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M2 Pharmocology > 1.1 Pharmacokinetics > Flashcards

1.1 Pharmacokinetics Flashcards

1
Q

What is the journey of a drug through the body?

A

1) Administration
2) Absorbed
3) distributed through the body to its site of action
4) Metabolised
5) Excreted
6) voided

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2
Q

Absorption: site of _________ permits entry of drug directly/indirectly into plasma

A

Administration

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3
Q

Distribution: drug may then reversibly leave the bloodstream and distribute into _______________

A

interstitial and intracellular fluids

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4
Q

What is a measure of total systemic exposure to the drug?

A

Area under the concentration-time curve over time (area under curve, AUC) i

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5
Q

Oral, Sublingual, buccal, rectal are considered _____ routes of administration

A

Enteral

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6
Q

What are the advantages of oral administration?

  • safest
  • economical
  • easily self administered
  • Low incidence of _________ while toxicities and/or overdose may be overcome with antidote e.g. ______
A

anaphylactic shock, activated charcoal

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7
Q

What are the disadvantages of oral administration?

  • Pathways are most complicated
  • Limited by ________ (as in cases of vomiting and GI problems)
  • Not suitable for drugs with ______ (may be inactivated by low gastric pH) or are alkaline
  • Food may affect absorption
  • Patient compliance is necessary
A

lower capacity; acid lability

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8
Q

What are the advantages of sublingual/ buccal route of administration?

  • ease of admnistration
  • Rich blood supply to mouth and tongue facilitate direct absorption into bloodstream, bypassing harsh GI environment and avoiding _____
  • Drug stability maintained because pH of saliva is ________
A

first-pass metabolism; relatively neutral

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9
Q

What are the disadvantages of sublingual/ buccal adminstration?

  • Limited to certain types of drugs with rapid direct systemic absorption (e.g. _____)
  • Limited to drugs that can be taken in small doses
  • Part of dose swallowed may be lost
A

nitroglycerin

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10
Q

Enteric-coated preparations: An enteric coating is a chemical envelope that protects the drug from stomach acid, delivering it instead to the less acidic intestine, where the coating dissolves and releases the drug.

  • Enteric coating is useful for certain drugs (for example, _______) that are acid unstable.
  • Drugs that are irritating to the stomach, such as _____, can be formulated with an enteric coating that only dissolves in the small intestine, thereby protecting the stomach.
A

omeprazole; aspirin

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11
Q

Extended-release preparations: Extended-release (abbreviated ER or XR) medications have special coatings or ingredients that control the drug release, thereby allowing for slower absorption and a prolonged duration of action. ER formulations can be dosed less frequently and may improve patient compliance. Additionally, ER formulations may maintain concentrations within the therapeutic range over a longer period of time, as opposed to immediate-release dosage forms, which may result in larger peaks and troughs in ________.

A

plasma concentration

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12
Q

ER formulations are advantageous for drugs with short half-lives. For example, the half-life of oral morphine is ______ , and it must be administered six times daily to provide continuous pain relief. However, only two doses are needed when extended-release tablets are used. Unfortunately, many ER formulations have been developed solely for a marketing advantage over immediate-release products, rather than a documented clinical advantage.

A

2 to 4 hours

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13
Q

What are the advantages of rectal route of administration?

  • Biotransformation of drugs by liver is minimized as 50% of venous drainage of rectal region bypasses _______
  • Useful if drug induces vomiting, if patient is vomiting or comatose, or in instances of refusal in children
  • Blood supply is also very good
A

portal circulation

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14
Q

What are the disadvantages of rectal route of administration?

  • Rectal absorption is often erratic and incomplete
  • Many drugs irritate the ________
A

rectal mucosa

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15
Q

What are examples of parenteral routes of administration?

A

intravenous, intramuscular, subcutaneous, percutaneous and inhalation

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16
Q

The parenteral route introduces drugs directly into the systemic circulation.

What is parenteral administration used for?

