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MHD - Exam 1 > Pharm - #7 > Flashcards

Pharm - #7 Flashcards

1
Q

New medicines initiated at ______ possible doses.

A

Lowest

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2
Q

What are 3 mechanisms of drug toxicity?

A
  1. ON-TARGET ADVERSE EFFECTS
  2. OFF-TARGET ADVERSE EFFECTS
  3. IDIOSYNCRATIC EFFECTS – MECHANISM NOT KNOWN
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3
Q

What are 2 examples of on-target adverse effects?

A

a. DRUG BINDING TO ITS INTENDED RECEPTOR (SITE OF ACTION)
ADVERSE EFFECT MAY BE EXAGGERATION OF INTENDED ACTION
- exaggeration of indented action

(conc. too high, suboptimal kinetics, deliberate/accidental dosing error)

b. duration of drug exposure
ex: anti-psychotics TARDIVE DYSKINESIA

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4
Q

WHat is off-target adverse effects?

Can you give an example of a drug that has an unintended consequence related to heart function?

A
  1. drug designed to bind to target A for therapeutic efficacy, but also binds to target B leading to toxicity
  2. antihistamine TERFENADINE– H1 antagonist – therapeutic site- also binds to hERG (human subunit of IKr potassium channels;

and inhibits potassium currents

–> increase in heart-rate corrected QTc interval

  • can lead to cardiac arrhythmias, including torsades de pointes and sudden death -

all new drug candidates tested for binding to hERG in vitro and if drug makes it to clinical trial evaluated for ability to prolong QT interval in individuals

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5
Q

WHat are 3 off-target adverse effects?

A
  1. drug binding to unintended target
  2. unintened activation of different receptor subtypes
  3. Enantiomers
  4. Idiosyncratic effects
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6
Q

Unintended activation of different receptor subtypes is called____

What drug is an example of this off-target adverse effect?

What patient poppulation is this contraindicated in?

A

Unintended activation of different receptor subtypes

  • drugs non-selectively target receptor subtypes

ex: B1 = HR & contractility
B2 adrenergic = smooth muscle cells of airways 7 vasculatre

  1. Beta blockers (b1 antagonist) to control HR and reduce oxygen demand
    - not all selective for B1 and can also effect B2
    = B2 blockade leads to BRONCHOCONSTRICTION
  2. Non-selective β-blockers contraindicated in asthmatics
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7
Q

Define the off-target adverse effect of enantiomers.

example of a drug?

How are entantiomers evaluated by the FDA?

A

Lock – key: drug receptors sensitive to 3-dimensional structure of drugs

Thalidomide:
racemix mixture of R & S

R = sedative
S = teratogen that leads to birth defects

3.Presently Enantiomers are evaluated by FDA as separate entities

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8
Q

What is an idiosyncratic effect?

What is it linked to?

A

UNKNOWN CAUSE - HAPPENS IN SMALL FRACTION OF PATIENTS
NOT SEEN IN PRECLINICAL OR CLINICAL TRIALS

– peculiar to a given individual

*** Linked to genetic polymorphisms: PK and/or PD variability **

UNPREDICTABLE: IF CAUSES ORGAN FAILURE OR DEATH
DRUGS REMOVED FROM MARKET

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9
Q

What are factors affecting drug toxicity? (5)

A
  1. Interaction of absorption
  2. Interaction with protein binding
  3. Interaction of metabolism
  4. Interaction of receptor binding
  5. Interaction of therapeutic action
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10
Q

What is another definition term for a drug that is highly protein bound that is displaced from plasma proteins by other drugs or become saturated in physiological states that lead to hypoalbuminemia?

A

Dispositional Antagonism

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11
Q

How is ethanol metabolized?
(2)

What does its metabolism impact?

A
  1. Alcohol Dehydrogenase
  2. CYP2E1

it also induces the expression of CYP2E1 at
the transcriptional level

  1. this impacts the metabolism of common over-the-counter drug acetaminophen
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12
Q

When is acetaminophen metabolized (phase I or II)

What else metabolizes a small amount? (alcohol uses this as well)

What is it metabolized to?Is this toxic?

A

actetaminophen is primarily metabolized in phase II reactions: glucuronidation and sulfation reactions

  1. CYP2E1
  2. to N-acteyl-p-benzoquinoneimine (NAPQI)

NAPQI is toxic, but is rapidly conjugated with glutathione to a non-toxic metabolite that is easily excreted when normal doses of acetaminophen are taken

-glutathione can be easily depleted and NAPQI can accumulate -
NAPQI is highly toxic

i. e. liver damage alcohol consumption (e.g. 6 cans of beer with 6-7 hr period) can induce expression levels of CYP2E1)this will lead to increased production of NAPQI if acetaminophen is taken at this time - increased risk of toxicity
- ALCOHOL, at least in part, is also metabolized by CYP2E1 and thus can competitively inhibit acetaminophen metabolism and be protective if consumed at the same time or shortly after taking an acetaminophen dose

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13
Q

What is another term for PAM (positive allosteric modulators) that bind to site of action of a drug

A

Potentiation

PAM – enhance agonist binding to site of action
(positive allosteric modulators)
NAM – decrease agonist binding to site of action

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14
Q

What is interaction of therapeutic action?

