Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

General Med 1 > Path - Pharm - Exam 3 > Flashcards

Path - Pharm - Exam 3 Flashcards

1
Q

How is site crucial to the success of antibiotic therapy and resistance control?

A

acquiring and maintaining effective drug concentrations at an infection site is crucial

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What is the difference between pharmacokinetics (PK) and pharmacodynamics (PD)?

A

PK – fate of drugs within the body. ADME:

  • Absorption
  • Distribution
  • Metabolism
  • Excretion

PD – the effects drugs exert on the body
- mechanisms of drug action

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the two modes of action of antimicrobial antibiotics?

A
  1. Bactericidal
    - Kills them, I,e, penicillins etc
    - preferred for serious infection where host defense is inadequate
    - MBC ~ MIC
2.	Bacteriostatic - 
Inhibition (i.e. stops them from reproducing) without necessarily killing them
- tetracyclines etc
- useful for most infections
- requires immune system assistance
- MBC>>MIC
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

What curve is used to measure drug exposure?

A
  • Area Under Curve (AUC)
  • [plasma] vs time
  • can find bioavailability and relative levels of exposure to oral vs IV route by comparing them
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

How can knowing how PK variables (fate of drug within body) influence drug efficacy (‘PD response’) improve antibiotic use?

A
  • better design of dosages and dosing interval
  • may help limit selection of drug resistant mirobe strains
  • especially important with critically-ill patients, i.e. sepsis
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What is the relationship between drug concentration and antimicrobial effect?

A

Concentration vs bacterial burden
Hill curve – starts high then suddenly declines (Z)
EC50 = halfway between the top and bottom of the curve
Emax = difference between bottom and top of curve

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What is MIC and how can it be determined?

A

Minimum inhibitory concentration – least amount which stops bacteria growing visibly
Calculated in vitro and then used as reference plasma concentration in humans

Agar plate + E test. Plastic strop with gradient of antibiotic concentrations.
‘Zone of Inhibition’ – no bacteria. End – MIC.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

What is post-antibiotic effect?

A

PAE shows if a drug has persistant action even after concentration levels fall below MIC

What is MBC?

Minimal bactericidal concentration
Least amount of antibiotic which KILLS bacteria

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

How can MIC be used to show the different PK-PD relationships?

A
  1. Time dependent PD
    T > MIC is Key PK-PD endpoint
  2. Concentration dependent PD
    Cmax:MIC , or
    AUC > MIC is Key PK-PD endpoint
  3. Mixed PD
    AUC : MIC is Key PK-PD endpoint
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

What is the relevant info about time dependent PD?

A

T > MIC is Key PK-PD endpoint

  • i.e. the time that you have a concentration > MIC
  • when [plasma]>MIC, rate and extent of killing is maximal regardless of [].
  • use of shorter dosing interval may improve outcomes

Antiobiotics:

  • beta lactams
  • vancomycin
  • macrolides
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What is the relevant info about concentration dependent PD?

A

AUC > MIC is Key PK-PD endpoint
- strong post-antibiotic effect

Antibiotics:
 Cmax/MIC = aminoglycosides
AUC>MIC = 
-	fluoroquinolones
-	ketolides
-	macrolides
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

What is the relevant info about concentration dependent PD?

A

AUC : MIC is Key PK-PD endpoint

  • i.e. killing related to drug concentration and time > MIC
  • mainly bacteriostatic
  • Ratio of 24 hr AUC to MIC

Antibiotics:

  • tetracyclines
  • macrolides
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

How do you decide on the type of PK-PD relationship?

A

Best R2 graph

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

What is the MPC?

A

Mutant prevention concentration (may actually be higher than MIC)
Plasma levels kept > MPC helps suppress resistance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

What factors are involved in the extrinsic, intrinsic, and combined pathway of coagulation?

A

Extrinsic: Starts with damaged Tissue (PT)
VII – VIIa (7)

Intrinsic: Starts with abnormal vessel wall (APTT)
XII – XIIa (12)
XI – XIa (11)
IX – IXa (9)

Common:
X – Xa (10)
Prothrombin (II) – Thrombin
-- fibrinogen (I) – fibrin (TT)
Thrombin + fibrinogen = thrombin-fibrin clot
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

What factor is involved in coagulation factor inactivation?

