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Pharma midterm 1 > 4-7. PHARMACOKINETICS > Flashcards

4-7. PHARMACOKINETICS Flashcards

1
Q

what is PK?

A

PK is a branch of pharmacology dedicated to the determination of the fate of substances administered externally to a living organism.

It describes what the body does to a drug, the movement of drugs into, through, and out of the body.

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2
Q

What does ADME mean?

A

Pharmacokinetics is often divided into ADME.

  • Absorption is the process of a substance entering the body.
  • Distribution is the dispersion or dissemination of substances throughout the fluids and tissues of the body.
  • Metabolism is the transformation of the substances and its daughter metabolites.
  • Excretion is the elimination of the substances from the body. In rare cases, some drugs irreversibly accumulate in a tissue in the body.
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3
Q

What is the difference between pharmacodynamics and pharmacokinetics?

A

-Pharmacodynamics explores what a drug does to the body, pharmacokinetics explores what the body does to the drug.

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4
Q

List the drug passages:

A
  • *Transcellular transport:**
  • Across cell-membranes, layers or membrane-pores
  • Diffusion (passive or free)
  • Filtration
  • Facilitated diffusion
  • Active transport
  • Pinocytosis
  • *Intercellular transport
  • **across gaps

-filtration

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5
Q

A semipermeable membrane can also be called:

A
  • Selectivel permeable membrane
  • Partially permeable membrane
  • Differentially permeable membrane
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6
Q

What is the definition of a semipermeable membrane?

A

It is a membrane which allow certain molecules or ions to pass by simple diffusion and facilitated diffusion.

-Ex: plasma membrane surrounding cells, made by a lipid bilayer.

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7
Q

What is the passage through the semipermeable membrane depending on?

A

Depends on:

  • Pressure
  • Concentration
  • Temperature of the molecules
  • Solutes on either side
  • Permeability of the membrane to each solute
  • Permeability may depend on the solute size, solubility properties or chemistry.
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8
Q

What is haemodialysis?

A

Haemodialysis is a method of removing excess fluid, salt and wastes from the blood, effectively replacing the excretion functions of failed kidneys.

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9
Q

Explain:
1. diffusion of drugs

  1. the lipid-water partition coefficient
  2. Other factors influencing diffusion
A
  1. Diffusion of un-ionized drugs (only un-ionized drugs can diffuse, they are usually lipid soluble) is the most common and most important passage over biologic membranes.
    - The drugs diffuse passively and down their concentration gradient.
  2. Diffusion can be influenced by:
    - Lipid–water partition coefficient of the drug. It is the ratio of solubility in an organic solvent to solubility in an aqueous solution.

-In general, absorption increases as lipid solubility (partition coefficient) increases.

  1. Other factors influencing:
    - The concentration gradient of the drug across the cell membrane
    - thickness and surface area of the cell membrane
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10
Q

What are the degree of ionization of a weak acid or base determined by?

A
  • The pK of the drugand pH of its environment according to the Henderson-Hasselbalch equation.
  • When the pK of a drug equals the pH of the surroundings, 50% ionization occurs.
  • A lower pK reflects a stronger acid; a higher pK corresponds to a stronger base.
  • Drugs with different pK values will diffuse across membranes at different rates.
  • The pH of the biologic fluid in which the drug is dissolved affects the degree of ionization and, therefore, the rate of drug transport.
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11
Q

Define filtration:

A
  • Filtration is the flow of small solvent and solute through protein channels (aqueous pores=aquaporins) in the membrane. Concentration gradients affect the rate of filtration.
  • Some substances of greater molecular weight, like certain proteins can be filtered through intercellular channels.
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12
Q

Define facilitated diffusion:

A

-Facilitated diffusion is movement of a substance down a concentration gradient. Facilitated diffusion is carrier mediated, specific, and saturable; it does not require energy.

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13
Q

Explain active transport:

A
  • Active transport is an energy-dependent process that can move drugs against a concentration gradient, as in protein-mediated transport systems.
  • Active transport occurs in only one direction and is saturable. It is usually the mode of transport for drugs that resemble actively transported endogenous substances such as sugars, amino acids, and nucleosides.
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14
Q

Shortly describe absorption:

A
  • Absorption is the movement of a drug into the bloodstream.
  • Drugs need a route of administration where it is taken up by the mucous surface to ensure the uptake (oral, via the skin..+ and specific dosage form is needed (tablet, capsule…+)
  • In Intraperitoneal, intramuscular injections and parenteral nutrition the absorption changes less and bioavailability is often near 100%
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15
Q

What does bioavailability mean?