What is another term? (2)

What is an example of 2 drugs that can increase the risk of bleeding due to these effects?

A
  1. Two different drugs that have distinct mechanism of action but have same therapeutic effect
  2. Additive/Synergistic Effect
    1) E.g. aspirin – (blocks platelet activation)

2) plus heparin (anti-coagulant)
= increase risk of excessive bleeding

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15
Q

What is the difference between chemical & dispositional antagonism?

A

Chemical antagonism – Chemical antagonism: chemical reaction between two drugs to neutralize their effects – chelation therapy***

Dispositional antagonism – alter absorption/distribution/excretion (i.e. disposition) so that less drug gets to site of action

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16
Q

Review the 1st 2 types of hypersensitivity reactions

A

i. Type I hypersensitivity response
- immediate hypersensitivity or anaphylaxis
- due to antigen-binding IgE on mast cells
- antigen may be foreign protein or endogenous protein modified by hapten
- manifest as wheal-and-flare reaction in the skin; hay-fever like symptoms may
develop in upper respiratory tract; asthmatic bronchoconstriction may pccur in lower respiratory tract

ii. Type II hypersensitivity response
- antibody-dependent cytotoxic hypersensitivity
- drugs bind to cells – usually red blood cells and is recognized by IgG
- IgG binding triggers cell lysis
Rare: can be caused by penicillin and quinidine

17
Q

Review the 3rd and 4th hypersensitivity reactions and what cause them.

A

iii. Type III hypersensitivity response
- immune complex mediated hypersensitivity
- usually occurs when IgG or IgM form against soluble antigens
- antigen-antibody complexes are deposited in tissues such as kidney, joints and
lung vascular endothelium- complexes activate leukocytes and complement in tissue – cause serum sickness, leading to damage

iv. Type IV hypersensitivity response
- due to activation of TH1 and cytotoxic T cells
- presents as contact dermatitis
- first exposure not a problem; second dermal exposure could activate T cells that
go to skin
- examples: reaction to poison ivy

18
Q

Autoimmunity induces ____ like syndrome..

What is the cause of RED MAN SYNDROME?

is it caused by IgE?

What are symptoms

What can it proceed to?

What can be given prophylatically?

A

Lupus like

  1. drugs acting directly on mast cells leading to degranulation
    - linked to i.v. infusion of DRUGS (e.g. antibiotic vancomycin)

***not caused by IgE

cutaneous wheals and urticarial to neck, arms, upper trunk

  • can proceed to angioedema and hypotension in rare cases
  • antihistamines prophylactically
19
Q

Skin rashes are diagnosed as _____ ____.

What is the most severe type of skin rash?

Where is there inflammation?

What are symptoms?

What is it observed with?

A
  1. Erythema multiforme
  2. Steven-Johnsons Syndrome
  3. morphologic appearance of mucous membrane and skin inflammation
  4. blisters and separation of the epidermis from the dermis
  5. observed with many commonly prescribed and over-the-counter drugs
20
Q

What is the indirect effect of immunotoxicity on immune system?

A

Non-selective cancer drugs target or kill proliferating neoplastic cells
(targeted therapy: Herceptin & Gleevec)

herceptin = her2neu
gleevec = treat chronic myeloid leukemia (CML)

** also damage the cells in the bone marrow, lymphoid tissues, intestines and hair follicles at therapeutic doses **

safety margin low for cancer drugs; always risk to damage normal tissues

-increased risk of infection if white blood cells are compromised

21
Q

What is the direct effect of immunotoxicity on immune system?(example of drug for COPD)

Caveat?(increased risk of what?)

A
  1. inhaled corticosteroids to treat patients with frequent and severe COPD
  2. reduces overall immune response – increased risk of pneumonias!
22
Q

What is the main cause of liver toxicity?(overdose of what)

What is depleted because of this overdose?

What accumulates?

Result = necrosis of what?

Antidote?

A
  1. Acetaminophen overdose
  2. acetaminophen
    over dose can lead to glutathione depletion
  3. which can lead to
    accumulation of toxic metabolite NAPQI – this metabolite can attach to cellular and mitochondrial proteins resulting in
  4. necrosis of hepatocytes
  5. N-acetylcysteine can be used as an antidote if given within 10 hrs of overdosing

**acetaminophen overdosing accounts for over 50% of acute liver failure in US per year

23
Q

What is idiosyncratic hepatotoxicity?