A

ATIII (antithrombin III) + thrombin = inactive complex

Protein S and Protein C inactivate factors Va and VIIIa

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

How are platelets activated and first aggregated?

A
  1. contact with damaged arterial wall activated platelets
  2. activated platelets release thromboxane A2 (TxA2) and ADP
  3. TxA2 and ADP enhance platelet aggregation and adhesion
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Describe the mechanisms of action of warfarin


A
  • Vitamin K is a cofactor for post-translational carboxylation of glutamic acid groups on factors II (prothrombin), VII, IX and X
  • Warfarin inhibits vitamin K recycling from KO (inactive) to KH2 (active)
  • Target = VKORC1
  • Weakly acidic
  • Lipophilic – well absorbed orally, therefore long term oral coagulant
  • Lipophilic – hepatic clearance CYP2C9
  • Variation in CYP2C9 activity and VKORC1 sensitivity – variation in warfarin sensitivity
  • > 4 fold variation in dose requirement

Consequences:

  • protection from thrombosis
  • bleeding
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Describe the adverse effects of warfarin

A

a) Pregnancy
- teratogenic (fetal malformation)

b) Protein S and Protein C hereditable deficiency
- transient hypercoagulable state which can result in skin necrosis
- treat with heparin if known deficiency

c) Circumstances that increase bleeding risk, i.e.
- active peptic ulcer at risk of bleeding
- liver disease with defective clotting factor synthesis
- platelet defects

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Be aware of major interactions affecting warfarin activity


A
  • some drugs compete for CYP450 (metabolism in liver)
  • some drugs induce CYP450
  • amount of vitamin K
  • conditions increasing/reducing coagulation factors
  • other anticoagulants or antiplatelet drugs

a) Drugs that affect absorption – decreased efficacy
b) CYP2C9 induction – decreased efficacy
c) CYP2C9 inhibition – increased bleeding risk

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

What are the clinical indications for heparin and warfarin


A
  • DVT
  • Pulmonary embolism
  • Arterial thrombosis
  • Atrial fibrillation
  • Thrombosis and embolic stroke

Use Heparin if:

  • Venous and arterial thrombosis – it’s more rapid
  • pregnant
  • known protein S/C deficiency
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What are the clinical indications for antiplatelet drugs?

A

Symptomatic atherosclerosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Be able to discuss the clinical monitoring of heparin and warfarin


A

Monitoring Warfarin Therapy:

  • take patient’s blood
  • activate extrinsic and common pathways with thromboplastin
  • measure PT (time to clot = prothrombin time)
  • Ratio of PT to normal = INR
  • INR 2-3 for most indications

Can reverse with:

  • vitamin K
  • fresh donor plasma or factor concentrates
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

Describe the mechanisms of action of heparin 


A
  • inactivation of Xa and thrombin
  • binds to Lysine on AT III
  • increased affinity for activated factors of intrinsic arm
  • therefore, accelerated inactivation of these
  • prevents conversion of fibrinogen to fribin
  • stops clot propagation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Describe the adverse effects of heparin


A
  • bleeding

- immune mediated platelet activation – thrombosis or bleeding

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

/What are the benefits of low molecular weight heparin?

A
  • more predictable activity and elimination so can be dosed on body-weight basis
  • slower elimination, so can be given by subcutaneous bolus (injection)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Name and describe the mode of action of drugs that block thrombin and Xa. Be aware of renal elimination.

A

Blocking Xa- II can’t be converted to thrombin

  • rivaroxaban
  • apixaban

Blocking thrombin – it can’t form thrombin-fibrin clot
- dabigatrin

Efficacy and bleeding risk comparable to or better than warfarin.

Renally excreted – caution with elderly and renal impairment

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What are the anti-platelet drugs?

