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Foundations To Medicine 2 > Pharmacokinetics > Flashcards

Pharmacokinetics Flashcards

1
Q

What are the main use of pharmacokinetics ?

A

A drug should be able to reach its site of action after administrstion

In few situations a drug is directly applied to its target tissue
Example: topical application of an anti-inflammatory agent to inflamed skin

-Much more commonly, a drug is given into one body compartment, e.g. the gut, and must move to its site of action in another compartment, e.g. the brain

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2
Q

If a drug is given orally to produce an effect in the CNS, what are the barriers to include?

A
  • the wall of intestine
  • The walls of capillaries that perfume the gut
  • The blood-brain barrier

And after bringing about its effect, the drug should be eliminated

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3
Q

What are the methods of drug permeation?

A
  • Aqueous diffusion( paracellular pathway)
  • Lipid diffusion(transcellular pathway)
  • Special carriers
  • Endocytosis & exocytosis (transcytosis)
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4
Q

Summarize drug absorption

A

Absorption= transfer of a drug from its site of administration to the bloodstream

  • The rate and efficiency of absorption depend on the route of administration
  • For IV delivery, absorption is complete: the total dose reaches systemic circulation
  • Drug delivery by other routes may result in only partial absorption
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5
Q

What are the enteral routes?

A

Oral

Sublingual

Rectal

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6
Q

What is the oral route?

A

Maximum convenience, but absorption may be slower and less complete than with parenteral routes

-Ingested drugs suffer first-pass effect: a fraction of the drug is metabolized in the gut wall and the liver before reaching systemic circulation

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7
Q

What is the sublingual route?

A

The drug enters systemic circulation directly. The drug bypasses first-pass effect

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8
Q

What is the rectal route?

A

Partial avoidance of the first-pass effect

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9
Q

What are the parenteral routes?

A
  • intravaneous
  • Intramuscular
  • Subcutaneous
  • Intradermal
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10
Q

What are the other routes, aside from enteral, and parenteral routes?

A
  • Oral inhalation
  • Nasal inhalation
  • Topical
  • Transdermal
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11
Q

What are the factors that influence drug absorption?

A
  • Effect of pH on drug absorption
  • Surface area available for absorption
  • Blood flow to absorption
  • Contact time at absorption surface
  • P-Glycoprotein
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12
Q

What is the effect of pH on drug absorption?

A

Most drugs are weak acids or bases that are present in solution as both the nonionized and ionized species

The nonionized molecules are usually liposoluble and can diffuse through the cell membrane

-The ionized molecules are usually unable to penetrate the lipid membrane because of their low liposolubility

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13
Q

Summarize the ionization of weak acids

A

For a weak acid the ionization. Reaction is:

HA —> A- + H+

The uncharged form HA (ie the protonated form) will permeate through membranes

The charged form A- (ie the unprotonated form) will not

Example:

R-COOH —> R-COO- + H+

Weaj acids diffuse the phospholipid bilayer in the HA state

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14
Q

Summarize the ionization of weak bases

A

For a weak base the ionization reaction is:

BH+ —> B + H+

The uncharged form B (ie the unprotobated form) will penetrate through the cell membrane

-The charged form BH+ (ie the protonated form) will not

Example:
R-NH3^+ —> R-NH2 + H+

Weak bases diffuse across the phospholipid bilayer in the unprotonatef form (B)

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15
Q

Summarize pH effect on drug absorption

A

The protonated form of a weak acid is the more liposolubke form

The unprotonated form of a weak base is the more liposolubke form

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16
Q

What is the purpose of Henderson-HasselBach equation?

A

The ratio between the protonated and unprotonated forms is a function of the pH and of the pK of the ionizable group

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17
Q

What is the Henderson hassalbach equation?

A

pH-pK= log[unprotonated form]/[protonated form]

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18
Q

According to the Henderson hasselbach equation, what happens when pH= pK?

A

When pH= pK, [unprotonated]= [protonated]

For each unit of pH above the pK, the [unprotonated] will be ten times the [protonated]

For each unit of pH below the pK, the [protonated] will be ten times the [unprotonated]

19
Q

What is ion trapping?

A

The most important application of this equation(H-H) is in the manipulation of drug excretion by the kidney

If a drug is in a liposoluble form during its passage down the renal tubule, a significant fraction will be reabsorbed by passive diffusion

If the goal is to accelerate excretion of the drug, it’s important to prevent its reabsorption from the tubule

This can be accomplished by adjusting urine pH to ionize the drug

As a result the drug will be trapped in the urine

Weak acids are excreted faster in alkaline urine; weak bases are excreted faster in acidic urine

Most drug absorption occurs at the small intestine because of its large surface area

20
Q

Why is the absorption favored in the small intestine over the stomach?

A

Blood flow to the intestine is much greater than the flow to the stomach: absorption from the intestine is favored over that from the stomach

21
Q

How does contact time affect absorption surface?

A

If a drug moves through the GI tract very quickly, as in severe diahhrea, it is not well absorbed

22
Q

What is the P-Glycoprotein?