  • drugs that are poorly absorbed from the GI tract (for example, _______) or
  • unstable in the GI tract (for example, _____).
  • patient is unable to take oral medications (unconscious patients) - circumstances that require a rapid onset of action.
A

heparin; insulin

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17
Q

What are the advantages of parenteral administration?

  • have the highest _____ and are not subject to first-pass metabolism or the harsh GI environment.
  • provides the most control over the actual dose of drug delivered to the body
A

bioavailability;

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18
Q

Disadvantages of paranteral?

  • irreversible and may cause pain, fear, local tissue damage, and infections
  • Requires rigorous ______ preparations to prevent infections through contamination of injection site
A

sterile

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19
Q

What are the advantages of IV injection?

  • useful for drugs that are not absorbed orally, such as the neuromuscular blocker ________.
  • IV delivery permits a rapid effect and a maximum degree of control over the amount of drug delivered.
  • administration is advantageous for drugs that cause irritation when administered via other routes, because the substance is rapidly diluted by the blood.
A
  • rocuronium
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20
Q

IV injection

  • When injected as a ____, the full amount of drug is delivered to the systemic circulation almost immediately.
  • If administered as an IV infusion, the drug is infused over a longer period of time, resulting in lower ______ and an increased duration of circulating drug levels.
A

bolus; peak plasma concentrations

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21
Q

What are the disadvantages of IV injection?

  • Unlike drugs given orally, those that are injected cannot be recalled by strategies such as binding to activated charcoal.
  • IV injection may inadvertently introduce infections through contamination at the site of injection.
  • strict aseptic techniques required
  • It may also precipitate blood constituents, induce ______, or cause other adverse reactions if the medication is delivered too rapidly and high concentrations are reached too quickly.
  • Need to deliver drug slowly in a controlled manner to avoid ______
  • unsuitable for oily substances
A

hemolysis; toxic bolus effect

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22
Q

Drugs administered IM can be in aqueous solutions, which are absorbed rapidly, or in specialized _____, which are absorbed slowly. Depot preparations often consist of a suspension of the drug in a nonaqueous vehicle such as _______.
As the vehicle diffuses out of the muscle, the drug precipitates at the site of injection. The drug then dissolves slowly, providing a sustained dose over an extended period of time. Examples of sustained-release drugs are ____.

A

depot preparations; polyethylene glycol;

haloperidol and depot medroxyprogesteroh

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23
Q

What are the advantages of intramuscular injection?

  • suitable if drug volume is moderate - suitable for ____ and certain irritating substances
  • preferable to intravenous if patient must self administer
A

oily vehicles

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24
Q

What are the disadvantage of intramuscular injections?

  • affects certain lab tests (e.g. _____)
  • can be painful
  • can cause ______ (precluded during anticoagulation therapy)
  • Nerve damage, pain, tissue necrosis, abscess if not skillfully given
A

creatine kinase; intramuscular hemorrhage

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25
Q

What are the advantages of subcutaneous injection?

  • Like IM injection, SC injection provides absorption via _____ and is slower than the IV route.
  • SC injection minimizes the risks of _____ or thrombosis associated with IV injection and may provide constant, slow, and sustained effects
  • ideal for some poorly soluble suspensions
A

simple diffusion; hemolysis

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26
Q

What are the disadvantage of subcutaneous injection?

  • This route should not be used with drugs that cause tissue irritation, because severe pain and necrosis may occur.
  • Drugs commonly administered via the subcutaneous route include __________.
  • unsuitable for drugs administered in large volumes
A

insulin and heparin

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27
Q

Transdermal: This route of administration achieves systemic effects by application of drugs to the skin, usually via a transdermal patch . The rate of absorption can vary markedly, depending on the physical characteristics of the skin at the site of application, as well as the lipid solubility of the drug. This route is most often used for the sustained delivery of drugs, such as the antianginal drug ______, the antiemetic _______, and nicotine transdermal patches, which are used to facilitate smoking cessation.

A

nitroglycerin; scopolamine

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28
Q

What are advantages of the transdermal patch?