A
  • Aspirin
  • Clopidogrel
  • Dipyridamole
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

Describe the mechanism of action of aspirin

A
  • acetylation of NH2 terminal serine of cyclooxygenase – irreversible
  • permanent loss of TxA2 production
  • defective platelet clot formation
  • protection from thrombotic disorders

When asprin alone doesn’t work, can protect patients from strokes with dipyridamole.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

Explain the important aspects of clopidogrel transformation & its mode of action on platelets


A

Clopidogrel’s active metabolite blocks platelet ADP receptors irreversibly

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

Explain the mechanism of action of the thrombolytic drug, tPA

A
  • tPA = tissue plasminogen activator
  • protein involved in breakdown of clots
  • it catalyzes conversion of plasminogen to plasmin – the major enzyme responsible for clot breakdown
  • IV admin
  • Relieves blockage of critical vessel (i.e. stroke)
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What are the two categories and subcategories of undesirable drug effects?

A
  1. Non-deleterious = side effects
  2. Deleterious
    a) pharmacological
    b) pathological
    c) genotoxic
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

What is the difference between adverse effects and toxicity?

A

Adverse effects = unwanted drug effects at normal doses

Toxicity = unwanted effects at supratherapeutic doses

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

Dose-response relationships in toxicity


A
  • Quantal Dose-Response Curve (DRC) = Dose or [blood] vs % responding
  • sigmoidal curve
  • different toxic responses can display different dose-response relationships (i.e different curves/slope)
    • see diagram in notes
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What is the therapeutic window?

A

A range of doses that produces therapeutic response without causing any significant adverse effect in patients

Usually starts at minimum effective concentration (MEC) and ends at minimum toxic concentration (MTC) or maximum effective concentration.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

What is the therapeutic index?

A 
Therapeutic Index = Dose resulting in toxicity /dose giving therapeutic response
i.e. ED50 to TD50. 
ED50 = effective dose at 50% responding
TD50 = toxic dose
LD50 – Lethal dose
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

Why do drugs cause toxicity?

A

a) toxicological bioactivation – i.e. become more toxic during metabolism in liver (especially CYP450). Products = ‘adducts’. EG – paracetamol. Induced hepatotoxicity syndromes.

b) predisposing genetic traits:
- CYP
- genetic deficiencies in CYP may mean they metabolize drugs more slowly
- can ensure that toxic thresholds are exceeded on repeated dosing
- may allow more metabolism via minor pathways to form toxic metabolites
- some patients may have diminished capacity for detoxification
- i.e. GILBERT’s SYNDROME

c) age

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

What is Gilbert’s syndrome?

A
  • decreased hepatic levels of UGT1A1 – catalyzes the glucuronidation of bilirubin, therefore causes accumulation of bilirubin
  • mild hyperbilirubinemia (jaundice)
  • effects hepatic clearance of paracetamol, irinotecan (cancer drug) etc
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

Discuss bioactivation and the liver

A
  • high metabolic activity renders liver vulnerable to reactive metabolited
  • drug-induced liver injury (DILI)
  • covalent binding to hepatocyte proteins may predict DILI potential
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

Understand that toxicology impacts the development of new drugs

A
  • toxicity is a key factor in drug failure

- early identification is key

41
Q

Provide a working definition of adverse drug reactions. How is it different to an adverse drug event?

A

ADR: Harmful, unintended reactions to medicines that occur at doses NORMALLY used for treatment.
Can be difficult to distinguish from side effects

ADE: Broader. While they occur while a patient is taking a drug, they are not necessarily related to the drug. I.e. includes unintentional harm due to misuse or non-use.

42
Q

Demonstrate basic appreciation of the extent of contribution ADRs make to the burden of human disease. (In Australia)

A
  • ~5% general hospital admit ions, ~1/3 admissions in >75yo
  • ~16% ED presentations at RAH
  • ~2m ADRs annually
  • ~130,000 hospitalizations per year
43
Q

What are the two broad categories (and others) of ADRs?

A

A. Type A = Augmented

  • Predictable on pharmacological grounds
  • An exaggeration of normal effects
  • can occur in virtually any normal patient
  • severity depends on dose
  • avoid by switching to alternative drug/changing dose
  • i.e. warfarin

B. Type B = Bizarre

  • Bizarre. Dose unrelated, idiosyncratic, unexpected.
  • more likely to cause death, emergencies
  • hypersensitivity reactions which occur in vulnerable patient
44
Q

What are the subcategories of Type B ADR?

