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Pharm block 1 > Drug-Drug interactions > Flashcards

Drug-Drug interactions Flashcards

1
Q

The efficacy of any drug is dependent upon what?

A

the complex interplay between multiple processes governing biodistribution and receptor-mediated response.

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2
Q

the four processes governing biodistribution can be broken down into what?

A

ABSORPTION, DISTRIBUTION, METABOLISM and ELIMINATION.

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3
Q

One factor governing drug absorption
following an oral drug dose is what?

Describe the time attribute

A

local pH in the upper and lower GI tract which can influence the degree of drug ionization

(dependent upon pH and pKa

time-dependent extent of drug uptake from the stomach or duodenum.

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4
Q

With regard to the stomach, there are several types of drugs that, when taken concurrently with other (target) agents, can reduce the extent of uptake into the body, i.e….?

A

they reduce the BIOAVAILABILITY of the concurrent target agent.

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5
Q

What are the drugs taken wrt the stomach that can reduce the bioavailability of the concurrent target?

A

extremely common antacids (Tums, Rolaids, etc.) together with prescription and over-the- counter (OTC) proton pump inhibitors (Prevacid OTC; Esomeprazole) and histamine H2 blockers (Famotidine, Nizatidine)

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6
Q

A combination of antacids, proton pump inhibitors and histamine H2 blockers have what effect on the gastric pH?

A

raise gastric pH from 1-1.5 to more neutral level

  • reduces systematization of drugs that rely upon an acid environment for easy passage across gastric wall
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7
Q

An interaction with drugs of foodstuffs that chelate or chemically bind up the target agent. What is the result of this? give examples

A

preventing its uptake across the intestinal wall

milk, laxative products, and bile acid resins

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8
Q

Describe how bile acid resins reduce biovailability

A

used to bind up bile acids and thereby reduce lipid levels, but which also bind some concurrent agents, thereby reducing bioavailability

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9
Q

simple antacids and bile acid chelators are rare examples of drugs that have their CHEMICAL action without what?

A

binding to any recognized pharmacologic receptor systems

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10
Q

A third type of drug-drug or indeed drug- foodstuff interaction can occur where target and concurrent agents are what?

A

substrate for the same active (protein) transporter systems

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11
Q

inter-individual differences in the level of gene expression for these carriers and their functional capacity occur via what?

What does this impact? (4)

A

single nucleotide polymorphic (SNP) mutations

can significantly impact drug absorption from the GI tract, the extent of first-pass metabolism by the liver, access to the CNS (via the blood- brain barrier) and elimination by the kidney

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12
Q

hepatocytes contain a number of these active pump mechanisms. What are they responsbile for?

A

pumping substrate (drug) from the blood into the hepatocyte

removing the substrate from hepatocyte into the bile canaliculus.

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13
Q

When there is competition for the active pump mechanisms of the hepatocytes, what happens?

A

there is the possibility for reduced drug removal from the blood passing in the hepatic portal vein and “unusually” high serum drug concentrations in consequence

all blood from the upper GI tract takes this route

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14
Q

rectal administration of drugs, by suppository, avoids this so-called “first-pass” effect because why?

A

the blood serving the distal portion of the tract does not return to the general circulation via this hepatic portal route

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15
Q

interactions involving hepatocyte mechanisms will generally lead to

A

increased bioavailability

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16
Q

Where the interaction involves the mechanisms responsible for removing the substrate (drug or metabolite) from the hepatocyte into the bile canaliculus, this will generally lead to what?

A

delayed hepatic elimination and possibly also to altered pattern of hepatic metabolism, given the longer residence time in this organ

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17
Q

Describe phase I metabolism

A
  • oxidative reactions conducted by a family of hemoproteins commonly referred to as the cytochromes P450
    *
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18
Q

Where are the cytochrome p450 located?

A

located either in the inner membrane of mitochondria or or in the endoplasmic reticulum of cells

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19
Q

What are the roles CYP?

A

synthesis of steroids and bile acids and π-hydroxylation of fatty acids (4, 5, 7, 8, 11, 17, 19, 21, 24, 27 & 51)

facilitate elimination of xenobiotics and steroids from the body (1,2,3)

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20
Q

What is a xenobiotic?

A

a chemical which is found in an organism but not normally produced or expected to be present in it (drugs)

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21
Q

What are responsible for the majority of metabolic reactions involving drugs?