A

-Bioavailability is a subcategory of absorption and is the fraction of an administered dose of drug that reaches the systemic circulation.

It is expressed as the letter F.

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16
Q

Explain absolute bioavailibility:

A
  • Absolute bioavailability measures the availability of the active drug in systemic circulation after non-intravenous administration (i.e. after oral, rectal, transdermal, subcutaneous administration).
  • In order to determine absolute bioavailability of a drug, a pharmacokinetic study must be done to obtain a plasma drug concentration vs. time plot and area under curve (AUC) for the drug after both intravenous (IV) and non-intravenous administration.
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17
Q

What can cause problems for absorption?

A
  • Some natural barriers like the blood-brain barrier, placenta can cause problems.
  • Factors such as poor compound solubility, chemical instability in the stomach, and inability to permeate the intestinal wall can all reduce the extent to which a drug is absorbed after administration.
  • Absorption critically determines the compound’s bioavailability. Drugs that absorb poorly when taken orally must be administered in some less desirable way, like intravenously or by inhalation.
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18
Q

Explain relative bioavailability:

A

-This measures the bioavailability of a certain drug when compared with another formulation of the same drug, usually an established standard, or through administration via a different route. When the standard consists of intravenously administered drug, this is known as absolute bioavailability.

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19
Q

Various physiological factors reduce the availability of drugs prior to their entry into the systemic circulation, name these:

A
  • Poor absorption from the gastrointestinal tract or from application site
  • Degradation or metabolism of the drug prior to absorption or due to hepatic –> first-pass effect
  • Whether a drug is taken with or without food will affect oral absorption,
  • Other drugs taken concurrently may alter absorption and metabolism:- interactions
  • Intestinal motility alters the dissolution of the drug and may affect the degree of chemical degradation of the drug by intestinal microflora.
  • Disease states affecting liver metabolism or gastrointestinal function will also have an effect.
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20
Q

what are the routes of administration?

A
  • *Topical/external:**
  • On skin
  • On mucous membranes, eye, nose, mouth, rectum

Internal:
Enteral: oral
Parenteral:
-Application of injections - „injectable” drugs Injection sites: Frequently: intravenous, subcutaneous, intramuscular
Less frequently: cutaneous (intradermal), i.peritoneal, i.arterial, i.cardial, i.thoracal /pleural/, i.articular, i.medullar, i.osseal, i.cerebral, epidural, subarachnoideal, peri-neural, retrobulbar, i.lingual

Special routes for veterinary application:

  • Intramammary applications
  • Intrauterin infusion
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21
Q

What are the sites of absorption?

A
  • *Stomach:**
  • Lipid-soluble drugs and weak acids, which are normally un-ionized at the low pH of gastric contents, may be absorbed directly from the stomach.

-Weak bases and strong acids are not normally absorbed from this site, since they tend to be protonated at the pH of gastric contents. (Ion trapping – accumulation e.g. macrolides)

  • *Small intestine:**
  • *-**The small intestine is the primary site of absorption of most drugs because of the very large surface area across which drugs, including partially ionized weak acids and bases, may diffuse.

-Acids are normally absorbed more extensively from the small intestine than from the stomach, even though the intestine has a higher pH.

22
Q

Explain dissolution:

A
  • In the most standard situation, a tablet is ingested and passed through the gullet to the stomach.
  • Because the stomach is an aqueous environment, this is the first place where a tablet will dissolve.
  • The rate of dissolution is a key target for controlling the duration of a drug’s effect, and as such, several dosage forms that contain the same active ingredient may be available, differing only in the rate of dissolution.
23
Q

What happens if a drug is supplied in a form that is not readily dissolved?

A
  • If a drug is supplied in a form that is not readily dissolved, the drug may be released more gradually over time with a longer duration of action.
  • Having a longer duration of action may improve compliance since the medication will not have to be taken as often.
  • Additionally, slow-release dosage forms may maintain concentrations within an acceptable therapeutic range over a long period of time, as opposed to quick-release dosage forms which may result in sharper peaks and troughs in serum concentrations.
24
Q

Why do we use the Noyes-Whitney equation? (trenger vi dette?)

