A.4 Flashcards
Routs of administration
- oral
- buccal/ sublingual
- intravenous (IV)
- intramuscular (IM)
- subcutaneous (Sc)
- rectal (suppository)
- inhalation
- topical
- transdermal
- intrathecal
forms of passive diffusion
- aqueous diffusion
- lipid diffusion
aqueous diffusion
small molecules through epithelial or endothelial pores (d: <0.4nm)
- Exceptions: BBB, BTB, Intestinal, Cutan epithel, minimal permeation placenta (below 1kDa permeation)
lipid diffusion
lipid solubility of the drug is the most important factor that determines the passive transport
- Only uncharged molecules can diffuse lipid membranes
Fat distribution
Accumulation in fat by highly lipid-soluble drugs
- Thiopental -> highly lipid soluble drug that acts for a short time during the fast distribution phase
Redistribution:
- In addition to crossing BBB, lipid soluble drugs redistribute into fat tissue prior to elimination
1st dose: In case of CNS drugs, the DOA of an initial dose may depend more on the redistribution rate than on the half-time
2nd dose: Decrease in blood-fat ratio -> decrease in rate of distribution to fat -> Increase in DOA!
Bioavailability
describes the rate and concentration at which ja drug reaches systemic circulation- the percentage of the dose that was initially administered: bioavailability=(AUCoral/AUCiv)*100
100% BA in IV.
- Other routes, BA is generally reduced by incomplete absorption, first-pass metabolism and any distribution into other tissues that occurs before the drug enters the systemic circulation
most lipid-solubility
Non-ionized molecules -> lipid soluble
What are special distribution barriers and what characterizes their distribution?
Placenta
- Most small mw drugs cross it, but fetal blood levels of the drug is usually lower than the maternal
- Safer in pregnancy: Water soluble, large molecules, protein bound
BBB
- Permeable only to lipid soluble drugs or thow of VERY low mw like lithium or ethanol
- Inflammation (Meningitis) -> increases permeability
P-Glycoprotein
P-Glycoprotein is a carrier found on the capillary endothelium in both CNS and placenta -> efflux transport -> protection
membrane transport mechanisms
Passive transport, active transport, lipid diffusion, pH partition
active transport
arrier mediated transport
Selective, saturable, ihibitable
- Facilitated diffusion or active transport
- Play a role in efflux and influx of drugs that are chemically related to endogenous substances or xenobiotics.
- Large, non-lipid soluble, endogenous molecules -> e.g. peptides, L-DOPA
- Xenobiotics -> number of carrier molecules can be changed -> e.g. inhibitors of protein synthesis
Endocytosis: Large molecules -> e.g. iron, vitamin B12, protein complex
Exocytosis: Transmitter release, mast cell granulation::Carrier mediated transport, endocytosis, exocytosis
plasma pH on drug concentration in the CNS
Increased plasma pH: exretion of weak acidic drugs from CNS -> Plasma
- Decreased plasma pH -> weak acidic drugs concentrate in CN
What does the distribution depend on?
- Organ size
- Bigger size -> better concentration gradient -> uptake - Blood flow
- Well perfused tissues usually achieve high concentration sooner - Solubility
- If drug has high blood solubility, need more drug to go into tissues! - Binding
- 1 albumin can bind 2 acidic molecules
- Free fraction is generally constant
- Unbound form is pharmacologically active
- Highly bound drugs -> slow elimination
- Competition between drugs for plasma protein binding sites may increase free fraction -> increased effect of displaced drug (Sulfonamides and warfarin bind Albumin, Sulfonamides will displace warfarin -> greater toxicity of warfarin
- Level of protein binding depends on: concentration of unbound drug, affinity for binding site, and concentration of binding drug::Different types influencing, and info about them}}
apparent volume of distribution (Vd)
Amount of drug in the body compared to that in the blood. It is a rate of distribution.
Low Vd = High % of the drug is bound to plasma proteins
High Vd = High % of the drug is sequestered in tissues
transporter superfamilies
ABC (ATB binding casett): 7 families
- Efflux using ATP as energy
- Excretion of drug into urine, bile and intestine
- Tumor drug resistance to chemotherapy
- P-glycoprotein: Brain, placenta outward transport
SLC (solute carriers): 48 families
- Influx (primary), efflux
- Use ion gradient to drive transport
- Primariliy involved in the uptake of small molecules into cells
