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Pharmacology-TJA > Pharmacologic predisposition > Flashcards

Pharmacologic predisposition Flashcards

1
Q

What are the components of the physiological disposition of drugs? (AMDE)

A

Absorption, distribution, metabolism, excretion.

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2
Q

“1st pass”

A

Refers to interaction between drug and metabolic systems it encounters when it is absorbed through the GI tract.

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3
Q

Partition coefficient

A

Experimentally determined measure of how lipid soluble a drug is and therefore how readily it will diffuse across a membrane. Higher partition coefficient means more lipid soluble and more rapid diffusion. This only matters for drugs that are absorbed through simple diffusing (primarily).

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4
Q

What are some characteristics of drugs that can diffuse across a membrane?

A

Small and unionized.

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5
Q

If a drug is a weak base, which form is unionized (will pass through a membrane)?

A

The dissociated form

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6
Q

If a drug is a weak acid, which form is unionized (will pass through a membrane)

A

The non-dissociated form (HA)

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7
Q

Henerson-Hasselbach equation:

A

[base]/[acid]=10^(pH-pKa)

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8
Q

ion trapping/pH partitioning

A

When the pH differs on either side of a membrane, there will be a difference in total drug concentration across the membrane.

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9
Q

If you have two compartments with different pH separated by a membrane, which compartment will have a higher amount of total drug if the drug is a weak acid?

A

The more basic compartment will have more total drug.

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10
Q

If you have two compartments with different pH separated by a membrane, which compartment will have a higher amount of total drug if the drug is a weak base?

A

The more acidic compartment will have more total drug.

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11
Q

Three advantages and disadvantages of the intravenous route

A

Advantages: Rapid onset of action, accurate control of blood levels, direct entry to central compartment. Disadvantages: non-removable, rapid injections cause high concentrations (which can lead to adverse events), embolism/fever/excessive fluid loss.

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12
Q

Intrathecal

A

route directly into CNS. For local effects and to circumvent barriers for spinal anesthesia, acute CNS infection, and brain tumors.

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13
Q

Does intramuscular or subcutaneous absorb more rapidly?

A

IM

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14
Q

Is IM or SC more likely to cause irritation

A

SC

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15
Q

What is a key shortcoming of the transdermal route?

A

The agent must me lipid soluble. Abrasions can lead to abrupt increase in the permeability of the epidermis.

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16
Q

What are most allergic reactions to in use of transdermal patches?

A

The adhesive.

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17
Q

What are the three enteral routes?

A
  1. Sublingual/buccal 2. Rectal 3. Oral
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18
Q

How are drugs absorbed in the sublingual route?

A

Through the blood supply of the mucous membrane and directly into systemic circulation (no first pass).

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19
Q

How are drugs absorbed in the rectal route

A

Through the mucosa of the rectum, with 50% into the pudendal veins and the systemic circulation, and 50% into the portal circulation.

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20
Q

What is the major site of absorption in the oral route?

A

The small intestine, due to large surface area and a long transit time. Where specifically depends on drug pH and lipid solubility.

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21
Q

What determines the rate at which a drug administered through the oral route will be absorbed?

A

The speed at which the stomach empties. Liquids, ulcers, and pancreatitis increase the speed. Solid food, fats, acids, trauma, GI obstruction can all slow down absorption.

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22
Q

Vessel rich group

A

brain, heart, liver, lung, kidneys

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23
Q

Breastmilk is slightly ____________ and therefore ___________ compounds tend to accumulate here relative to plasma

A

breast milk is slightly acidic, so basic compounds tend to accumulate

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24
Q

Where does most drug metabolism occur

A

The liver.

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25
Q

t(1/2)=

A

(0.7*Vd)/Cl

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26
Q

k=

A

rate constant of elimination

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27
Q

Vd

A

volume of distribution- it is a characteristic of the drug, not an actual volume. It’s unit is liters/kg or liters/m^2

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28
Q

total amount of drug =

A

sum of ionized and unionized forms

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29
Q

Which drug will clear the system faster, one bound to albumin or one that is free?

A

Free drug will be filtered out in the kidneys. Albumin is too large to enter the filtrate and stays in the blood, along with drug bound to it.

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30
Q

Where does most absorption of oral drugs take place?

