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PH 2306 - Toxicopharm > Mod 7 Exam > Flashcards

Mod 7 Exam Flashcards

1
Q

Pharmacodynamics vs. pharmacokinetics

A

dynamics = effect of a drug

kinetics = fate of the drug

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2
Q

Bioavailability definition and equation (oral admin)

A

% of the drug that enters the systemic circulation unchanged

BA = AUC(oral)/AUC(IV) x 100%

note: oral = hill graph; IV = downwards ski slope

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3
Q

Acquired functional tolerance vs. dispositional

A

AFT - due to repeated dosage.

Dispositional - due to decrease quantity of the drug reaching target

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4
Q

Examples of parenteral route drug admin. What’s unique about this method?

A

IV, IM, subscutaneous, intraperitoneal

membrane bypass

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5
Q

Which mode of drug admin does not experience the first pass effect?

A

sub-lingual

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6
Q

What types of capillaries do you see in the brain?

A

BBB - occluded (tight gates except for area postrema, hypothalamus, pituitary gland)

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7
Q

Where would you see fenestrated capillaries?

A

kidneys, pituitary, exocrine glands (secretion or excretion)

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8
Q

Typical range for molecular weights of drugs

A

40-450 Da

1000 Da max; or else it can’t cross the capillaries

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9
Q

If there are 2 or + drugs competing for albumin binding sites…what would you expect to see?

A

elevated levels of free drug in the blood

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10
Q

MC mode of bio-membrane movement

A

passive diffusion (water and lipid soluble) down a [C] gradient

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11
Q

What is the relationship between the partition coefficient and lipid solubility of a drug? What is the cut off phenomenon?

A

greater the partition coeff, the more soluble it is

after a certain point, absorption slows down

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12
Q

T or F: the absolute solubility of a drug is less important than its ratio of solubility water and lipid

A

T

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13
Q

3 physio-chemical characteristics that govern drug movement across membranes (aka.absorption)

A

MSD

molecular size
solubility
degree of ionization

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14
Q

Define each

agonist
full agonist
partial agonist

antagonist
reversible competitive antagonist
irreverisble antagonist
non-competitive antagonist

A

Agonist = drugs + receptor = response
Full agonists = drugs + receptor = maximal response
Partial agonists = drugs + receptor = cannot produce maximal response

Antagonists = drugs + receptor = no response (block endogenous or pharm agonists)
Reversible competitive antagonists = compete with agonists for the same site on a receptor and they bind reversibly.
Irreversible antagonists may also compete with agonists for the binding site, but they bind irreversibly to the site.
Non-competitive antagonists (allosteric) bind to different sites on the receptor than the site to which the agonist binds and inhibits the action of the agonist

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15
Q

State the two equations for pKa-pH for acid and bases.

When is 50% of the molecule ionized?

A

pKa - pH = log [unionized/ionized] = acids (freely release protons)
pKa - pH = log [ionized/unionized] = bases (freely accept protons)

50% ionization when pH = pKa

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16
Q

Differentiate what an acidic drug vs a basic drug would do in the stomach (aka. low pH enviro).

A

acidic drug will not ionize in an acidic environment thus it can cross membranes to be absorbed; vv for a basic drug (thus its absorption is worse in the stomach or a low pH enviro)

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17
Q

What is the first pass effect?

A

usually in the liver; once something gets into the systemic circulation; liver sees it first and will process/remove it from the blood.

this explains the dramatic decrease of the [C] of a drug

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18
Q

What % of the pop. can have a variant in order for it to be deemed significant?

A

1%

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19
Q

How many half lives to reach steady state on average? When does this usually apply?

A

5 HLs

oral admin

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20
Q

How do you calculate the apparent drug volume of distribution?

A

C=M/V

make sure you consolidate units

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21
Q

What’s first order kinetics?

A

HL of a drug is the time elapsed for its [C] to be reduced by 50% during elimination phase

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22
Q

LD50/ED50 = what?

LD1/ED99 = what?

A

therapeutic index

certain safety factor/margin of safety

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23
Q

Potency vs. efficacy

A

efficacy = are you producing the desired effect?

potency = dose required to produce 50% of the max response….OR to produce the therapeutic effect in 50% of the subjects (ED50)

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24
Q

When you think of “seven transmembrane” receptors, what do you think of?

A

G-protein-coupled receptors (fam of cell surface receptors) - hormones, NT, PG

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25
Q

Naloxone is a what to an opioid receptor (ie. morphine)?

A

pure antagonist at the Mu Receptor

26
Q

EPI is a what to an salbutamol receptor?

A

physiological antagonist

27
Q

Inhibitor of alcohol dehydrogenase?

A

fomepizole

28
Q

Why do you get less drunk off methanol than ethyl alcohol?

A

methanol cannot cross BBB as easily. note: it is transformed into formaldehyde, formic acid which can cause nerve damage and acidosis

29
Q

LDR (log dose response) represents what?