A

a) non-immune mediated: can be idiosyncratic in that they involve
patients with specific inherited genetic traits
i) metabolic abnormalities
ii) inability to compensate
b) immune mediated – allergies
i) immediate reaction
ii) non-immediate reaction

45
Q

Identify examples of conditions involving defects in drug metabolism.

A
  1. Acetylator Status
    - Some drugs undergo extensive acetylation in liver
    - involves N-acetyltransferase (NAT)
    - NAT exists in fast and slow forms (most Asians = fast)
    - if slow – increased risk of ADRs
    - i.e. Drug-Induced Lupus Syndrome
  2. CYP450 Status
    - CYP – oxidative drug metabolism
    - polymorphisms can alter rates of plasma clearance of active drug or bioactive metabolite
    - can effect clinical responses, i.e. risk of haemorrhaging from warfarin if CYP2C9 deficient.
46
Q

Identify examples of conditions involving impaired ability to compensate for drug-induced metabolic changes.

A
  1. The Pophyrias
    - involved defects within steps in heme biosynthesis
    - many drugs can induce pseudoporphyria:
    - skin fragility
    - erythema
    - blistering
    - i.e. NSAIDS, tetracyclines
    - occurs in vulnerable patients
  2. Malignant Hyperthermia
    - involves faulty skeletal muscle calcium homeostasis
    - inherited mutations in RyR1 calcium channel – channel opening is more likely sustained in the presence of anaesthetics
    - volatile anaesthetics trigger massive Ca2+ release – causing metabolic stimulation and contractile response
    - uncontrolled metabolism
    - clinical signs:
    - O2/CO2 consumption/production
    - hyperthermia
    - muscle rigidity
    - rhabdomyolysis (the destruction of striated muscle cells)
47
Q

Identify 2 subcategories of immune-mediated Type B ADRs

A
  1. immediate (IgE-mediated)
    - 1hr and up to several days after last drug dose
    - DCs present antigen to naïve T cells – adaptive immune response initiated.
    - Then re-exposure
  • Stephen Johnson syndrome
  • toxic epidermal necrolysis
48
Q

What are some of the broad reasons for variation in efficacy and side effects of drugs?

A
  • age
  • pathological state (i.e. kidney/liver disease)
  • physiological state (pregnancy)
  • drug interactions
  • genetic factors
  • ethnicity
49
Q

What is pharmacogenetics?

A

The use of genetic analysis to predict drug response, efficacy and toxicity.

50
Q

What is a single nucleotide polymorphism (SNP)?

A

A single base change in a DNA sequence that exists in a population with a frequency of >1%.

51
Q

What are the proteins relevant for drug efficacy or toxicity?

A

Protein involved in:

  • metabolizing enzymes
  • transporters (drug uptake)
  • site of drug action (receptors, ion channels etc)
52
Q

What are the possible consequences of drug metabolism?

A
  • usually, it converts drugs to metabolites that are more water soluble and therefore more easily excreted
  • can convert pro-drugs to therapeutically active compounds (i.e. codeine)
  • can convert to toxic metabolites
53
Q

Name and describe some examples of genetic polymorphisms in drug metabolism:

A

Muscle relaxant succinulcholine:

  • hydrolysis by butyrylcholinesterase impaired in 1:3500 white subjects
  • impairment prolongs drug induced muscle paralysis and apnea

Acetylation of drugs can occur at fast or slow rates

  • isoniazid (anti-TB drug)
  • can’t give too much to slow acetylation people
  • ~50% in Europeans and 90% Japanese/Chinese
54
Q

Discuss Alcohol metabolism polymorphisms:

A

Metabolism:
Sep 1: (alcohol dehydrogenase) ethanol – oxidation – acetaldehyde
Step 2: (aldehyde dehydrogenase) – acetaldehyde – oxidation – acetic acid