A

Sm intestine. pH and surface area are primary determinants. Most drugs are weak bases which tend to be sequestered in the more acidic compartment. Therefore more basic drugs are absorbed further from the stomach.

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31
Q

What determines the rate by which a drug taken PO will enter the circulation?

A

The time it takes for the stomach to empty into the intestine is the primary determinant. The rate is increased by fluid intake, ulcers, pancreatitis. It is decreased by presence of solids, lipids, labor, diabetes, pneumonia, ab trauma and gi obstruction.

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32
Q

Why do many drugs accumulate in breast milk?

A

It is slightly acidic and most drugs are weak bases.

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33
Q

Pros of IV route

A

Rapid onset of action, accurate control of blood levels.

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34
Q

In general, what does cytochrome p450 do?

A

Phase 1 metabolic reactions (oxidation, reduction, hydrolysis)

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35
Q

What are phase II metabolic reactions?

A

Conjugations: glucaronidation, sulfation, methylation, acetylation, glutathione conjugation.

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36
Q

Cons of IV route

A

non-removable. High concentrations if rapid injection (even if transient can cause adverse effects). Embolism, fever, excessive fluid loads.

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37
Q

Why use the intrathecal route?

A

Circumvents blood-brain barrier. Used for spinal anesthesia, acute CNS infections, brain tumor treatments.

38
Q

Advantages of IM route vs subcutaneous

A
  1. IM more rapidly absorbed 2. IM less sensitive to irritants 3. SC must use small volumes 4. SC more painful and more susceptible to infection (local abcess)
38
Q

Advantages of inhalation route (4):

A
  1. Large surface area 2. High blood flow 3. Efficient absorption of atomized particles, aerosols, gases 4. Local and systemic delivery
38
Q

Disadvantages of inhalation route (3):

A
  1. Requires specialized metering equipment 2. Allergic reactions- can cause rapid anaphylaxis. 3. Route for drugs of abuse.
38
Q

Advantages of sublingual/buccal route (2):

A
  1. No first pass (absorbed directly into SVC) 2. Rapid onset of action
39
Q

Advantages (3) and disadvantages (1) of the rectal route:

A

Advantages: 1. Wide variety of drugs available 2. Can be administered to unconscious patient 3. 50% of drug absorbed will bypass the 1st pass (entering pudendal circulation) Disadvantages: 1. Absorption is incomplete, irregular

40
Q

Disadvantages of oral route (3):

A
  1. Can irritate the GI tract 2. Drug can be inactivated/destroyed by pH, GI enzymes, liver 3. Irregular absorption/slow onset
41
Q

In what order are tissues perfused?

A
  1. Blood 2. Vessel-rich group 3. Muscle 4. Fat
42
Q

Which organs are in the vessel-rich group (VRG)?

A

Heart, lungs, brain, liver, kidneys.

43
Q

How does the blood-brain barrier prevent passage of drugs into the brain (2 reasons)?

A
  1. Brain capillaries are not fenestrated like typical capillaries, and thus do not allow free passage of drug through. So drugs must diffuse through cells of capillary walls. Only highly hydrophobic drugs can pass through both membranes of capillary cells and adjacent glial cells. 2. Several active transporters (including multi-drug transporter) pump drug back out.
44
Q

Why do most drugs pass through the placenta to the fetus?

A

Placenta has normal cell membranes. Any drug that is taken orally and available to mother will pass through the placenta.

45
Q

What are the 4 major outcomes for drugs when they are metabolized?

A
  1. Drug–> inactive metabolite (95% of the time) 2. Drug–> toxic metabolite 3. prodrug (eg codeine) –> active drug (morphine) 4. Drug–> active metabolite **A drug can undergo more than one metabolic reaction.
46
Q

What are the phase I metabolic reactions?

A

Oxidation, reduction, hydrolysis

47
Q

What do phase III metabolic enzymes do?

A

Transport drug to blood or bile in liver.

48
Q

What is the difference between microsomal and non-microsomal oxidations?

A

microsomal oxidations occur in the smooth ER. non-microsomal oxidations occur in the mitochondria. The cytochrome p450 system is microsomal.

49
Q

what are CYP3A4 and CYP3A5? Why is this significant for patients?

A

Two isoforms of cytochrome p450 in the smooth ER of hepatocytes that are responsible for metabolism of 50% of drugs. This is important because drugs that share the same metabolic pathway can interact.