A

P-Glycoprotein (MDR1) is a transporter protein responsible for transporting several drugs across cell membranes

P-glycoprotein reduces drug absorption

23
Q

What is bioavailability(F)?

A

Fraction of administered dose of a drug that reaches the systemic circulation

24
Q

What is the determination of bioavailability?

A

By plotting plasma concentrations of the drug vs. time, the area under the curve (AUC) can be measured

Bioavailability is determined comparing the AUC after a particular route of administration with the AUC after IV injection

  • The AUC reflects the extent of absorption of the drug
  • For drugs administered IV, bioavailability is 100% by definition
25
Q

How is bioavailability calculated?

A

F= (AUC oral)/(AUC IV) x 100

26
Q

What is drug distribution?

A

The process by which a drug leaves the blood stream and enters the extracellular fluid and/or the cells of the tissues

27
Q

What are the factors influencing drug distribution ?

A

The amount of drug distributed into tissues is mainly determined by:

  • Blood flow
  • Drug binding to plasma proteins
  • drug tissue binding
  • Drug liposolubility
28
Q

What organs get most of the drug?

A

Initially, liver, kidney, brain, and other well perfumed organs receive most of the drug

Delivery to muscle, most viscera, skin, and fat is slower

29
Q

Describe drug binding to plasma proteins

A
  • Many drugs circulate in the bloodstream bound to plasma proteins
  • Reversible binding to plasma proteins slows distribution from the blood to other tissues
30
Q

Summarize drug tissue binding

A
  • Many drugs accumulate in tissues
  • Many liposoluble drugs accumulate in fat
  • Accumulated drug May serve as a reservoir that prolongs drug action
31
Q

What is a drug liposolubility?

A

Drug liposolubility is a major factor affecting drug distribution, particularly to the brain, where the blood-brain barrier restricts the penetration of polar molecules

Drug penetration into the brain depends on transcellular rather than paracellular transport

32
Q

What is the blood-brain barrier ?

A
  • The endothelial cells of the brain capillaries have continuous tight junctions
  • Astrocytic “end feet” surround the outside of capillary endothelial cells
  • The P-glycoprotein actively transports drugs back into the systemic circulation

To enter CNS the drug has to be highly liposoluble or have an active transporter

33
Q

What are the two methods of drug elimination ?

A
  • Metabolism

- Excretion

34
Q

Why can many drugs diffuse across cell membranes?

A

Many drugs are Lipophilic

  • This property enables drugs to pass cell membranes and gain access to their site of action
  • But Lipophilic compounds are not easily excreted because they are reabsorbed through the tubular membranes
35
Q

When the metabolism of drugs are more hydrophilic in their metabolites, what are these essential for?

A
  • Termination of their biological activity

- Their elimination from the body

36
Q

Describe the general metabolites of drugs

A

In general, metabolism generates more polar, inactive metabolites that are readily excreted from the body

However, in some cases, metabolites with potent biological activity or even toxic properties are generated

37
Q

What are the sites of drug metabolism?

A

The liver is the main organ of drug metabolism

  • This fact figures prominently in the phenomenon known as the first-pass effect
  • The liver is quantitatively the most important organ in metabolizing drugs
  • But every tissue in the body is capable of drug metabolism to some degree
  • Particularly active sites include the GI tract, the kidneys, the skin, and the lungs
  • The GI tract also contributes to the first-pass effect
38
Q

What is the cytochrome P450 system?

A
  • Enzymes of the cytochrome P450 system, are responsible for the metabolism of 80% of all drugs in clinical use
  • The cytochrome P450 is a superfamily of heme proteins present in bacteria, fungi, insects, plants, fish, and mammals
39
Q

What is enzyme induction on the CP450?

A

Some cytochrome P450 are inducible

  • P450 enzyme induction typically occurs via increased transcription
  • Certain drugs increase the synthesis of one or more P450 isoforms

Examples are:
-Rifampin

  • Phenobarbital
  • Carbamazepine
40
Q

How do drugs enter hepatocytes?

A

Drugs can enter hepatocytes and bind to xenobiotic receptors

-This activates the receptor, allowing it to translocate to the nucleus and bind to the promoters of various enzymes

41
Q

What are the clinical consequences of induction ?

A

Induction has important clinical consequences

  • A drug can increase its own metabolism
  • A drug can increase the metabolism of a coadministered drug
  • This May reduce drug plasma concentrations below therapeutic levels
42
Q

What are the typical examples of drugs that inhibit cytochrome P450?

A
  • Cimetidine
  • Erythromycin
  • Chloramphenicol
  • Grapefruit juice
43
Q

What happens when the enzymes that metabolize drugs are inhibited?

A

The metabolism of drugs that are metabolized by the inhibited enzyme will decrease

Drug levels may reach toxic concentrations

Example: grape juice inhibits felodipine metabolism

44
Q

What is the most common method of drug excretion ?

A

The reactions of metabolism enhance the hydrophilicity of drugs and their metabolites, enabling them to be excreted

  • Renal excretion is the most common mechanism of drug excretion
  • A small number of drugs are excreted in the bile

Foundations To Medicine 2 (37 decks)

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