A

CYP 3A4/5 and 2D6

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22
Q

Patients with polymorphism of certain CYP genes cn have reduced enzyme activity or absence of enzyme function. So patients are categorized as what?

A

ultra-rapid metabolizer (UM),

extensive metabolizer (EM),

poor metabolizer (PM)

leads to significant patient-patient variation in drug action or toxicity.

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23
Q

Describe phase II conjugation processes

A
  • reactions attaching a large water-soluble moiety to increase polarity, involve primarily glucuronide>sulphate>glutathione conjugation
    reactions
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24
Q

What is a vital process in the
removal of prescription drugs from the body?

Of those metabolized, what process is involved in the majority?

A

metabolism

majority involved CYP-mediated process

25
Q

The process of conjugation can lead to what?

A
  • the elimination of some drugs without recourse to further metabolism
26
Q

Most drugs are inactivated by the process of what?

A

metabolism

27
Q

Anything that interrupts the metabolite pathway or rate can lead to what and, depending upon the dosing rate, causes what?

Where would a physician observe this?

A
  • persistence of drug
  • accumulating drug levels in the body

observe in patient’s vital signs or lab values classical toxicities associated with accumulating drug

28
Q

If the drug impacts the CNS you would see what?

A

diminished consciousness or coma.

29
Q

If a metabolite in the metabolism pathway is interrupted, wrt to the CNS what could be the results in CNS, neuronal tissue, and heart?

A

CNS => diminished consciousness or coma.

neuronal tissue =>drug might precipitate seizures, due to increased electrical activity

heart => might experience irregularities in conduction cycle or rate and secondarily suffer from abnormal BP and HR

30
Q

T/F Not every metabolic reaction leads to an inactive drug

A
31
Q

Some products can have comparable activity to parental drug and contribute to what?

A

the overall clinical effect that you the physician observe

32
Q

What are Prodrugs?

A
  • bioreversible derivatives of drug molecules that undergo an enzymatic and/or chemical transformation in vivo to release the active parent drug, which can then exert the desired pharmacological effect
33
Q

What typically converts prodrugs into its active form?

A

phosphatases, esterases, amidases or
peptidases in plasma or other tissues

34
Q

What are two principal reasons why a developer might take the prodrug approach with drug design?

A
  1. a drug might be so insoluble in aqueous solution as to present a problem for formulation or iv administration
  2. a developer might make use of tissue specific enzymatic activity to permit bio-activation in a localized area
35
Q

CYP activation of prodrugs to their respective active species is very important for certain drugs. What are 3 important examples of this?

A

anticancer drugs

cardiovascular drugs

opiate analgesics

HMG Co-A reductase inhibitor family

36
Q

Describe the CYP activation of anticancer drugs

A

CYP2B6 and CYP2C19 are highly polymorphic, such that some of their variant alleles have reduced or no activity compared with the wild- type allele.

These and other genetic factors are thought to play a role in the interindividual variation in both response and toxicity associated with cyclophosphamide-based therapies.

37
Q

Describe the CYP actiivation of tamoxifen

A

Tamoxifen itself has little affinity for the estrogen receptor; to exert its antiestrogenic effects in breast, tamoxifen must first be hepatically metabolized by CYPs to two active metabolites

It is now widely accepted that 2D6 genetic variants and drug interactions with 2D6 inhibitors can influence plasma concentrations of active tamoxifen
metabolites and negatively affect the therapeutic
outcome.

38
Q

Describe the CV drug losartin wrt to CYP actiivation

A
  • an angiotensin II receptor antagonist employed in the control of HTN
  • produced by 2C9 that is 10-40-fold more potent than the parental species, and it has a longer duration of action
  • patients with the PM phenotype for 2C9 experience a poorer drug response, dose-for-dose, than do EM or UR profile.
39
Q

Describe what the HMG Co-A reductase inhibitor family of drugs treat

A

treatment of hyper-lipidemias and work to lower the low-density lipoprotein (LDL) cholesterol concentrations in plasma by blocking cholesterol biosynthesis in the liver, which leads to an increase in the LDL clearance and an upregulation of LDL receptors.

decrease very low- density lipoprotein cholesterol and triglyceride concentrations and increase high-density lipoprotein cholesterol levels slightly

reduction in plasma levels of LDL cholesterol diminishes the risk for major cardiovascular events