50
Q

What must be present for drug metabolism by P450?

A
  1. P450 2. Oxygen 3. An electron source (NADPH) 4. P450 reductase
51
Q

What are the stages of the “first pass”

A
  1. some P450s are in gut wall and metabolize drug there 2. Mesenteric vein–>portal vein 3. p450s in liver
52
Q

what is induction?

A

Increased metabolism of a drug in response to exposure to that drug or another drug that is metabolized. Often induction is broad, meaning that use of one drug can induce increased expression of several families of p450, affecting their own metabolism as well as that of other drugs.

53
Q

How does induction occur at the molecular bio level?

A

Drugs (and other targets) that interact with p450 activate type II nuclear receptors that increase expression of mRNA for p450.

54
Q

in general, what are the consequences of induction?

A

Increased rate of metabolism. This means an increased first pass effect and lower drug bioavailability/reduced drug exposure at target.

55
Q

List some examples of common p450 inducers:

A

EtOH (chronic), barbiturates, contraceptives, cigarettes, cannibus, some TB antibiotics (rifampin, isoniazid)

56
Q

What is p450 inhibition? What are the consequences?

A

Some drugs inhibit metabolic activity of p450 by disrupting heme. This results in reduced first pass, increased bioavailability, and reduced drug clearance.

57
Q

What are some common drugs that inhibit p450?

A

Cimetadine (Tagamet), erythromycin, clarithromycin.

58
Q

Monoamine oxidase is responsible for…

A

non-microsomal metabolism of epinephrine and norepinephrine in the cytosol of hepatocytes.

Also for metabolism of histamine.

59
Q

Is alcohol dehydrogenase an microsomal or nonmicrosomal phase I metabolic enzyme? Aldehyde dehydrogenase? What types of reactions are these? What is special about aldehyde dehydrogenase?

A

Both are nonmicrosomal- exist in cytosol. Reactions are hydroxylations. Many drugs inhibit aldehyde dehydrogenase leading to a build-up of acetaldehyde in hepatocytes when patient drinks EtOH and adverse events.

60
Q

Where do hydrolytic enzymes (like amidases and esterases) operate? What are some drugs metabolized through this system?

A

These enzymes exist in many organs AND blood plasma, so many of these reactions occur in circulation. Acetylcholine, aspirin, many antibiotics and lipid lowering drugs are metabolized through this system.

61
Q

Are reductions common phase I metabolic reactions? When/where do they occur?

A

No, they are rare. They tend to occur under low oxygen in the GI tract and liver. Prednisone and sulindac (pro-drug) are examples of drugs that are reduced.

62
Q

What are the 5 types of conjugation reaction that drugs go through in metabolism (Get Some MAG)? What effects do they have (in general) on drug solubility?

A

Glucuronidation, Sulfation, Methylation, Acetylation, Glutathione conjugation. They almost always lead to inactive metabolites. Glucuronidation, sulfation, and glutathione conjugation lead to increased water solubility. Methylation and acetylation decrease water solubility.

63
Q

How do glucuronidation and sulfation aid in drug clearance?

A

Both glucuronated and sulfated products tend to be ionized at physiologic pH, and are therefore not reabsorbed from the filtrate in the kidneys. Glucuronic acid specifically has an active transport system (UDP-glucuronyl transferase) that moves it (and whatever is conjugated to it) into the filtrate.

64
Q

What is UDPGA?

A

UDP-glucuronic acid. This is the activated cofactor for UDP-glucuronyl transferase system in the liver.

65
Q

Do all patients methylate and acetylate substances at the same rate? Why/why not?

A

No, methylation and acetylation are under genetic control. Some patients do it fast, others do it slow. Slow acetylation and methylation are associated with toxicity because inactive metabolite is not formed as quickly as expected.

66
Q

What is the role of glutathione conjugation in metabolism?

A

It is the “chemical mop” that has as substrate chemically reactive compounds that could otherwise be dangerous.

67
Q

How is drug metabolism affected in a patient with heart disease?

A

For many drugs, delivery of blood to the liver is the rate-limiting step of metabolism. Heart disease reduces blood flow to liver and thus decreases metabolism for these drugs. Some antihypertensive drugs also have this effect.

