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86 Cards in this Set

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Drug is borne by ? to the site of ?.
Drug is borne by blood (via blood vessels) to the site of action.
? pumped by heart per minute (?) is important.
The volume of blood pumped by heart per minute (cardiac output) is important.
What is cardiac output equivalent to?
Cardiac output = stroke volume X heart rate
At rest, average cardiac output is what? What is this due to?
At rest, avg cardiac output (due to 69 left ventricle contractions per minute) is 5.5L per minute.
What is blood pressure equivalent to?
Blood pressure = cardiac output X peripheral resistance
Left ventricle contraction produces a systolic blood pressure of ?, and moves blood at ? through the aorta.
Left ventricle contraction produces a systolic blood pressure of 120mmHg, and moves blood at 300mm/sec thru the aorta.
In a 70 kg adult what is the intracellular water volume?
27
What is the interstitial water volume in a 70kg adult?
12
What is the plasma water volume in a 70kg adult?
3
What is the blood cell water volume in a 70kg adult?
2
What is the total blood volume in a 70kg adult?
5L
Name 2 factors affecting drug entry into tissues.
1. physicochemical nature of cell membranes

2. physicochemical properties of drug
List some aspects of the physicochemical nature of cell membranes that are factors affecting the entry of drug into tissues.
1. Protein + bi-layer of phospholipid

2. Under certain pathophysiological conditions (ex, burns and meningitis) permeability could change.

3. Unique features of tissue such as blood-brain barrier.
List some aspects of the physicochemical properties of drugs that are factors affecting the entry of drug into tissues.
1. Lipophilic drugs traverse cell membranes more easily than polar ones.

2. Small molecules traverse membranes more easily than larger ones or those forming drug-protein complexes.
How do most drugs enter cells?
Most drugs enter cells by way of spontaneous passive diffusion.
Passive diffusion is ? dependent and governed by ?. What is the rate of drug diffusion?
Passive diffusion is temperature dependent and governed by Fick's Law of Diffusion.

The Rate of drug diffusion:
dQ/dt = -DKA(Cp - Ct)/h
Give the rate of drug diffusion and define the variables?
dQ/dt = -DKA(Cp - Ct)/h

h = thickness
A = surface area of membrane
D = diffusion constant
K = lipid-water partition coefficient
Cp = drug concentration in plasma
Ct = drug concentration in tissue

Their is a negative sign because there is a net transfer of drug from the capillary lumen to the extracellular fluid and tissue.
What is hydrostatic pressure?
It is the pressure difference between capillaries entering and those leaving tissue.
Hydrostatic (filtration) pressure is caused by what?
Hydrostatic (filtration) pressure is caused by capillary blood pressure being higher than that of tissue at the arterial end.
What is hydrostatic pressure responsible for?
It is responsible for the transfer of water-soluble drugs penetrating spaces between endothelial cells.
When blood pressure of tissues is higher than venous capillaries what does it create?
It creates 'absorptive' pressure, so filtrate gets transferred to venous capillary.
What may distribution be limited by?
1. Flow limited (such as in congestive failure)

2. Diffusion limited (such as during inflammation when there is increased capillary permeability)
What is the first-order distribution constant for a drug into an organ?
Kd = Q/VR

Kd = distibution constant
Q = blood flow to the organ
V = volume of the organ
R = ratio of drug concentration in the organ to that in the venous blood
The ratio of drug concentration in the organ to that in venous blood (R) may be estimated from what?
R may be estimated from the oil/water partition coefficient (Po/w).
A drug with a high oil/water partition coefficient (Po/w) will have a ? ratio of drug conc. in the organ to that in venous blood (R).
A drug with a high Po/w will have a high R.
A large blood flow (Q) ? distribution time. A large volume (V) ? distribution time.
A large blood flow (Q) decreases distribution time; a large volume (V) increases distribution time.
What is the formula for the first-order distribution half-life?
td1/2 = 0.693/kd
What does R indicate?
R = ratio of drug concentration in the organ to that in the venous blood.

It indicates the extent to which an organ accumulates a drug.
What does a high R indicate?
A high R (due to either protein binding or high solubility of the drug in the tissue) means it takes longer for distribution to complete. (ex. flutamide, digoxin)
A high level of accumulation in tissues results in what?
A high level of accumulation in tissues results in a long elimination half-life (ex. etretinate, DDT); plasma levels may not correlate well with pharmacodynamic action if tissue is target tissue.
Name 4 mechanisms of accumulation.
1. Dissolution in lipids

2. reversible binding to biomolecules (ex. protein, melanin, calcium)

3. Irreversible binding to biomolecules (ex. in chemotherapy purine/pyrimidine drugs that bind to nucleic acids)

4. Enzymatic or active transport systems.
Any undetected source that reduces the plasma drug concentration increases what?
Any undetected source that reduces the plasma drug concentration increases the apparent volume of distribution.
Give two examples of sources that may reduce the plasma drug conc; thus increasing the apparent volume of distribution.
Sources may include:

1. Binding to proteins within tissues

2. Binding of metabolites to tissues following metabolism of drug
What may be an indication of a reduction in plasma drug concentration that increases the apparent volume of distribution?
A Vd greater than combined plasma volume and body water indicates that this could be the situation.
When might an irreversible binding of a drug to a protein sometimes occur?
Irreversible binding to protein sometimes occurs when an activated form of a drug attaches to a protein via a covalent bond (ex. acetaminophen hepatoxicity, chemical carcinogenesis)
Which is more typical, reversible or irreversible binding?
Reversible binding is more common.
What is reversible binding usually due to?
Reversible binding is usually due to weak bonds such as hydrogen bonds and van der waals bonds.
Are protein-bound drugs active?
Protein-bound drugs are usually not active pharmacologically?
What are protein bound drugs unable to cross?
Protein-bound drugs are unable to cross cells or cell membranes.
Drug-protein binding may be ?: There can be ? in protein binding. (ie, ?)
Drug-protein binding may be allosteric: There can be cooperativity in protein binding (ie, binding of first drug molecule can affect the binding of successive molecules to the same protein molecule)(ex, O2 binding to Hb)
List 5 factors affecting protein binding.
1. Drug properties