A

dose of a drug that will produce the desired therapeutic action without side fx

30
Q

When would the LDR graph shift right?

A

increase [agonist]

31
Q

If you see the maximum response/point dropping (drug is diminishing while shift), it is likely that it is an ____________ ANTAGONIST

A

IRREVERSIBLE

in a competitive antagonist, there is no decrease in max point because

Reversible competitive antagonists compete with agonists for the same site on a receptor and they bind reversibly.

32
Q

Signs of carbon monoxide poisoning

A

CO higher affinity to Hb than O2

cherry red blood

33
Q

What is the P450 system?

A

system to metabolize exo/endogenous substances

cytochrome P450 (CYP) = fam of isoenzymes (liver and GI)

any drug can be a substrate for one isoenzyme

P450 changes the compound, marks it for elimination

requires O2

34
Q

Oxidation, demethylation, deanimation, and hydrolysis (reduction) are all..

A

phase 1 reactions - conversion for other biological use, as well as phase 2 reactions

35
Q

glucuronidation, acetylation, sulfation are all…

A

phase 2 reactions - TERMINATE BIOLOGICAL ACTIVITY; more easily excrete-able

36
Q

Name a probe drug for P450 function

A

dextromethorphan (cough supressant in cough syrups)

you can use dextro to track its HL to assess P450 function

37
Q

Enzyme induction/inhibition of durg and toxin biotransformation…what are the consequences?

A

faster generation of toxic metabolites

38
Q

Steatosis vs. cirrhrosis, and cholestasis?

A

 Steatosis (fatty liver): accumulation of TG in hepatocytes; normally reversible response; does not usually lead to cell death.

 Cirrhosis: chronic lesion resulting from repeated injury and subsequent repair; hepatocyte or cholestatic damage.

 Cholestasis: bile stasis or damage to bile ducts, ductules or canaliculi.

39
Q

Reduced glutatione = ?

A

GSH

this is protective mechanism in liver cells

Glutathione (GSH) is an antioxidant in plants, animals, fungi, and some bacteria and archaea. … Glutathione exists in both reduced (GSH) and oxidized (GSSG) states.

40
Q

Zone 1 vs. Zone 3 of the liver. Which one is most often damaged due to lipid accumulation?

A

Zone 1 = periportal: hepatocytes are more aerobic and have more GSH. Also contain
alcohol dehydrogenase.

Zone 3 = centrilobular: hepatocytes have a higher level of cytochrome P450 and lipid synthesis is higher in this area. This zone is most often damaged (lipid accumulation).

41
Q

The _______ cells, which line the sinusoids and constitute another major group of cells in the liver may also be involved in the removal of foreign substances from the blood by phagocytosis.

A

Kupffer

42
Q

Acetaminophen-induced toxicity (Tylenol)

Acetaminophen (paracetamol) is a widely used analgesic and antipyretic drug with minimal anti-inflammatory activity that is relatively safe when taken at recommended oral doses.
Inhibits prostaglandin synthesis in the CNS and restores set point temperature regulation and increases pain threshold, but has less effect on cylcooxygenase in peripheral tissues.
Has been taken for suicidal intent.
Responsible for hepatic damage that may require transplantation.
It causes centrilobular hepatic necrosis.

Mechanisms of acetaminophen toxicity.

A 
Formation of a reactive metabolite through the action of 
P450 isozyme (phase I) —> Depletes hepatic GSH due to oxidization of GSH to GSSG and to form a conjugate (neutralize) —> increase in intracellular Ca & binding of the reactive metabolite + sulfhydryl groups and hepatic/mito proteins —> cellular necrosis
43
Q

Mechanisms of iproniazid toxicity (treatment of TB, also an antidepressant)

A

Iproniazid discontinued due to the potential for serious hepatotoxicity associated with its use, particularly in individuals classified as slow acetylators.

44
Q

Mechanisms of carbon tetrachloride toxicity.

A

Carbon tetrachloride: Can be converted into trichloromethyl radical, can be converted into chloroform (can overload P450 system and trigger too many ROS)

Tetrachloride + chloroform = depressants of CNS

45
Q

3 Serum enzymes used to assess liver damage.

A

ALP, ALT, AST

 Alanine aminotransferase: ALT – found mainly in liver; increase reflects
primarily hepatocellular damage.
 Aspartate aminotransferase: AST – less specific than ALT; hepatocellular
damage.
 Alkaline phosphatase: ALP – increase reflects cholestatic injury.

46
Q

Methemoglobin and its use to treat cyanide poisoning?

A

 It is used as a treatment for cyanide poisoning. It can also be toxic if there is
too much in the body.
 Methemoglobin (oxidized hemoglobin) has a greater affinity for cyanide than
hemoglobin.
 Induce methemoglobinemia with sodium nitrite
 Tissue death can happen very rapidly and the toxic effect is known as
histotoxic hypoxia.