  • Ideal for drugs that are lipophilic (e.g. ________)
  • also ideal for drugs that have poor oral bioavailability, and are quickly eliminated from the body
  • partially bypasses the ______ effect
  • convenient and painless
A

fentanyl, nitro- glycerin/glyceryl trinitrate GTN, hyoscine, ethinylestradiol;

first pass

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29
Q

What are the disadvantages of a transdermal patch?

  • May cause local allergic reactions
  • Limited to drugs that can be taken in small daily doses and are highly ________
  • May cause delayed delivery of drug to pharmacological site of action and delayed onset of action
  • Stratum corneum acts as main barrier to diffusion of drugs and is limited to highly lipid soluble drugs that can penetrate skin sufficiently to produce systemic effects
A

lipophilic

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30
Q

Oral inhalation: Inhalation routes, both oral and nasal, provide rapid delivery of a drug across the large surface area of the mucous membranes of the respiratory tract and pulmonary epithelium. Drug effects are almost as rapid as those with IV bolus. Drugs that are gases (for example, some anesthetics) and those that can be dispersed in an aerosol are administered via inhalation. This route is effective and convenient for patients with _________, because the drug is delivered directly to the site of action, thereby minimizing systemic side effects.

A

respiratory disorders (such as asthma or chronic obstructive pulmonary disease)

31
Q

Examples of oral inhalation drugs?

A

Examples of drugs administered via inhalation include bronchodilators, such as albuterol, and corticosteroids, such as fluticasone.

32
Q

What are the advantages of inhalation drugs?

  • Delivers drug directly to lungs, allowing rapid absorption given rich blood supply
  • Effective for patients with respiratory problems
  • Appropriate for children given ease of teaching and self-administration
  • Ideal route for small molecules, gases, volatile liquids and aerosols
  • fewer ____
A

systemic side effects

33
Q

What are the disadvantages of inhalation?

A
  • most addictive route (drug can enter the brain quickly)
  • patient may have difficulty regulating dose
  • some patients may have difficulty using inhalers
34
Q

Intrathecal/intraventricular: The blood–brain barrier typically delays or prevents the absorption of drugs into the central nervous system (CNS). When local, rapid effects are needed, it is necessary to introduce drugs directly into the cerebrospinal fluid. For example, _______ is used in treating cryptococcal meningitis

A

intrathecal amphotericin B

35
Q

Topical: Topical application is used when a local effect of the drug is desired. For example, ________ is a cream applied directly to the skin for the treatment of fungal infections

A

clotrimazole

36
Q

Passive diffusion:

  • The driving force for passive absorption of a drug is the concentration gradient across a membrane separating two body compartments.
  • Passive diffusion does not involve a carrier, is not saturable, and shows a low structural specificity. The vast majority of drugs are absorbed by this mechanism.
  • Water-soluble drugs penetrate the cell membrane through __________, whereas lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane lipid bilayers.
A

aqueous channels or pores

37
Q

[ mechanism of absorption]

Passive diffusion:

  • The driving force for passive absorption of a drug is the concentration gradient across a membrane separating two body compartments.
  • Passive diffusion does not involve a carrier, is not saturable, and shows a low structural specificity. The vast majority of drugs are absorbed by this mechanism.
  • Water-soluble drugs penetrate the cell membrane through __________, whereas lipid-soluble drugs readily move across most biologic membranes due to their solubility in the membrane lipid bilayers.
  • Influenced by _____ for ionizable drugs
A

aqueous channels or pores;

pH partition hypothesis

38
Q

[mechanism of absorption]
Facilitated diffusion:
- Other agents can enter the cell through _________ that facilitate the passage of large molecules.
- These carrier proteins undergo conformational changes, allowing the passage of drugs or endogenous molecules into the interior of cells and moving them from an area of high concentration to an area of low concentration.
- It does not require energy, can be saturated, and may be inhibited by compounds that compete for the carrier.

