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Flashcards in Pharmacokinetics Deck (34):

What determines the rate of a drug entering the site of action?

1) Absorption- movement of drug from the site of administration to the blood
2) Distribution- delivery of drug from the blood to the tissues and target site(s)


Why are ionized drugs not well absorbed?

The degree of ionization will affect the partition coefficient and therefore the extent of diffusion.


What does a larger pKa indicate for an acid?

The larger the pKa the weaker the acid (opposite is true for bases).

Remember that compounds ionize at the opposite pH. Acids ionize at basic pH (vice versa). In an overdose, sample for acidic drugs in the blood (basic) and basic drugs in the stomach (acidic).


Name 7 mechanisms of drug transport across a membrane.

1) Passive diffusion
2) Filtration
3) Bulk flow
4) Active transport
5) Facilitated transport
6) Ion-pair transport (forms a complex with an ion to cross the membrane)
7) Endocytosis


What is the partition coefficient?

Partition coefficient is the ratio of concentrations of a compound in the two phases of a mixture of two immiscible liquids at equilibrium.

It is essentially a measure of how hydrophilic/hydrophobic a drug is.


Describe the properties of oral drug absorption.

- High blood supply
- High absorption of drugs that have a high partition coefficient (lipophilic/hydrophobic)
- Drug absorption is 4x faster in the mouth than in GI and transit time is fast.


Describe the properties of sublingual drug absorption.

- High absorption => dissolved in saliva and then passed into a highly vascularized sublingual area
-Bypasses the GI and goes directly to the blood stream


Describe the properties of drug absorption in the stomach.

*Primary function is NOT absorption*
- Only weak acids are absorbed (most drugs are weak bases)
- Can get "ion trapping" of weak bases that are absorbed back from the blood, into the stomach in the non-ionized form and are then ionized and poorly reabsorbed


Describe the properties of drug absorption in the small intestine.

- Large surface area, single layer of cells, rich and high volume blood supply
- Most drugs are absorbed in the proximal jejunum
- Most drugs are transported by passive diffusion, so pKa of drug and pH of lumen are critical
- If the transit time is decreased then absorption is limited


Describe the properties of drug absorption in the large intestine.

- Less absorption than the small intestine (decreased surface area, less vascularized, increased solid luminal contents)
- Rectal suppositories are useful for patients with emesis, GI surgery/obstruction, uncooperative (children) or unconscious, or to avoid hepatic metabolism


List factors that affect GI absorption.

- Gastric emptying time
- Intestinal motility
- Food composition
- Formulations of drugs
- Metabolism and digestion


Describe the properties of drug absorption in the lung.

- Inhaled gases, anesthetics, aerosols, smokes, dusts, etc
- Large surface area, thin cell layer, highly vascularized, large blood flow
- High partition coefficient => lipophilic/hydrophobic
- Anesthetics cross very easily, difficult to remove
- Toxicants can easily enter the body through the lung


Describe the properties of drug absorption via the skin.

- Local absorption instead of systemic dosing due to slow diffusion
- Slow diffusion can be utilized for long term dosing (skin patches-nicotine)
- Many toxins can enter through the skin or can be carried by solvents, soaps, etc though skin
- Highest absorption via eyes/scrotum; lowest via hands/feet


Describe the properties of intramuscular/subcutaneous drug absorption

- Advantages => rapid, precise, large volumes, does not have the complications of IV
- Disadvantages => painful, causes tenderness, local tissue necrosis, possible microbial contamination, and nerve damage


Describe the properties of intravenous drug absorption/

- Advantages of IV => direct to blood, so circumvents entire absorption process. useful for drugs with narrow therapeutic index, poor absorption, or problems with metabolism. This is an extremely rapid method of transport
- Disadvantages of IV => in the case of overdose, cannot remove drug or block/slow absorption. There is a risk of embolism, microbial contamination, local necrosis, or immune reaction if too concentrated or rapid delivery.


What are the factors that influence drug distribution (6)?