  • alleles that encode for higher Vmax:
  • ADH1B Arg47His
  • ADH1Clle349Val
  • found in lower frequencies in alcoholic individuals
  • frequencies greater in Eastern Asians, therefore lower rate of addiction
55
Q

Discuss Cytochrome P450 enzyme family polymorphisms

A

CYP2D6 polymorphisms:

  • CYP2D6 is responsible for metabolism of a number of drugs
  • antidepressants, antipsychotics, cardiovascular drugs etc
  • > 100 polymorphisms, based on phenotype patient is classified:
  • a) UMs (ultrarapid metabolizers)
    - i.e. multiple copies of gene (duplications)
  • b) EMs (extensive)
  • c) PMs (poor)
    - SNPs that alter AA sequence of encoding protein
    - SNPs that alter RNA splicing
    - Deletions of gene
56
Q

How can you test for CYP2D6 polymorphisms?

A

AmpliChip CYP450 – microarray based test

  • 29 known polymorphism for CYP2D6 and 2 majors in CYP2C19 analyzed
  • blood sample
  • sent to doc – will aid in therapy selecting and dosing
57
Q

How is warfarin administration improved by genetic testing? How variability explained?

A
  • Testing (PGx Predict) on CYP2C9 and VKORC1
  • optimize doe for management of blood clots and bleeding
Inter-patient variability is principally explained by:
-	genotype (CYP2C9 and VKORC1)
-	age
-	gender
-	height ant weight
-	concomitant medications
NOT just genetic
58
Q

Why does knowing whether a person has a genetic polymorphism not necessarily translate to phenotype?

A

Most drugs:
- are metabolized by several different enzymes
- can be transported by alternative types of protein
- interact with one or more targets
If several steps within pathway display variation = polygenic – multiple overlapping distributions will occur.

59
Q

What is an example of a transporter gene that could have relevant polymorphism?

A

P-glycoprotein transporter gene ABCB1

  • energy dependent cellular efflux of substrates
  • i.e. one polymorphism associated with higher bioavailability of digoxigenine
60
Q

What are examples of drug targets (i.e. receptors) that could have relevant polymorphism? How does race affect this?

A
  • B2 adrenoreceptor affecting response to B2 agonists
  • ACE (enzyme) affecting the renoprotective actions of ACE inhibitors
  • African Americans respond less well than European Americans to beta blockers, ACE inhibitors and angiotensin receptor blockers
  • AA may respond as well or better than EA to diuretics and calcium channel blockers
  • EA and AA hypertensive individuals typically differ in characteristics such as salt sensitivity, plasma volume and renin levels
  • Nonadrenergic mechanisms might contribute more to blood pressure maintenance in AA than in EA
61
Q

What are some of the caveats and ethical considerations for genetics and drug responses?

A
  • current studies of drug response still small and study design varies
  • ethnic/racial groups – often differences in drug response
  • ethnicity/race may contribute to disparities in the future
  • causal relationship hard to establish – effects most often not mediated by a single variant in a single gene
62
Q

Define the difference between benign and malignant tumours

A

Benign – remains localized

Malignant – not localized. Can be primary or secondary

63
Q

/What are the origins of cancer?

A
  • some cancer rates don’t vary worldwide – background mutations rate
  • Most are secondary to external factors:
    - melanoma - Australia
    - stomach – Japan
    - liver – China
  • i.e. environmental initiators:
  • tobacco
  • UV
  • poor diet
  • infections
  • alcohol
  • Increases with age
64
Q

What is the broad multistep process for cancer formation?

A
  1. Initiation
    - normal cell – initiated cell
    - carcinogens, radiation, viruses, random errors
  2. Promotion
    - initiated cell – pre-neoplastic lesion
  3. Conversion
    - pre-neoplastic lesion – malignant tumor
  4. Progression
    - malignant tumor – clinical cancer
    - clinical cancer – advanced cancer
65
Q

How can smoking initiate lung cancer?

A
  • tobacco smoke - >60 carcinogens
  • metabolic activation (PAHs/NNK) – reactive forms – DNA adducts – gene mutations
  • commonly mutated genes – p53, K-RAS
  • AND smoke is an irritant – inflammation – promoter
66
Q

Describe the intrinsic barriers that must be overcome for invasive cancer to develop

A

What are the 8 capabilities of Cancer cells and 2 enabling factors?