40
Q

Another class of drugs for which CYP activity is important in terms of activity or toxicity is for some members of the statin, or HMG Co-A reductase inhibitor family. Describe these

A

Both parent drugs undergo extensive first-pass metabolism mainly involving 3A4 to pharmacologically active products.

concurrent use of 3A4 inhibitors has been shown to increase plasma drug concentrations by up to 20-fold.

a word of caution is required in regards to drug interactions involving CYPs. Just because an interaction can occur, it doesn’t mean that it will have clinical significance

41
Q

Describe lovastatin and simvastatin

A
42
Q

What is clopidogrel?

A

together with aspirin, achieved significant reductions in major cardiovascular events in patients with acute coronary syndrome in general and particularly among those treated invasively by percutaneous coronary intervention.

43
Q

Describe the CV drug clopidogrel wrt CYP activation

A

metabolically derived through CYP action.

2C19 seems to be the primary CYP responsible for the bioactivation of clopidogrel in humans

2C19 PM are at significantly higher risk of suffering adverse cardiovascular events, such as myocardial infraction, stent thrombosis, and death.

44
Q

What are the cornerstone of the management of cancer pain and post- operative pain and are used increasingly for the management of chronic non-cancer pain?

A
45
Q

What is a weak opioid analgesic, and a prodrug?

A

codeine

46
Q

T/F wrt codeine, there IS significant evidence that EM’s are at increased risk of drug toxicity.

A

true

47
Q

conjugation reactions add large water-soluble moieties to what?

A

drugs or to the products of phase I metabolism.

48
Q

The phase II reactions are heavily dependent upon what?

A

the easy availability of substrate, such as gluroronyl, sulphate or glutathione.

49
Q

When the “system” becomes overwhelmed, as in the case of acetaminophen overdose, describe what happens wrt to glutathione and metabolism.

A

glutathione stores become depleted

highly reactive intermediate of phase I metabolism binds immediately to surrounding protein, in this case hepatic tissue, giving rise to the acute hepatic failure for which overdose with this drug is famous.

50
Q

What is the response to the acetaminophen overdose?

A

antidote is to supply exogenous glutathione,

this prevents further toxicity but does not reverse the damage that has already been created.

51
Q

The purpose of the induction of drug- metabolizing enzymes is primarily for

A

accelerated metabolism of the chemicals being exposed to, which often inactivates and/or detoxifies these chemicals

52
Q

Describe the actions of inducer chemicals of CYP induction

A
  1. first bind the intracellular aryl hydrocarbon receptor (AhR)
  2. liganded AhR is translocated into the nucleus in a heterodimeric complex with the AhR translocator protein.
  3. nuclear AhR complex, acting as a ligand-dependent transcription factor, binds specifically to the aryl hydrocarbon responsive element (AhRE) in the CYP gene
  4. subsequently activates its expression.
53
Q

What are the 4 features generally associated with CYP induction?

A
  1. The CYP isoform that is induced after exposure to a chemical very often is the one capable of effectively metabolizing this chemical.
  2. Usually more than one CYP isoform are induced to varying degrees.
  3. Although exposure to an inducer chemical stimulates the biosynthesis of some CYP isoforms, often the biosynthesis of some other isoform(s) is simultaneously inhibited.
  4. The inducibility and the magnitude of induction of a CYP isoform often differ dramatically in different tissues/cells following exposure to the same inducer.
54
Q

the process of induction lags behind the initial exposure to the inducer for what reason?

How long does this last?

A

nuclear transcription must occur for the synthesis of new protein

persists for the life of the CYP protein after the inducer is no longer present

55
Q

CYP inhibition can be either what type of reactions?

A

either competitive or irreversible

56
Q

T/F The mechanism by which a drug inhibits CYP enzymes is predictable from the chemical structure

A

false, The mechanism by which a drug inhibits CYP enzymes is not necessarily predictable from the chemical structure

57
Q

T/F CYP inhibition mechanism can only be determined experimentally

A

true

58
Q

T/F metabolites of one CYP-mediated reaction can inhibit concurrent CYP pathways or indeed induce enzyme activity

A

true

59
Q

Drugs can do what to their own metabolism, or that involving other CYP pathways.

A

induce or inhibit

Pharm block 1 (7 decks)

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