A

Unknown mechanism of liver failure
- drugs have to be removed from market

ex: troglitazone (insulin sensitizing agent) - removed from market when discovered that 1 in 10,000 pts. died from acute liver failure

– large sample size key to revealing toxicity

24
Q

What are the most common causes of RENAL toxicity?

example of a drug?

mechanism?
Cells die by necrosis or apoptosis?

A
  1. CAUSED by certain antibiotics, NSAIDs
  2. Example: gentamicin – aminoglycoside antibiotic:
  3. inhibition of lysosomal hydrolases in proximal tubules
    - changed lysosome structure
    • lysosomes burst
  • cells die by necrosis!!!!! (NOT BY APOPTOSIS)
  • may be reversible by stopping treatment

**nephrotoxicity can lead to changes in renal hemodynamics, tubular damage, and obstruction, glomerular nephropathy or interstitial nephritis

25
Q

What are teratogensis?

A
  • drugs given to pregnant women can affect fetus
  • teratogenesis is the induction of structural defects in the fetus caused by a teratogen

maternal absorption, distribution, metabolism and excretion will dictate drug exposure to fetus

26
Q

categories of teratogenesis:

Which is controlled studies; no risk to fetus in first trimester and no evidence of risk throughout pregnancy = SAFE DRUG!!!

Which is:risk observed in preclinical studies, but no studies in women have been done

Which is:risk observed in preclinical studies, but no studies have been done in women, but benefit may outweigh risk

Which is:some evidence of risk to fetus, but benefit may outweigh risk

Which is:clear evidence of risk to fetus, but risk clearly outweighs benefit!!!!

A

Category A – controlled studies; no risk to fetus in first trimester and no evidence of risk throughout pregnancy = SAFE DRUG!!!

Category B – no risk observed in preclinical studies, but no studies in women have been done

Category C – risk observed in preclinical studies, but no studies have been done in women, but benefit may outweigh risk

Category D – some evidence of risk to fetus, but benefit may outweigh risk

Category X – clear evidence of risk to fetus, but risk clearly outweighs risk!!!!

27
Q

Discuss Drug induced neurotoxicity

A

D. DRUG-INDUCED NEUROTOXICITY

  • mainly caused by certain anti-cancer drugs- associated with peripheral nerves, but CNS can be affected too– peripheral neuropathy has been linked to vinca alkaloids (e.g. vincristine, vinblastine), taxanes (e.g. paclitaxel) and platinum compounds (e.g. cisplatin)
  • vinca alkaloids and taxanes work by disrupting microtubules, thereby altering axonal trafficking in motor and sensory neurons, which explain why they cause peripheral neuropathies
28
Q

Discuss Drug induced skeletal muscle toxicity.

A 
E. DRUG-INDUCED SKELETAL MUSCLE TOXICITY 
- drug class that cause skeletal muscle injury include statins, corticosteroids and zidovudine
  • statins affect geranyl-geranylation of muscle proteins – likely cause of
    muscle damage
  • corticosteroids affect many cellular processes which can impact muscle growth/structure - reversible
  • zidovudine – used to treat HIV- HIV can cause myopathy

– drug causes myopathy in preclinical trials

– mechanism leading to myopathy unknown

29
Q

Discuss Drug induced Cardiovascular toxicity (3 major classes)

A
  • can be divided into three major class
    1. many drugs interact with cardiac potassium channels to cause QTc prolongation
    2. drugs can directly act on myocytes and lead to toxicity
    3. some drugs are toxic to heart valves
30
Q

Discuss Drug induced Pulmonary toxicity

A
  • injury can be acute and reversible exacerbations of asthmatic symptoms or chronic injury due to remodeling and/or fibrosis- beta-agonists can cause reversible obstruction of airways- chronic injury has been linked to bleomycin (chemotherapeutic agent) and amiodarone (antiarrhythmic)
  • repeated insult to lung epithelial cells lining conducting airways and alveoli may be followed by regeneration- repeated cycles of epithelial injury can lead to fibrosis where excessive collagen is deposited into alveolar space leading to loss of function
31
Q

Discuss carcinogenesis due to drug therapy

A

G. CARCINOGENESIS DUE TO DRUG THERAPY
- drugs can damage DNA – leading to uncontrolled growth

– carcinogenesis is a complex process that can take years to develop – drugs that cause DNA damage are avoided

  • but to treat neoplasias

– DNA damaging drugs are used

  • these drugs can affect blood cell progenitors and cause myeloid dysplasia and/or acute myeloid leukemia (AML)

– 10-20% of AML in US caused by such anticancer drugs

MHD - Exam 1 (13 decks)

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