  1. Self-sufficient in growth (+) signals
  2. Insensitive to growth inhibitory (-) signals
  3. Can evade apoptosis
  4. Can proliferate indefinitely
  5. Can promote angiogenesis
  6. Can spread away from primary tumor – invasion and metastasis
  7. Cellular energy deregulation
  8. Immune system avoidance

Enabling factors:

  • genome instability
  • inflammation

EACH capability must be overcome to produce an invasive cancer.

67
Q

What is the progressive microbiological changes for tumor progression?

A
  • normal tissue (i.e. epithelium)
  • hyperplasia – minimal change but increased proliferation
  • dysplasia – cells no longer look normal
  • Visible lump, i.e. carcinoma, adenoma, papilloma
  • local invasion - breach
  • metastasis
68
Q

Understand how common mutations permit tumour cells to breech these protective barriers

A

How does normal growth control exist?

  • normal cells quiescent (G0) until they receive mitogenic signals
  • GFs instruct cells to proliferate – enter into cell cycle – G1-S
  • Act via transmembrane GF receptors (GF-R)
  • Neighbouring cells also release growth inhibitory factors

Signal transduction route:

  1. GF – ligand (extracellular)
  2. GF-R
  3. Phosphorylation
  4. IC signaling cascade
  5. Activation of targets
69
Q

How does uncontrolled proliferation occur (capability 1)?

A

Signaling can be co-opted (diverted for different use) at any step in the signal transduction route

Tumor capability 1 – self sufficiency in growth signals.

  • cancer cells have greatly reduced dependency on GFs
  • oncogene activation: Produced own growth signals
  • a) Autocrine GF production
  • b) Over-expression of GF-R
  • c) constitutive activation of GF-R
  • d) constitutive activation of IC signaling
    - Ras/Raf/MAPK proliferation pathway
    - PI3K/Akt growth/survival pathway
70
Q

How does insensitivity to inhibition occur (capability 2)?

A

SA: mutated tumor suppression genes so cell cycle can’t break

Brakes commonly regulate cell cycle and either:

a) force cells into G0
b) induce cells to enter a post-mitotic state (i.e. terminal differentiation)

  • Many breaks regulated through tumor suppressor genes (TSGs)
  • Familial cancers often due to mutated TSG allele
  • i.e. RETINOBLASTOMA – Rb pathway is disrupted in most human tumors
71
Q

How does familial retinoblastoma work?

A

HYPOphosphorylated Rb sequesters (removes) E2F to block G1/S cell cycle progression
HYPERphosphorylated Rb releases E2F so cell cycle can progress

Mutation results in uncontrolled proliferation – bilateral retinoblastomas

72
Q

How does evasion of apoptosis occur (capability 3)?

A
  • enhanced hormone receptor (ER and AR) expression – survival signal
  • enhanced anti-apoptotic protein expression
  • most common pathway: mutation of p53 which is a key DNA damage sensor
  • activates apoptosis in cells with severe DNA damage/metabolic problems
  • dominant negative or inactivating mutations are seen in ~50% tumors
73
Q

How does cell immortalization occur(capability 4)?

A

SA: Re-expression of telomerase

  • Normal cell divides a finite number of time – Hayflick #
  • Tumor cells inactivate this mechanism
  • Mitotic counting device = telomeres which lose data every division (50-100 bp loss per division)
  • Telomere loss – senescence – apoptosis
  • Telomerase – DNA polymerase with template to transcribe telomere repeats (6bp)
  • normally expressed embryonically
  • re-expression immortalizes cells
  • 85-90% tumors have increased expression
74
Q

How does angiogenesis occur(capability 5)?

A

SA – it shifts the balance of +ve and -ve signaling proteins for angiogenesis.

  • cells need nutrients and O2
  • flick in angiogenic switch
  • Shift in balance occurs by:
    a) increase in angiogenesis activators, OR
    b) decrease in angiogenesis inhibitors
  • New vessels aberrant (leaky)
75
Q

How does invasions and spread occur (capability 6)?

