Drug Disposition I Flashcards
Processes by which drugs cross biological membrane: (3)
Passive diffusion lipid aqueous
Passive transport
Active Transport
The most common and important mechanism of drug movement is active lipid diffusion, in which the drug dissolves in the lipid membrane and diffuses across driven by a concentration gradient. True or false?
false, passive diffusion
Rate of passive lipid diffusion depends on (3)
concentration gradient (affected by blood flow)
surface area
lipophilicity
2 major classes of drug transporters: Most drugs transported by which one?
Uptake& Efflux
Efflux
SLC transporters co-transport solutes like sodium. What type of transporter is this?
uptake
ABC transporters use ATP is an example of what transporter?
efflux
pump things out of the cell
Most drugs are ____ electrolytes.
weak
Ionized forms of chemicals do penetrate lipid membranes. True or false?
false
do not
Degree of drug ionization: (2)
pKa–intrinisic property of drug
pH of surrounding medium
weak acids: mainly ionized at pH __ pKa. weak bases: mainly ionized at pH __ pKa
>
The nonionized form is free to be absorbed across the gastric epithelial cell layer. Once it reaches the plasma, it encounters a pH that is now above its pKa. Therefore, aspirin will now be mostly in the ionized form. The rapid ionization of aspirin in the plasma maintains the concentration gradient of the diffusible (nonionized) form of aspirin, and diffusion will continue until equilibrium is reached. Thus, the total amount of aspirin at equilibrium (which never occurs in reality, this is only a conceptual example) will be 8000-fold higher in the high pH compartment. This is known as ___ ____.
ion trapping
What type of tissue contains : tight junctions lipid diffusion only
gastrointestinal epithelium
Molecules cross ______ endothelial cell layer by: Transcellular diffusion Aqueous diffusion Receptor-mediated endocytosis/pinocytosis Bold = most common
capillaries
Most capillaries are ______: (porous regions within and between cells) admit water-soluble molecules up to 60 kDa via ______ transport.
fenestrated
paracellular
________ capillaries are very leaky and allow RBCs and WBCs to pass
Discontinuous
_______ capillaries have tight junctions (but differ in the degree of pinocytosis)
Continuous
______ is the main drug barrier in the brain.
BBB
In the placenta, the human trophoblast basement membrane is quite porous. Admits most drugs < ____ MW
600
Factors affecting oral absorption: (7)
solubility stomach acid pH range tight junctions, lipid solubility surface area transport to liver via portal vein and first pass metabolism Intestinal motility, gastric emptying, blood flow
Enteral routes of drug administration: (3)
oral
sublingual (to avoid first pass metabolism and liver)
rectal
Parental routes of drug administration: (7)
IV IM subcutaneous inhalation nasal transdermal topical
Pulmonary administration of drugs: (4)
Gaseous anesthetics
Smoking
Aerosols for topical effects on lungs e.g. albuterol for asthma Aerosols for delivery to systemic circulation droplet or particle size is critical
Gaseous diffusion of anesthetics depends on: (3)
solubility in blood
drug concentration
ventilation
____ _____, not concentration, in blood determines delivery to CNS.
Partial pressure
____ soluble anesthetics have faster rise in arterial partial pressure and equilibrate with tissues faster.
Less
The fraction (percentage) of the administered dose that reaches the systemic circulation is called _____.
Bioavailability
What factors affect bioavailability? (3)
Dissolution in gastrointestinal fluids Absorption
First pass metabolism in liver
____ ____ can vastly affect drug distribution by binding to the drug.
Plasma proteins
Apparent volume of drug distribution: Formula? Units?
amount of drug (mg) plasma concentration (mg/ml)
liters
The apparent volume of drug distribution can be much lower than body volume if drug is sequestered in compartment other than blood. True or false?
false
higher than body volume
KNOW! What is used to determine the dose required to achieve desired plasma concentration (single or loading dose)?
apparent volume of distribution
Most drugs bind to ____ which is ____ ____.
albumin
plasma proteins
Basic drugs tend to bind to ____-acid _______
alpha-1
glycoprotein
What is an acute phase protein that rises in the blood during inflammation?
alpha-1 acid glycoprotein
Which of the following is false regarding binding to plasma proteins? Only free drug crosses membrane and is pharmacologically active Slows onset of drug action: slows rate of equilibration with e/c fluids and can reduce amount of drug available for equilibration Tends to increase Vd (app)
tends to decrease Vd (app)
What factors affect drug distribution (cellular reservoirs)? (3)
Fat–lipid-soluble drugs Bones/teeth–metals form insoluble phosphates
Increased Vd,
biological half-life
Rapid anesthesia due to rapid entry into brain (2)
Blood flow Crosses bbb easily
Three phases of propofol PK Redistribution phase (~___ min) Rapid metabolic clearance (~___ min) Slow phase (____ hr) elimination from poorly perfused tissues
3
45
3-4 hours
Amount of drug excreted = glomerular filtration + ___________ - ___________
tubular secretion tubular reabsorption
______ _______ (units of ____) is volume of plasma from which drug is fully removed per unit time
Renal clearance ml/min
Only _____ drug (both non-ionized and ionized) is filtered
free
Influenced by: plasma protein binding volume of distribution blood pressure and blood flow
GFR
Tubular reabsorption of sodium, water, creates a _________ _____ of drug.
concentration gradient
Drug reabsorption occurs via ______ diffusion, primarily in ______ _____ and _____ _____.
passive
distal tubule and collecting duct
_____ soluble, less polar drugs (unmetabolized) are ______.
Lipid
reabsorbed
______ drug is _____ in urine
Ionized
excreted
______ _____ of pH of the renal filtrate in drug overdose toxicity acidic drugs: enhanced excretion in alkaline urine (NaHCO3)
Therapeutic modulation
_____ transport of drug from the blood into the renal tubular filtrate
Active
Specific acid and base transport systems occur in the ________ tubule
proximal
Biliary and fecal excretion (2)
Enterohepaticcirculation Prolongs duration of drug action
