; Omeprazole , Erythromycin, Ketoconazole, Ritonavir, Cimetidine, Grape Fruit juice

Omeprazole inhibitor of warfarin metabolism, hemorrhage & bleeding reaction

Cimetidine inhibit the metabolism of Theophylline

Grape Fruit Juice inhibit CYP3A4 inhibit the met. Of simvastatin, clarithromycin, Nifedipine

PHASE 1 REACTION NOT INVOLVING P450 SYSTEM

1)Amine oxidation( e.g catecholamines or Histamine)

2)Alcohol dehydrogenation= e.g Ethanol oxidation

3)Esterases =e.g met. Of Provastatin in liver

4)Hydrolysis = e.g Procaine

PHASE II=consist of conjugation reaction with endogenous substances such as Glucuronic acid,

Sulfuric acid , Acetic acid, Amino acid for too lipophilic drugs

Results in more water soluble co2)Neonate are deficient in Glucuronidation conjugating system , vulnerable to

Chloramphenicol which is inactivated by the glucuronic acid addition resultin GREY-BABY 

SYNDROME 

3)Drugs already containing –OH, -NH2, COOH enter directly into phase ll without phase l 

4)Isoniazid first acetylated(Phase ll) then hydrolyzed (Phase l) 

5)Probenecid competes with Pencillin for elimination through proximal tubular secretion 

6)Ion Trapping= weak acid eliminated by alkalinization and weak base eliminated by 

acidification of urine in Distal Convulated tubules 

7)Amphetamine weak base acidify by NH4CI 

8)Lungs involved in elimination of Halothane, Isoflurane (ANaesthatic gases) 

CL total=CLhepatic+ CLrenal + CLpulomnary + CLother 

DESIGN & OPTIMIZATION OF DOSAGE REGIMEN 

1)Continuous –Infusion Regimen= slow administration of single I.V dose e.g zolpidem 

2)Steady state Conc.=Css= amount of drug being administered equals the amount being 

eliminate 

90% of steady state drug conc. Achieve in 3.3 t1/2 

Steady state conc. Of drug rises directly with infusion rate, not affected by dosing frequency 

3)Maintenance of dose=drugs are administered to maintain steady state conc within 

therapeutic window dosing rate= (target Cplasma) (CL)/F 

4)Loading dose=a single dose to achieve the desired plasma level rapidly followed by an infusion 

to maintain steady state 

Loading dose= Vd x Cp/F, for I.V the bioavailability 100%

 so loading dose=Vd x Cp 

Vd is useful in dose adjustment