A
25
Q

What can alter the absorption from the GI?

A
  • Gastric emptying time and passage of drug to the intestine may be influenced by gastric contents and intestinal motility.
  • A decreased emptying time generally decreases the rate of absorption because the intestine is the major absorptive site for most orally administered drugs.
  • Gastrointestinal (GI) blood flow plays an important role in drug absorption by continuously maintaining the concentration gradient across epithelial membranes.
  • The absorption of small, very lipid soluble molecules is “blood flow limited,” whereas highly polar molecules are “blood flow independent.”
  • Stomach acid and inactivating enzymes may destroy certain drugs. Enteric coating prevents breakdown of tablets by the acid pH of the stomach.
26
Q

What are som factors that may alter the absorption?

A
  • Interactions with food, other drugs, and other constituents of the gastric milieu may influence absorption.
  • Ingredients in oral preparations or the special formulation of those preparations can absorption.
  • The first-pass effect (is a phenomenon of drug metabolism whereby the concentration of a drug is greatly reduced before it reaches the systemic circulation) influences drug absorption by metabolism in the liver or by biliary secretion.
  • After absorption, a drug must pass through the liver before reaching the general circulation and its target site.
  • If the capacity of liver metabolic enzymes to inactivate the drug is great, only limited amounts of active drug will escape the process. Some drugs are metabolized so extensively as a result of hepatic metabolism during the first pass that it precludes their oral use.
27
Q

Routes of administration: (picture)

A
28
Q

Parenteral administration includes three major routes:

A

intravenous (IV),

intramuscular (IM),

and subcutaneous (SC).

29
Q

Describe parenteral administration:

A
  • Parenteral administration generally results in more predictable bioavailability than oral administration.
  • With IV administration, the drug is injected directly into the Bloodstream, without absorption (100% bioavailable).
  • Most rapid introduction of drugs into the body and is useful in the treatment of emergencies when absolute control of drug administration is essential.
  • After IM and SC administration, many drugs can enter the capillaries directly through “pores” between endothelial cells.
  • Depot preparations for sustained release may be administered by IM or SC routes, but some preparations may cause irritation and pain.
30
Q

List the other significant routes of drug administration?

A
  1. Inhalation
  2. Intrathecal
  3. rectal
  4. sublingual - buccal
  5. topical
31
Q

Routes of drug administration - inhalation:

A
  • Inhalation results in rapid absorption because of the large surface area and rich blood supply of the alveoli. Inhalation is frequently used for gaseous anesthetics, but it is generally not practical. Inhalation may be useful for drugs that act on the airways, such as epinephrine and glucocorticoids, which are used to treat bronchial asthma.
32
Q

Routes of drug administration - intrathecal

A
  • Intrathecal administration is useful for drugs that do not readily cross the blood–brain barrier.
33
Q

Routes of drug administration- rectal

A
  • Rectal administration minimizes first-pass metabolism and may be used to circumvent the nausea and vomiting that sometimes result from oral administration.
34
Q

Routes of administration - sublingual-buccal

A
  • Sublingual - Buccal administration is useful for drugs with high first-pass metabolism, such as nitroglycerin, since hepatic metabolism is bypassed. (rarely applicable in veterinary medicines; e.g. uses of analeptics, sedatives)
35
Q

Routes of administration - topical

A
  • Topical administration is used widely when a local effect is desired or to minimize systemic effects, especially in dermatology and ophthalmology. Preparations must be non-irritating. Drugs administered topically may sometimes produce systemic effects.
36
Q

Explain distribution:

A
  • Distribution is a branch of PK which describes the reversible transfer of drug from one location to another within the body.
  • Often carried via bloodstream to its effector site.
  • Drug distribution - a drug leaves the bloodstream and enters the extracellular fluids and tissues, or is the moves from the bloodstream to the various tissues of the body.
  • From there, the compound may distribute into tissues and organs, usually to differing extents.
37
Q

What does the distribution of a drug between tissues depend on?

