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Flashcards in Pharmacology III Deck (8)
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1
Q

What is distribution?

A
  • Transfer of drugs from the bloodstream to tissues around the body
2
Q

How are drugs distributed in the body?

A
  • “Compartments” in the body, such as tissues and fluids, determine the rate at which drugs are taken up or cleared out (these rates can be calculated mathematically)
  • Movement between compartments allow drugs to be distributed
3
Q

What factors affect distribution?

A
  • Physicochemical properties of the drug, including pKa, lipid solubility, molecular weight, etc.
  • Concentration gradient between blood and tissues, which results from bulk flow in the capillaries and simple diffusion
  • Ratio of blood flow to tissue mass, which can result from surface area for drug transfer into tissues
  • Affinity of the drug to bind to proteins and other molecules in the blood
4
Q

What are some physiological determinants that affect distribution?

A
  • Body fluids account for 60% of the body, intracellular fluids are 40%, extracellular are 20%, interstitial fluid 13%, blood (plasma) 6%,
  • Fat and transcellular fluid also are compartments
  • Distribution affects the plasma drug concentration (Apparent Vd (L/kg) is the apparent volume of drug needed to disperse the drug throughout the body evenly at the concentration found in plasma
  • A high amount of blood flows to the brain/ kidney/ endocrine organs, intermediate flow to the liver/ skin/ muscle, low to bone/ fat/ muscle (variably)
  • Some drugs have more affinity for some organs more than others (iodine to thyroid, aminoglycosides to kidney)
5
Q

What are the tissue barriers that affect Distribution?

A
  • Specialized barriers including the blood-brain barrier, ocular, prostatic, testicular, synovial, mammary, placenta
  • The different transcellular fluid compartments include CSF, intraocular, synovial, pericardial, pleural, peritoneal
6
Q

What are the importance of the tissue barriers in regards to drug distribution?

A
  • Selective transport mechanisms allow accumulation of a drug against its concentration gradient (e.g. active excretion of penicilin drugs into the urine)
  • Drug efflux transporters, including P-glycoprotein in the choroid plexus transports drugs out of the CSF into the blood and is part of the BBB, and the low concentrations of penicillin in the CNS due to an active organic anion transporter
  • The BBB Is composed of tight junctions and glial cells that require drugs to pass exclusively through cell membranes to enter, while CSF is continually drained and recycled to keep the brain clear of any toxins, and most substances are actively removed from the brain via P-gp
7
Q

What is the importance of Plasma Protein Binding

A
  • Plasma proteins can distribute drugs via binding to insoluble drugs, while soluble drugs can dissolve into solution, and erythrocytes/ lymph
  • Acidic drugs bind to albumin, while basic drugs bind to a1-acid-glycoproteins, beta-globulins, and others, and other molecules have specific drugs they bind to (iron to transferrin, etc), with the process of binding being mostly reversible
  • Bound drugs stay in the bloodstream and are inactive (unless there is blood vessel leakage)
  • Binding has the potential to be saturated (though not usually at pharmacological dose)
  • Can result in drug displacement (warfarin and phenylbutazone in horses)
  • The percentage at which drugs are bound to plasma protein varies between species, and other factors such as disease and age can affect it
  • When drugs are highly bound to plasma protein, minor changes to protein binding can cause major changes, as only the unbound drug is active (drug effects are based on the estimated protein binding
8
Q

What other factors can affect distribution?

A
  • Stereochemistry of drug/ metabolite
  • Tissue binding resulting in increased drug distribution (iodine)
  • Metabolic rate
  • Excretion rate
  • Redistribution (e.g. thiopental)