Basic Principles of Pharmacology III

Question 1

Volume of Distribution

Answer 1

• Vd = Dose/Concentration in plasma
• extracellular fluid- plasma + interstitial fluid
• total body water - plasma + interstitial + intracellular
• you know how much dose you gave and then you measure the plasma concentration by blood sample and you get the average Vd

Question 2

Volume of Distribution in different body compartments

Answer 2

• drug remains in plasma, Vd=3 L
• drug permeates extracellular fluid, Vd= 12L
• drug permeates total body water, 40 L
• actual volumes of distribution vs apparent volumes of distribution
• high plasma protein binding- so it stays in the plasma and is only 3L volume distribution when we expected 12
• high degree of tissue binding, drugs highly lipid soluble, Vd >40

Question 3

Factors affecting distribution

Answer 3

• blood flow- drugs will distribute first to the more vascular organs with higher blood flow
• ability of drug to enter a fluid space- pH, binding, transport, lipid solubility
• time after administration- equilibrium with various compartments may take a long time to achieve
• redistribution- drug may have to distribute from initial compartments to the target tissue
• size of the patient- Vd can vary with the size of the patient- many drugs are dosed on the basis of weight or body surface area, especially in Peds or chemo

Question 4

Placenta and drug distribution

Answer 4

• no barrier to drugs that are <1000 in molecular weight or lipid soluble
• fetal liver and kidney are immature
• teratogenic effects- especially in first trimester, abnormal tissue differentiation
• toxic effects- may be chronic or acute, chronic- addiction, birth weight, specific organ abnormalities, acute- respiratory depression, hyperbilirubinemia, vascular problems
• avoid unnecessary drugs during pregnancy
• use time tested drugs when necessary

Question 5

Blood brain barrier

Answer 5

• an anatomical protective barrier, created by the existence of tight junctions between the capillary endothelial cells and also between the choroid plexus cells in the ventricles
• to enter the CNS a drug must be lipid soluble or transported by a carrier mediated mechanism
• charged particles are trapped in the capillary

Question 6

Consequences of BBB

Answer 6

• can affect apparent drug potency
• may need to use lipid soluble precursors of the active drug
• will create special problems in treating overdoses of lipid soluble or electrolyte drugs
• may necessitate the direct injection of certain drugs into the CNS
• charging drug distribution by pH manipulation
• overdose with CNS toxicity

Question 7

Weak acid drug overdose

Answer 7

• too much aspirin or barbiturates
• the HA is neutral and can go into the brain where it does to H+ and A- which is toxic, give HCO3 bicarb to favor HA to go to plasma and A- can be excreted

Question 8

Weak base drug overdose

Answer 8

• decreasing plasma pH
• RN2 add to H+ and get to toxic RNH3+ in brain
• if you add acid to plasma you can shift equilibrium to get RNH3+ that can be excreted

Question 9

Protein Binding of Drugs

Answer 9

• only free drug can interact with receptor
• to albumin, other plasma proteins or tissue sites
• can change the apparent Vd- larger if tissue binding occurs, smaller if plasma protein binding occurs
• can result in unexpected drug toxicities- act as reservoirs of active drugs
• drug storage: may need to fill the storage sites before enough free drug is available to interact with receptor- eg loading dose
• short term- protein binding, long term- lipid binding or bone

Question 10

Potential Adverse Drug Interactions

Answer 10

• drug displacement= more free drug at receptor = greater pharmacologic response
• one drug is administered and absorbed into the blood stream
• some fraction of the administered dose is bound to plasma protein while the remainder is unbound or free
• unlike the protein bound drug, the free drug molecules are able to cross the capillary membrane and exert a pharmacological effect at a tissue site