A
  1. carcinoma in situ
  2. move and degrade basement membrane
  3. intravasation
  4. stick to blood vessel wall
  5. extravasation
  6. survive and proliferate in new environment
76
Q

What are some examples of familial cancer syndromes involving tumor suppressor genes?

A
  • *Retinoblastoma: Rb – controls cell cycle progress
  • *Li-Fraumeni Syndrome: p53 – apoptosis
  • Neurofibromatosis: NF1
  • Von Hippel-Linau disease: VHL
  • Familial Adenomatous Polyposis (APC)
77
Q

What are some examples of familial cancer syndromes involving genome maintenance/DNA repair genes?

A
  • lynch syndrome – HNPCC

- breast and ovarian cancers – BRCA1 and BRCA2

78
Q

What are some of the terminologies used in chemo?

  • Neoadjuvant
  • Adjuvant
  • Induction
  • Consolidation
  • Definitive
  • Palliative
A

. Neoadjuvant - given before surgery to shrink tumour & make surgery less extensive
. Adjuvant - given after surgery to destroy remaining cells and prevent recurrence
. Induction - given to induce remission, commonly used in the context of leukaemia treatment
. Consolidation - given once remission is achieved
. Definitive - curative e.g. for an early stage tumour that 
is chemotherapy sensitive - testicular cancer
. Palliative - not curative and used for symptom management

79
Q

What is the problem with traditional chemo and specificity?

A

They act on highly proliferative cells, including normal tissue:

  • GI tract epithelial cells
  • Hair follicles
  • BM/haematopoeitic cells
80
Q

What are the 3 main side effects of traditional chemo drugs in general?

A
  • GI toxicity
  • mouther ulcers
  • nausea
  • vomiting
  • diarrhea
  • Hair loss (alopecia)
  • Myelosuppression – infection, anemia, bleeding
81
Q

Describe the mechanisms of action of some important classical chemotherapeutic drugs in general

A

Many interfere with DNA synthesis and/or function, therefore inducing apoptosis

Mechanisms:

a) chemical damage to DNA
- adducts
- DNA strand crosslinks
- DNA-protein crosslinks
b) Impaired synthesis of DNA bases
c) Inhibition of transcription or translation
d) Disruption of cell division mechanics

82
Q

/What are the different types of alkylating agents?

A

a) Classical
- nitrogen mustrards
- cyclophosphamide
- chlorambucil
- melphalan
- nitrosoureas
- lomustine
- streptozoticin
- alkylsulphonates
- busulphan

b) platinum-based
- cisplatin
- carboplatin
- ocaliplatin

83
Q

Describe the mechanisms of action of alkylating agents.

A 
They alkylate DNA at guanine bases to form:
-	DNA adducts – leads to strand breaks
-	DNA strand cross links – cannot be replicated or transcribed
Platinum-based can lead to:
-	mono-adduct
-	inter-strand cross-link
-	intra-strand cross-link
-	protein-DNA cross-linke

Independent of cell-cycle
Dose-dependent effects

84
Q

Describe the mechanisms of action of anti-metabolites:

A

Interfere with S phase
Deprive cells of building blocks required for growth and division:

a) folic acid antagonists – blocks DHFR (dihydrofolate reductase) so cellular folates depleted (needed for purine synthesis)
DRUGS:
- methotrexate (MTX)

b)	DNA base analogues – disrupt DNA synthesis and function of analogues
DRUGS:
 	- 5 fluorouracil
 	- mercaptopurine
 	- gemcitabine
85
Q

Describe the mechanisms of action of mitotic inhibitors:

A

Interfere with M phase
Interfere with mitotic spindle

a) Vinca Alkaloids – binds tubulin to prevent MT and mitotic spindle formation
DRUGS:
- vincristine
- vinblastine

b) Taxanes – bind MTs (microtubules) to prevent their disassembly at mitosis
DRUGS:
- paclitaxel

86
Q

Describe the mechanisms of action of cytotoxic antibiotics:

A

a) Anrthacyclines:
- intercalate between base pairs
- also inhibits topoisomerase II (Topoisomerase inhibitors)
- both prevent DNA replication
- BUT cardiotoxic
- DRUGS:
- doxorubicin
- daunorubicin

b) Bleomycins:
- induce single and double strand breaks
- BUT cause pulmonary fibrosis
- DRUGS:
- Bleomycin A2 and B2

87
Q

What hormones are used in chemotherapy?