2. protein properties

3. Drug-protein affinity: Ka

4. Drug-Drug interactions

5. Disease condition of the patient
Generally speaking, what are the drug properties that affect protein binding?
The physicochemical properties and quantity of drug in the body.
Generally speaking, what are the protein properties that affect protein binding?
The physicochemical properties and quantity of protein available for binding.
The variable associated with the drug-protein affinity that may affect protein binding?
Ka
What drug-drug interaction may affect protein binding?
1. Competition for binding sites.

2. The binding of one drug alters the affinity of protein for another drug.
How may a disease condition for a patient affect protein binding?
It may reduce blood-protein binding (ex. hepatic disease)
List some of the blood proteins involved in drug protein binding?
1. Albumin

2. Alpha1-acid glycoprotein

3. Lipoproteins
What is the mw of albumin?
65kDa
What is albumin largely responsible for?
It is largely responsible for maintaining the osmotic pressure of blood.
What might bind to albumin?
1. Weak acidic drugs (like salicylates and penicillin)

2. Free Fatty Acids

3. Bilirubin

4. Some hormones (like cortisone and thyroxine)
Albumin has ? binding sites for which different drugs ?.
Albumin has several binding sites for which different drugs compete.
Name some drugs that compete for binding site I of albumin?
Sulfonamides, phenytin, valproic acid and phenylbutazone compete for binding site i.
Name some things that compete for binding site II of albumin?
Medium chain fatty acids, probecinid, benzodiazepines, and some penicillins compete for binding site II.
The blood protein alpha1-acid glycoprotein is aka what?
AAP or orosomucoid
What is alpha1-acid glycoprotein?
It is a globulin.
What is the mw of alpha1-acid glyoprotein?
44kDa
What drugs might bind to AAP?
Many basic drugs bind to AAP. Such as propranolol or lidocaine.
Globulins (like AAP) (alpha, beta, and gamma) have a ? ? and ? ? for endogenous substances such as ?.
Globulins have a high affinity and low capacity for endogenous substances such as corticosteroids.
What is the mw of lipoproteins?
Range, 200-3400kDa.
Give 3 examples of lipoproteins?
1. VLDL (very low density ")

2. LDL (low-density)

3. HDL (high-density)
What do the lipoproteins do?
They bind to and transport plasma lipids to the liver.
Give an examples of an immunoglobulin blood protein that is involved in drug protein binding?
IgG
Some drugs bind ? to RBCs. What does this mean?
Some drugs bind strongly to RBCs. For such, the hematocrit influences the total amount of drug in the blood. Binding to albumin reduces binding to RBCs.
What does the variable fu represent?
Unbound drug fraction
Generally speaking drugs with little ? ? ? have large fu (unbound drug fraction). What does this mean?
Generally drugs with little plasma protein binding have large fu (unbound drug fraction). So they diffuse more into tissues and so have a large Vds.
High protein binding in blood ? ? to targets of action in tissues?
High protein binding in blood reduces penetration to targets of action in tissues.
What does the variable fut represent?
Unbound drug fraction in the tissue.
The volume of distribution, fu and fut should only be measured when?
They should only be measured under equilibrium conditions. (when drug concentrations between the plasma and tissue equilibrate)
For drugs excreted mainly by filtration in the kidney, as plasma protein binding increases, so does what else?
The elimination half-life.
For drugs eliminated by active renal secretion, the elimination half-life can be ? even with high protein binding.
The elimination half-life can be short even with high protein binding. (Recall secretion preferentially strips blood protein of drug)
For drugs eliminated by both renal and biliary secretion what is there poor correlation between?
There is poor correlation between plasma protein binding and clearance.
What does clearance equal?
Cl = kVd
In relation to Vd and Cl what does t1/2 equal?
t1/2 = 0.693(Vd/Cl)
What does a high Vd ensure?
A large Vd may assures a long t1/2 but a low Vd may also assure a long t1/2 (?)
What does non-restrictively eliminated mean?
A non-restrictively eliminated drug (like propranolol) are eliminated even when they are protein bound.
For non-restrictively eliminated drugs elimination is not exclusively what?
It is not exclusively hepatic.
What does restrictively eliminated mean?
Restrictively eliminated drugs (like phenylbutazone and piroxicam) generally have small hepatic extraction ratios (ER<fu) and do not have first pass effects.
What is the law of mass action?
The rate of a chemical reaction is proportional to the product of the concentrations of the reactants.
What does the variable r represent?
The moles of bound drug/total moles of protein.

r = [PD]/([PD] + P)

PD = drug-protein complex
Can a protein have more than one kind of binding site for a molecule.
yes (ex. binding of salicyclic acid to albumin)
What does the dissociation constant (kd) equal?
kd = 1/ka
What is a double reciprocal plot?
1/r against 1/[D].

It gives a slope of 1/nKa and a y-int. or 1/n.

Since both r and [D] can be determined, ka may be calculated.

Slope = 1/nKa
What is a scatchard plot?
r/[D] vs r
What is the slope of a scatchard plot?
-ka
What would a non-linear scatchard plot indicate?
Suggest complexities exist, like there could be more than one type of binding site.
At constant protein levels, what happens to all available binding sites?
They get bound even at low drug concentrations. At low drug concentrations the fraction of bound drug is high. After saturation free drug levels rapidly increase.