A

The distribution of a drug between tissues is dependent on:

  • permeability between tissues (between blood and tissues in particular),
  • blood flow and perfusion rate of the tissue
  • the ability of the drug to bind plasma proteins and tissue.
  • The volume of distribution (VD) of a drug is a property that quantifies the extent of distribution.
38
Q

How is the drug distributed if the site of action is intracellular?

A

The drug must diffuse across the cellular membranes, in this case - lipid solubility is improtant for the effectivness.

39
Q

Why is the blood flow important for drugs?

A
  • In most tissues, drugs can leave the circulation by diffusion across or between capillary endothelial cells.
  • Thus, the initial rate of distribution of a drug depends heavily on blood flow to various organs

brain, liver, kidney > muscle, skin > fat, bone

  • At equilibrium, or steady state, the amount of drug in an organ is related to the mass of the organ and its properties, as well as to the properties of the specific drug.
40
Q

Describe redistribution of a drug:

A

-When the relative distribution of a drug in the body changes with time. This is usually seen with highly lipophilic drugs such as thiopental that initially enter tissues with high blood flow (e.g., the brain) and then quickly redistribute to tissues with lower blood flow (e.g., skeletal muscle and adipose tissue).

41
Q

What are the factors affecting drug distribution:

A

Medicinal substance: Dose, application route

Rate of distribution: Membrane permeability, blood perfusion

Extent of distribution: lipid solubility, pH- pKa, plasma protein binding, intracellular binding

42
Q

Explain the binding of drugs by plasma proteins:

A

Drugs in the plasma:

  • as free form
  • bound to plasma proteins or other blood components (RBC)
  • Plasma protein binding is highly variable, it depends on the specific drug.
  • Binding is generally reversible.
  • Only the free drug diffuses through capillary walls; extensive binding slows down the time it takes for the drug to reach the site of action and prolongs the duration of action.
  • Some plasma proteins bind many different drugs, while other proteins bind only one.
  • For example, serum albumin tends to bind many acidic drugs, while α1-acid glycoprotein and globulins tends to bind many basic drugs.
43
Q

Which drugs (acidic agents) has their binding site on Albumins?

A

Bilirubin, Bile acids, Fatty Acids, Vitamin C, Salicylates, Sulfonamides, Barbiturates, Phenylbutazone, Penicillins, Tetracyclines, Probenecid

44
Q

Which drugs (base agents) has their binding site on Globulins?

A

Adenisine, Quinacrine, Quinine, Streptomycin, Chloramphenicol, Digitoxin, Ouabain, Coumarin

45
Q

Blood Perfusion Rate of different organs: (tabell)

A
46
Q

Percent Unbound for Selected Drugs : (tabell)

(binding of drugs by plasma proteins)

A
47
Q

What are the barriers to drug distribution?

A
  1. Blood-brain barrier
  2. Placental barrier
48
Q

Explain the Blood-brain barrier related to drug distribution

A

-Because of the nature of the blood–brain barrier, ionized or polar drugs distribute poorly to the CNS, including certain chemotherapeutic agents and toxic compounds, because they must pass through, rather than between, endothelial cells. - Inflammation, such as that resulting from meningitis, may increase the ability of ionized, poorly soluble drugs to cross the blood–brain barrier. - The blood–brain barrier may not be fully developed at the time of birth.

49
Q

Explain the placental barrier related to the drug distribution:

A

Lipid-soluble drugs cross the placental barrier more easily than polar drugs; drugs with a molecular weight of less than 600 pass the placental barrier better than larger molecules.

  • The possibility that drugs administered to the mother may cross the placenta and reach the foetus is always an important consideration in therapy.
  • Drug transporters (e.g., the P-glycoprotein transporter) transfer drugs out of the foetus.
50
Q

What is Volume of distribution (Vd)?

A

It is the volume of total body fluid into which a drug “appears” to distribute.

It is defined as the volume in which the amount of drug would need to be uniformly distributed to produce the observed blood concentration.

51
Q

What can we tell by the Vds?

A
  • Drugs that distribute extensively have relatively large Vd values and vice versa.
  • A very low Vd value may indicate extensive plasma protein binding of the drug.
  • A very high value may indicate that the drug is extensively bound to tissue sites.

Among other variables, Vd may be influenced by age, sex, weight, and disease processes (e.g., oedema, ascites).

Pharma midterm 1 (14 decks)

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