A

specialized transmembrane carrier proteins

39
Q

[mechanism of absorption]

Active transport:

  • This mode of drug entry also involves specific carrier proteins that span the membrane.
  • A few drugs that closely resemble the structure of naturally occurring metabolites are actively transported across cell membranes using specific carrier proteins.
  • Energy-dependent active transport is driven by the hydrolysis of _____. It is capable of moving drugs against a concentration gradient, from a region of low drug concentration to one of higher drug concentration.
  • The process is saturable.
  • Active transport systems are selective and may be competitively inhibited by other cotransported substances.
A

adenosine triphosphate

40
Q

[mechanism of absorption]
Endocytosis and exocytosis:
- This type of absorption is used to transport drugs of exceptionally large size across the cell membrane.
- Endocytosis involves engulfment of a drug by the cell membrane and transport into the cell by pinching off the drug-filled vesicle.
- Exocytosis is the reverse of endocytosis. Many cells use exocytosis to secrete substances out of the cell through a similar process of vesicle formation.
- ________ is transported across the gut wall by endocytosis, whereas certain neurotransmitters (for example, norepinephrine) are stored in intracellular vesicles in the nerve terminal and released by exocytosis.

A

Vitamin B12

41
Q

Lipid soluble drugs (e.g. anaesthetics) are usually __________ that dissolve into membranes; water soluble drugs (e.g. most drugs) are usually weak acids/bases and become charged
- ionization process depends on pKa of molecule and pH of medium

A

small volatile molecules

42
Q

Explain the pH partition hypothesis

A

A drug passes through membranes more readily if it is uncharged (in its unionized state)

  • For a weak acid, the uncharged, protonated HA can permeate through membranes more easily
  • For a weak base, the uncharged, deprotonated B can permeate through membranes more easily

Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms

43
Q

[factors affecting absorption]

Explain the pH partition hypothesis

A

A drug passes through membranes more readily if it is uncharged (in its unionized state)

  • For a weak acid, the uncharged, protonated HA can permeate through membranes more easily
  • For a weak base, the uncharged, deprotonated B can permeate through membranes more easily

Therefore, the effective concentration of the permeable form of each drug at its absorption site is determined by the relative concentrations of the charged and uncharged forms

44
Q

[Other factors affecting absorption of drug]

  • Blood flow to the absorption site: The intestines receive much more blood flow than the stomach, so absorption from the intestine is favored over the stomach.
  • Total surface area available for absorption: With a surface rich in brush borders containing _____, the intestine has a surface area about 1000-fold that of the stomach, making absorption of the drug across the intestine more efficient.
A

microvilli

45
Q

[Other factors affecting absorption of drug]

  • Contact time at the absorption surface: If a drug moves through the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed. Conversely, anything that delays the transport of the drug from the stomach to the intestine delays the rate of absorption of the drug. [Note: The presence of food in the stomach both dilutes the drug and slows gastric emptying. Therefore, a drug taken with a meal is generally absorbed more slowly.]
  • Expression of P-glycoprotein: P-glycoprotein is a transmembrane transporter protein responsible for transporting various molecules, including drugs, across cell membranes. It is expressed in tissues throughout the body, including the ____________, and is involved in transportation of drugs from tissues to blood. That is, it “pumps” drugs out of the cells. Thus, in areas of high expression, P-glycoprotein reduces drug absorption. In addition to transporting many drugs out of cells, it is also associated with multidrug resistance.
A

liver, kidneys, placenta, intestines, and brain capillaries

46
Q

What is bioavailability? What are some factors affecting bioavailability?

A 
Bioavailability is the rate and extent to which an administered drug reaches the systemic circulation. 
It is affected by 
- first pass hepatic metabolism 
- solubility of the drug 
- chemical instability
- nature of the drug formulation
47
Q

[factors affecting bioavailability]
What is first pass metabolism?
- When a drug is absorbed from the GI tract, it enters the _____ before entering the systemic circulation. If the drug is rapidly metabolized in the liver or gut wall during this initial passage, the amount of unchanged drug entering the systemic circulation is decreased. This is referred to as first-pass metabolism.