1) Capillary permeability
2) Blood flow to tissue mass ratio (perfusion rate)
3) Regional differences in pH
4) Transport mechanisms available
5) Extent of plasma protein binding => most drugs are bound reversibly to plasma protein but only unbound drugs can pass through capillaries and membranes, be metabolized, and have pharmacological effect
6) Permeability characteristics of specific tissue membrane


What is the most important protein for drug binding?

Albumin is the most important protein for drug binding. It is present in high concentrations and has a net negative charge. Albumin can bind hydrophobic drugs at lipophilic sites (high partition coefficient). Albumin's binding sites are non-specific so many drugs can bind and compete for binding.


Describe the selective accumulation of drugs in the kidney.

Kidney has a CO of 20-25% and is therefore susceptible to drug toxicity.


Describe the selective accumulation of drugs in the eye.

Melanin (retinal pigment) can bind drugs


Describe the selective accumulation of drugs in fat.

Fat can accumulate drugs with high partition coefficients but due to low blood flow drugs are slow to enter/exit fat. However, during fasting fat can release drug boluses/toxin stores => essentially a sink for drugs


Describe the selective accumulation of drugs in the lung.

The lung has 100% CO and can selectively accumulate basic amines.


Describe the selective accumulation of drugs in bone/teeth.

Drugs are absorbed into the crystal matrix. Permits slow entry and release of drugs.


Which drugs can pass the blood brain barrier?

Only high partition coefficient (lipophilic), non-ionized free drug can pass through cells at the blood brain barrier. Inflammation can increase permeability and leave the brain susceptible to toxicants.


What are the limitations presented by the blood testis barrier?

Like the blood brain barrier, the blood testis barrier has tight capillary junctions that can impede therapy => cancer chemotherapy for testicular and germ cell cancers.


Which drugs pass through the placental barrier?

The placental barrier is not really a barrier. High partition coefficient drugs can readily pass through the placenta and it should be assumed that the dose of the drug given to the mother is what is given to the fetus.


Define pharmacodynamics.

Pharmacodynamics is what the drug does to the body.


Define pharmacokinetics.

Pharmacokinetics is what the body does to the drug.


What is the one compartment model?

The simple one compartment model assumes that:
- The body is a single homogenous fluid filled compartment.
- An IV administration results in an instantaneous release of drug into the compartment
- The drug is instantaneously distributed homogeneously in the compartment
- The drug is eliminated primarily by metabolism (liver) and/or physical removal (kidney)


What is the multi-compartment model?

The multi-compartment model demonstrates that:
- Many drugs are modeled poor by one compartment and require two+ compartment sot model their pharmacokinetic behavior.
- Examples: 1) drugs that are distributed rapidly to highly perfused tissues and more slowly to other tissues and 2) drugs that are metabolized rapidly or very slowly


What type of kinetics does drug elimination follow?

Elimination usually follows first order kinetics=> a constant fraction of drugs is removed by elimination per unit time

If the route of elimination is saturated, it can follow zero order kinetics => where a constant amount of drug is removed/unit time.


What is T1/2?

T1/2 is the time it takes to decrease a given concentration in the blood by half either through elimination from the body or movement to another compartment.

T1/2 =ln2/K=0.693/K ; where K is the elimination constant

T1/2 is dependent on clearance and the volume of distribution.


What is the primary factor that defines elimination rate?

Clearance is the primary parameter that defines the elimination rate.

Clearance = Elimination constant x Volume of distribution
(Cl =K x Vd)

To assess clearance in patients, relative renal excretion of most drugs correlates well with creatinine clearance (24hrs)


What is the Area Under the Curve (AUC) and how do we interpret it?

The AUC is the space underneath the curve in a drug's blood concentration vs time graph. A drug's AUC and graphically shape represent a ratio of the amount of drug in circulation and the clearance of the drug

For accurate dosing a drug's fractional dose should be determined:
F = AUC (oral)/AUC (IV)


In chronic administration how long does it generally take to reach steady state at a constant infusion rate?

It takes approximately about 4 half lives to reach steady state at a constant infusion rate.

Steady state concentration is dependent on the infusion rate, Ko, and clearance.

Note that time to steady state is independent of dose and depends on only the rate of elimination K(el)

Loading dose = steady state concentration x distribution volume