68
Q

What two factors affect how renally eliminated drugs are reabsorbed in the nephron?

A

Lipid solubility and ionization state. Non-polar uncharged molecules will be reabsorbed into the blood from the filtrate.

69
Q

How can renal excretion be facilitated medically?

A

By altering the pH of the urine (5-7). More acidic urine will trap weak base, more basic urine will trap weak acids.

70
Q

What are OATs, OCTs, and P-glycoprotein?

A

Organic anion transporters and organic cation transporters transport organic cations and anions AGAINST their respective concentration gradients into the kidney filtrate. These exist in the liver as well for biliary excretion. OATs and OCTs Some drugs inhibit one or the other and can therefore affect clearance of themselves and other drugs.

71
Q

Which drugs tend to be eliminated through biliary excretion?

A

Large molecular weight drugs, glucuronides, glutathione metabolites, sulfates, steroid hormones and conjugates.

72
Q

What are some pharmokinetic considerations for elderly patients?

A

Drier- smaller central compartment. Decreased Renal function (both filtration and blood flow), decreased liver size and function (smaller 1st pass), reduced p450 function (except cypA4), decreased perfusion of tissues.

73
Q

How can you estimate drug clearance efficiency of the kidneys?

A

Measure patient creatinine clearance, which is proportional to renal drug clearance. Then apply the Cockrott-gault equation. 140-age * wt(kg)/72 * [serum creatinine) = drug clearance (multiply by 0.85 for females).

74
Q

Which drug metabolic effects do NOT change with aging?

A

Absorption does not change with age (except transdermal route which is reduced).

75
Q

What are some pharmacodynamic changes that occur in elderly adults?

A

Most receptors, including alpha and beta adrenergic receptors, have decreased sensitivity. This means there is a loss of tachycardic response to sympathetic stimulation and an increase in vasoconstriction due to decreased vasodilatory effects by beta 2 adrenergic receptors. Conversely, CNS sensitivity tends to increase in the elderly. So drugs that depress CNS function should be given in lower doses.

76
Q

Why are there more adverse drug reactions among the elderly?

A

Basically, they take more drugs for more diseases. They are not at an increased risk of adverse events after controlling for the number of drugs they take.

77
Q

List some clinical strategies for reducing adverse events in elderly patients?

A

Evaluate need for therapy, take a CAREFUL history that includes all drugs and supplements that they take. Know the pharmacology of the drug. Begin therapy with low doses and titrate to the patient. Regularly review the plan and try to simplify therapy and eliminate unnecessary drugs. Always be suspicious.

78
Q

What is the critical period for organ development in a fetus?

A

1st trimester.

79
Q

teratogens

A

Drugs that can cause birth defects when taken by pregnant women. Most famous is thalidomide which causes body and limb malformations.

80
Q

DES

A

a drug marketed to women who had serial miscarriages. Caused increased risk of clear cell carcinoma of vagina (a VERY rare cancer).

81
Q

What are the largest causes of birth defects among women in the US?

A

Unknown, followed by congenital and cytogenic.

82
Q

Teratogenic class A

A

The best human studies show no risk.

83
Q

teratogenic risk category B

A

No evidence of risk in humans. Animal studies either show risk that has not been found in humans or animal studies show no risk and no adequate human studies have been conducted. Eg prednisone.

84
Q

teratogenic risk category C

A

Risk cannot be ruled out. Human studies are lacking and animal studies are either positive for fetal risk or lacking as well. Most drugs fall in this category.

85
Q

teratogenic risk category D

A

positive evidence of risk, but benefits may outweigh risks. Warfarin, lithium.

86
Q

tetragenic risk category X

A

Evidence of risk, contraindicated. Eg thalidomide.

87
Q

What are some pharmokinetic considerations for young and growing children?

A

Elimination mechanisms are not fully developed in newborns (cause of physiologic jaundice), blood-brain barrier is more permeable, Vd is relatively larger because they are more hydrated.

88
Q

What is the enterohepatic cycle?

A

Glucuronidated drugs are actively transported into the biliary duct and into the intestine. There gut bacteria remove glucuronic acid and the drug is free to be reabsorbed. Essentially it is a reservoir of drug. Antibiotics can reduce drug bioavailability if drug is primarily eliminated through biliary mechanism.

Pharmacology-TJA (6 decks)

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