A

portal circulation

48
Q

[factors affecting bioavailability]
Very hydrophilic drugs are poorly absorbed because of their inability to cross lipid-rich cell membranes. Paradoxically, drugs that are extremely lipophilic are also poorly absorbed, because they are totally insoluble in aqueous body fluids and, therefore, cannot gain access to the surface of cells. For a drug to be readily absorbed, it must be ____________. This is one reason why many drugs are either weak acids or weak bases.

A

largely lipophilic, yet have some solubility in aqueous solutions.

49
Q

[other factors affecting bioavailability of drug]

Chemical instability: Some drugs, such as ______, are unstable in the pH of the gastric contents. Others, such as insulin, are destroyed in the GI tract by degradative enzymes.

Nature of the drug formulation: Drug absorption may be altered by factors unrelated to the chemistry of the drug. For example, particle size, salt form, crystal polymorphism, enteric coatings, and the presence of excipients (such as binders and dispersing agents) can influence the ease of dissolution and, therefore, alter the rate of absorption

A

penicillin G

50
Q

Drug distribution is the process by which a drug reversibly leaves the bloodstream and enters the interstitium (extracellular fluid) and the tissues. For drugs administered IV, absorption is not a factor, and the initial phase (from immediately after administration through the rapid fall in concentration) represents the distribution phase, during which the drug rapidly leaves the circulation and enters the tissues. What factors affect drug distribution?

A

cardiac output and local blood flow, capillary permeability, the tissue volume, the degree of binding of the drug to plasma and tissue proteins, and the relative lipophilicity of the drug

51
Q

[factors affecting distribution- blood flow ]
The rate of blood flow to the tissue capillaries varies widely. For instance, blood flow to the “vessel-rich organs” (brain, liver, and kidney) is greater than that to the _______. Adipose tissue, skin, and viscera have still lower rates of blood flow. Variation in blood flow partly explains the short duration of hypnosis produced by an IV bolus of propofol (see Chapter 13). High blood flow, together with high lipophilicity of propofol, permits rapid distribution into the CNS and produces anesthesia. A subsequent slower distribution to skeletal muscle and adipose tissue lowers the plasma concentration so that the drug diffuses out of the CNS, down the concentration gradient, and consciousness is regained.

A

skeletal muscles

52
Q

[factors affecting distribution of drugs- capillary permeability]

Capillary permeability is determined by capillary structure and by the chemical nature of the drug. Capillary structure varies in terms of the fraction of the basement membrane exposed by slit junctions between _____ cells.

  • In the liver and spleen, a significant portion of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass.
  • In the brain, the capillary structure is continuous, and there are no slit junctions .
  • To enter the brain, drugs must pass through the endothelial cells of the CNS capillaries or be actively transported. For example, a specific transporter carries levodopa into the brain.
  • By contrast, ________ the CNS because they dissolve in the endothelial cell membrane. Ionized or polar drugs generally fail to enter the CNS because they cannot pass through the endothelial cells that have no slit junctions . These closely juxtaposed cells form tight junctions that constitute the blood–brain barrier.
A

endothelial; lipid-soluble drugs readily penetrate

53
Q

[factors affecting distribution of drug- binding of drugs to plasma proteins and tissues]

  • Plasma- protein can tie up the drug, preventing it from being effectively distributed.
  • In plasma, lipid soluble drugs bind reversibly to extracellular plasma proteins (namely _____) to facilitate transport in aqueous medium
  • Plasma proteins act as drug reservoirs to maintain free-drug concentration as a constant fraction of total drug in plasma to slow transfer out of vascular compartment; equilibrium: drug + protein drug-protein complex
  • Drugs may also bind to tissue proteins causing accumulation in tissues; may create tissue reservoirs but prolonged action risks local drug toxicity. For example, acrolein, the metabolite of cyclophosphamide, can cause _______ because it accumulates in the bladder
A

albumin; hemorrhagic cystitis

54
Q

[factors affecting distribution of drug- lipophilicity]
The chemical nature of a drug strongly influences its ability to cross cell membranes. Lipophilic drugs readily move across most biologic membranes. These drugs dissolve in the lipid membranes and penetrate the entire cell surface. The major factor influencing the distribution of lipophilic drugs is ______. In contrast, hydrophilic drugs do not readily penetrate cell membranes and must pass through ______.