A

Breast Cancer:

  • Tamoxifen and other SERMs
  • Aromatase inhibitors

Prostate Cancer:
- anti-androgens

Lymphoid Cancers:
- corticosteroids

88
Q

What are some of the specific side effects of specific chemo drugs?

A
  • pulmonary fibrosis - Bleomycin
  • haemorrhagic cystitis – Cyclophosphamid
  • cardiomyopathy – doxorubicin and other anthracyclines
  • hepatic damage – methotrexate
  • skin pigmentation – 5 fluorouracil
  • neurotoxicity – paclitaxel and other mitotic inhibitors. Cisplatin
  • nephrotoxicity and otoxicity - cisplatin
89
Q

Why are chemo drug combos more effective?

A
  • cells in G0 are resistant
  • tumors with higher % of cells actively dividing are more susceptible
  • different drugs act at different stages, some acting on any stage including G0
  • therefore drug combos are more effective
90
Q

/Which cancer drugs are non-phase dependent?

A
  • alkylating agents
  • 5-fluorouracil
  • anthracyclines
91
Q

/What cancer drugs are cell cycle specific?

A
  1. S-phase dependent:
    - anti-metabolites
  2. M-phase dependent:
    - vinka alkaloids
    - taxanes
  3. G2-phase dependent:
    - antibiotics
  4. G1-phase dependent
    - corticosteroids
92
Q

What are the potential outcomes of chemo/radiation?

A
  1. initial treatment induced remission, i.e. reduces tumor size
  2. if tumor detectable – 2nd dose of chemo/radiation
  3. if undetectable, remaining cells are either:
    - killed by immune system (CD8+ T cells) = cure
    - still actively growing = minimal residual disease – reappears
    - formant – may be re-activated after many years
93
Q

Name a targeted cancer therapy. Mechanism?

A

Tyrosine Kinase Inhibitors

Mechanism:

  • TKs transmit pro-growth signals to cell nucleus and are activated in many tumor
  • Specific inhibitors can target TKs:
    a) antibodies
    b) small molecule inhibitors

Specifically, can land up with:

a) Monoclonal antibodies – target and block specific proteins
b) Angiogenesis inhibitors
c) Small molecule inhibitors

94
Q

What are the side effects of kinase inhibitors?

A

Generally less toxic than classical chemo

a) cutaneous effects
- skin rash
- hair loss
- acne like folliculitis
- increase facial hair/eyelash growth
b) endocrine:
- thyroid dysfunction
- bone density changed
- glucose metabolism changes
c) cardiovascular
d) musculoskeletal
e) haematological – myelopsupression

BIGGEST problem = resistance to inhibitor

95
Q

Understand how resistance to chemotherapy can arise

A
  1. primary – seen with 1st dose
  2. acquired – develops during Px

Can develop multiple drug resistance (MDR)

Mechanisms: (many)

  • decreased activation of metabolism-dependent drugs
  • increased metabolism inactivation of toxic drugs
  • accumulation of drug due to decreased uptake or increased effluc
  • increased DNA repair
  • altered expression of target enzymes
  • mutations in target protein
96
Q

How many cells do traditional chemotherapy drugs affect?

A

Only a fixed proportion, not a fixed number.

Overcome by:

  • drug combos?
  • Target delivery to tumors?

To eradicate a tumor, drug kill % must be > cell number

97
Q

What is Rivaroxaban?

A

It is the first available orally active direct factor Xa inhibitor.

98
Q

Which is not a test for CF in infants?

a) Genetic testing
b) Sweat test
c) Immunoreactive trypsinogen
d) Liver enzyme test

A

D

General Med 1 (24 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions