Pharmacokinetics I Flashcards
Xenobiotic
Anything that enters the body
Drug
Brings about change in biological function through its chemical actions
Prodrug
Inactive form of a drug, converted to an active form in the body
Pharmacodynamics
Action of drug ON the body
Drug disposition
Qualitative; how the body handles the drug
How it’s absorbed, distributed, metabolized, eliminated
Pharmacokinetics
Quantitative description of drug disposition
First pass metabolism occurs where?
Liver
“A” in ADME
Absorption: transport drugs from site of admin to circulation
“D” in ADME
Distribution: delivery of drug via blood to tissues, drug must have adequate concentration at site of action to produce effect
“M” in ADME
Metabolism: parental compound converts to metabolite, compound made more amendable for excretion, occurs in liver, typically inactive metabolites but pharmacologically active
“E” in ADME
Excretion: via kidney or intestine
Most critical step for bioavailability?
Absorption
Factors that determine absorption
1) property of the drug (size, acid/base, lipophilic/hydrophobic)
2) vehicle/formulation
3) route of admin and conditions at route of admin
Route of admin most critically effects…
Rate of drug absorption
What does route of drug admin influence?
Extent and speed drug is absorbed
1st pass metabolism or not
Efficacy and therapeutic effect
Drug Route Administration - Enteral/Enteric
Oral - per os, PO
Buccal/sublingual - BU/SL
Rectal - REC
Oral Route of Admin characteristics & issues
Enteral Most common Safest Large SA Intestine is site of absorption
Issues: slow & subject to liver first-pass metabolism
Buccal/Sublingual Route Admin: characteristics
Enteral
Small area, HIGH vascularization
Rapid absorption to VENOUS blood
Bypass liver first pass liver metabolism
Route of admin: rectal
Enteral Performed if oral is precluded Suppository, foam, or liquid form Drug placement isn’t well controlled Absorbed 50% hepatic portal vein (proximal- first pass metabolism) and 50% to venous blood (distal- bypasses first pass metabolism)
Drug Amin Routes - parenteral
!! Bypass first pass metabolism !! Subcutaneous (SC) Intramuscular (IM) Intravenous (IV) Intrathecal (IT) Inhalation Intranasal
Subcutaneous Injection
Poor blood flow
Sustained, slow release
Small volumes of drugs
Intramuscular Injection
High blood flow = prompt absorption
Large volumes, prolonged release
Intravenous Injection
Instant delivery - 100% absorption
Prone to adverse effects
Intrathecal Injection
Subarachnoid space of spine
Bypasses BBB
Rapid effect on meninges or cerebrospinal axis
Used for spinal anesthesia
Inhalation
Action on bronchioles, rapid access to circulation
High vascularization
Inhalation anesthetics, asthma inhalants
Intranasal
Parenteral
Acts on nasal mucosa
Future drugs via vaccines
Topical Drug Admin
Ophthalmic drops
Dermal
Ophthalmic drops
Instillation into eye for local effect
Dermal
Topical
Local acting
Systemic absorption - oily vehicles, transdermal patches, Iontophoretic and phonophoretic delivery
Transdermal Iontophoretic Delivery
Delivery of ionic molecules into tissues by electric current
(-) charged drug driven into skin from cathode to anode
Route of Drug Admin (quickest to slowest)
IV Inhalation SL IM SC REC PO Transdermal
Bioavailability
Fraction (F) of the dose of unchanged drug that reaches systemic circulation by any route
- IV dose drugs have 100% bioavailability
- other admin route <100%
Bioavailability depends on:
Chemical form of drug
Rate of absorption
Contact time with absorbing surface
Enzymes and efflux transporters
Drug Movement Across Biological Membranes
A - enter circulation
D - traverse within the body, critical concentration needed at site of action
M - drug moves into liver
E - drug/metabolites must be eliminated
Mechanisms by which drugs are transported after admin
Passive Transfer - bulk flow/filtration, passive diffusion
Carrier-Mediated Transport - facilitated diffusion, active transport, receptor-mediated endocytosis
Bulk Flow/Filtration
Passage of compounds through intercellular pores
Drug flows through intercellular clefts or fenestra
Filtration/Bulk Flow Drug Size
MW < 300-500 daltons
Filtration/Bulk Flow Drug Types
Ionic, lipophilic, hydrophilic, etc.
Examples of Bulk Flow/Filtration
Peripheral capillaries
Glomerular filtration in kidney
Passive Diffusion
Passage of drugs by dissolving into and diffusing across lipid membranes through intercellular cleft
MOST IMPORTANT TRANSPORT PROCESS, most common route of transport for enteral route
Properties of molecules that cross by passive diffusion
1) uncharged, non-ionized
2) lipid soluble (lipophilic, hydrophobic)
- non-polar groups increase solubility (CH2, CH3, aromatic rings)
- polar groups decrease lipid solubility (OH, COOH, NH, sulfates, ionized groups)
3) correlation of absorption and lipophilicity
Lipophilicity
Measured by distribution in an immiscible mix of organic-aqueous solvent
Passive Diffusion of Non/ionic Drugs
Small MW organic acids or bases that exist as ionized and non-ionized forms (non-ionized can diffuse, ionized cannot)
Classified as acids or bases based on the uncharged (neutral) form of drug
Charged & Uncharged Forms of Acidic Drugs
Acidic drug is neutral molecule which can reversible dissociate into an anion (conj. base) to yield a proton donor
Charged and Uncharged Forms of Basic Drugs
Basic drug is a neutral molecule which can form a cation (conj. acid) by combining with a proton (proton acceptor)