A

blood flow to the area; slit junctions

55
Q

Blood Brain Barrier

  • Formed by presence of tight junctions between endothelial cells and peripheral processes of astrocytes
  • Prevents passive diffusion of drugs into CSF, thereby excluding water soluble drugs (polar or ionized molecules) or high molecular weight compounds
  • Lipid soluble drugs (e.g. ____________) are able to cross cell membranes and enter freely, limited only by cerebral blood flow
A

barbiturates, propofol, synthetic opioids

56
Q

What is the apparent volume of distribution, Vd? How is it calculated?

A

The apparent volume of distribution, Vd, is defined as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma. It is calculated by dividing the dose that ultimately gets into the systemic circulation by the plasma concentration at time zero (C0).

57
Q

Vd has an important influence on the half-life of a drug, because drug elimination depends on the amount of drug delivered to the liver or kidney (or other organs where metabolism occurs) per unit of time. Delivery of drug to the organs of elimination depends not only on blood flow but also on the fraction of the drug in the plasma. If a drug has a large Vd, most of the drug is in the ______ and is unavailable to the excretory organs. Therefore, any factor that increases Vd can increase the half-life and extend the duration of action of the drug.

A

extraplasmic space

58
Q

[Distribution of water compartments in the body]
Plasma compartment: If a drug has a high molecular weight or is extensively protein bound, it is too large to pass through the slit junctions of the capillaries and, thus, is effectively trapped within the plasma (vascular) compartment. As a result, it has a low Vd that approximates the plasma volume or about 4 L in a 70-kg individual. _______ shows this type of distribution.

A

Heparin

59
Q

Extracellular fluid: If a drug has a low molecular weight but is hydrophilic, it can pass through the endothelial slit junctions of the capillaries into the interstitial fluid. However, hydrophilic drugs cannot move across the lipid membranes of cells to enter the intracellular fluid. Therefore, these drugs distribute into a volume that is the sum of the plasma volume and the interstitial fluid, which together constitute the extracellular fluid (about 20% of body weight or 14 L in a 70-kg individual). __________ show this type of distribution.

A

Aminoglycoside antibiotics

60
Q

Total body water: If a drug has a low molecular weight and is lipophilic, it can move into the interstitium through the slit junctions and also pass through the cell membranes into the intracellular fluid. These drugs distribute into a volume of about 60% of body weight or about 42 L in a 70-kg individual. _______ exhibits this apparent Vd.

A

Ethanol

61
Q

What is clearance? What is the equation for clearance?

A

Volume of blood that is completely and irreversibly cleared of drug per unit time
Related to volume of distribution and the rate at which the drug is eliminated
Total clearance is a composite estimate reflecting all mechanisms of drug elimination, calculated as Cl = 0.693 x Vd / t1/2

62
Q

What is first order kinetics of metabolism?

  • Rate of elimination of a drug where the amount of a drug decreases at a rate that is proportional to the ____________ (Michaelis-Menten kinetics)
  • Dependent on the concentration of the drug at any given time and applies to most drugs in clinical usage
A

concentration of the drug remaining in the body

63
Q

zero order kinetics of metabolism

  • Implies a saturable (usually enzymatic) metabolic process where rate of metabolism and drug elimination remains constant over time and independent of concentration (constant amount of drug being eliminated at a time)
  • Obeyed by few drugs e.g. __________
  • Implies a saturable metabolic process
A

ethanol, phenytoin, salicylates

64
Q

[Drug clearance by kidney- glomerular filtration ]
Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus. Free drug (not bound to albumin) flows through the capillary slits into the Bowman space as part of the glomerular filtrate (Figure 1.19). The glomerular filtration rate (GFR) is normally about 125 mL/min but may diminish significantly in renal disease. Lipid solubility and pH do not influence the passage of drugs into the glomerular filtrate. However, variations in ____________ do affect this process.