47
Q

3 metal induced kidney damage

lead
mercury
cadmium

A

Lead: chronic exposure causes tubular cell atrophy

Mercury: accumulates in the kidney. Inorganic mercury may be trapped in the brain (Mad Hatter disease). Mercury binds to cellular components such as enzymes, especially to proteins containing sulfhydryl groups.

Cadmium: accumulate in the kidney as a complex with low molecular
weight protein metallothionein. When the complex is reabsorbed in the
proximal tubule (endocytosis) cadmium is released and causes cell damage probably by binding to sulfhydryl containing proteins.

48
Q

When there is a proximal tubule injury of the kidney, there is a….

When there is a glomerular injury of the kidney, there is a….

A

high concentration of low molecular weighted proteins

high concentration of…low AND high weighted proteins (ie. large amounts of albumin)

49
Q

How is probencid related to penicillin?

A

 Probenecid competes with penicillin for active secretion by the tubular acid secretion system, which also secretes uric acid.

 Facilitates the reabsorption of penicillin because it was very expensive when it was first manufactured.

50
Q

3 renal processes

A

glomerular filtration
tubular re-absorption
tubular secretion

51
Q

Acidifying the urine promotes the excretion of chemically ____ drugs.

Alkalizing the urine promotes the excretion of chemically ____ drugs.

A

basic

acidic

52
Q

In a healthy kidney, only what form a drug can be filtered out?

A

unbound (free fraction)

53
Q

3 MC ROS

A

superoxide, hydroxyl radical, hydrogen peroxide

54
Q

3 endogenous scavengers for ROS in the body

A

superoxide dismutase, catalase, and glutatione peroxidase

antioxidants can also be neutralizers

55
Q

Protective role of scavengers and GSH.

A

Superoxide + superoxide dismutase = hydrogen peroxide. Hydrogen peroxide is reduced to water by catalase and glutathione peroxidase (mito cytosol)

Hydroxyl radicals are produced by several reactions. The enzyme that removes hydroxyl radicals is glutathione peroxidase.

56
Q

Reduced glutathione = ?

Oxidized glutathione = ?

A
  • GSH: reduced glutathione (donates H to become GSSG)

- GSSG: oxidized glutathione

57
Q

The enzyme responsible for the detoxification reaction that removes hydroxyl radicals is ….

A

Remover of hydroxyl radicals is glutathione peroxidase.

58
Q

GSSG crosses plasma membranes more readily than GSH – convert back to GSH so it doesn’t leave the cell. What co-factor is requied?

A

need cofactor NADPH to recycle GSSG to GSH

59
Q

Receptor-mediated toxicity

A

Caused by the binding of the parent compound to a receptor, an enzyme, or an ion channel.

Toxicity is dose-related and often predictable; specific to tissues if you know their targets (receptors). Adverse events will stop if exposure stops.

Drugs or chemicals that bind to the same receptor will act as agonists, partial agonists, or antagonists.

Only a handful of pure antagonists that can act as pharmacological antidotes to reverse acute toxicity (compare to antihistamines, antihypertensives, proton pump inhibitors).

Naloxone for emergency treatment and naltrexone (stronger than naloxone) for opioid(heroin) addiction treatment.

60
Q

Organophosphate pesticides

A

Toxicity is caused by inhibition of cholinesterase (hydrolysis of acetylcholine) Inhibition involves a blockade of the active site of the enzyme (pseudo substrate).

In the case of malathion or parathion metabolism is necessary to produce an inhibitor such as malaoxon.

The enzyme is phosphorylated and effectively blocked.
The toxicity will depend on the affinity of the enzyme for the inhibitor. Inhibition may become permanent with ‘aging’.

Treatment involves pralidoxime and atropine.

61
Q

What enzyme maintains high levels of NADPH, and indirectly maintains high levels of GSH to protect Hb from oxidizing agents

A

G6P-dehydrogenase

62
Q

Biotransformation Article

A

Drug biotransformation includes:

1) Activation (from an inactive precursor); L-dopa (inactive) is converted to dopamine (active) in the basal ganglia
2) Maintenance of activity (transformed again into another active metabolite); diazepam (active) into oxazepem (active)
3) Inactivation - pentobarbital (active) into hydroxylated metabolites (inactive).

Generally speaking, biotransformed substances are MORE WATER SOLUBLE.

Xenobiotics: substances that are foreign to the body or to an ecological system

Usually it’s the same enzymes that transform xenobiotics that play a role in the synthesis of endogenous substances (steroid hormones, CHOL, bil acids)

Phase I reactions:
- Make the molecule more polar by added a functional group
Phase II reactions:
- Conjugation; combine the result of Phase I with endogenous substances (glucuronic acid, glutathione)
- Usually result in decrease pharm activity
- Most drug go through both phases, but some can be eliminated after Phase I (depends on the parent drug)

Liver: most important organ for BT (others: GI, lungs, skin, kidneys)
Intestine – gut bacteria can biotransform drugs as well, and the drug can be reabsorbed and re-enter the liver via the portal vein

PH 2306 - Toxicopharm (1 decks)

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