A

GFR and protein binding of drugs

65
Q

[Drug clearance by kidney- proximal tubular secretion]
In the proximal convoluted tubule, _________ are actively secreted
- Transport systems show low specificity and therefore competition between drugs for carriers can occur
- Premature infants and neonates have incompletely developed tubular secretory mechanisms and may thus retain certain drugs in glomerular filtrate

A

acids/bases

66
Q

[Drug clearance by kidney- distal tubular absorption]
As a drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of the perivascular space. The drug, if uncharged, may diffuse out of the nephric lumen, back into the systemic circulation. Manipulating the urine pH to increase the fraction of ionized drug in the lumen may be done to minimize the amount of back diffusion and increase the clearance of an undesirable drug. As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine. This process is called “_________.” For example, a patient presenting with phenobarbital (weak acid) overdose can be given bicarbonate, which alkalinizes the urine and keeps the drug ionized, thereby decreasing its reabsorption

A

ion trapping

67
Q

Role of drug metabolism: Most drugs are lipid soluble and, without chemical modification, would diffuse out of the tubular lumen when the drug concentration in the filtrate becomes greater than that in the perivascular space. To minimize this reabsorption, drugs are modified primarily in the liver into more polar substances via _________. The polar or ionized conjugates are unable to back diffuse out of the kidney lumen

A

phase I and phase II reactions

68
Q

[Drug clearance by liver]

  • Drugs that are concentrated in bile (usually large molecular weight conjugates) are excreted hepatically
  • Bile is _______ and has both lipophilic and polar characteristics, and is thus able to cope with a broad range of materials
  • Active transport system that secretes stuff into the bile (bile acids and large molecular weight conjugates glucuronides)
A

amphipathic

69
Q

[Drug clearance by liver]

  • As the drug passes into the blood supply of the liver, it diffuses through the _______ into the hepatocytes
  • The drug may either be metabolized and enter the systemic circulation or excreted directly into the bile collecting duct if it is a __________
  • The bile collecting ducts then produce bile which is excreted into the small intestine where it can be removed as part of the faecal material
A

sinusoids; large molecular weight substance

70
Q

[Drug excretion- enterohepatic cycling]
- Represents a complication of biliary excretion as the drug may be reabsorbed after the drug/metabolite is excreted into the gut which is taken to the liver to be excreted again, creating a cycle of drug persistence which extends the half-life of the drug in the body
- Often, gut flora in the intestine can facilitate the reabsorption process e.g. by cleaving _________, liberating drug for reabsorption into systemic circulation
sup

A

glucuronide-drug derivative

71
Q

The steady-state plasma concentration (Css) is _________ to the infusion rate. For example, if the infusion rate is doubled, the Css is doubled

A

directly proportional

72
Q

Furthermore, the Css is ________ to the clearance of the drug. Thus, any factor that decreases clearance, such as liver or kidney disease, increases the Css of an infused drug

A

inversely proportional

73
Q

Time required to reach the steady-state drug concentration: The concentration of a drug rises from zero at the start of the infusion to its ultimate steady-state level, Css The rate constant for attainment of steady state is the rate constant for total body elimination of the drug. Thus, 50% of Css of a drug is observed after the time elapsed, since the infusion, t, is equal to t1/2, where t1/2 (or half-life) is the time required for the drug concentration to change by 50%. After another half-life, the drug concentration approaches 75% of Css. The drug concentration is 87.5% of Css at 3 half-lives and 90% at 3.3 half-lives. Thus, a drug reaches steady state in about ___________

A

four to five half-lives.

M2 Pharmocology (20 decks)

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