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Clin Sci IMS, Respiratory, Renal, Cardiovascular, Nutrition & Energy > Week 3 - Pharmacology + Neoplasia > Flashcards

Week 3 - Pharmacology + Neoplasia Flashcards

1
Q

What is a medicine?

A

Chemical preparation containing one or more drugs administered with the purpose of producing a therapeutic effect

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2
Q

Describe pharmacological principles

A

Active ingredient, selectively bind to certain receptors -exert cellular effect and exert effect on system.
Produces therapeutic effect in a concentration related or concentration related or concentration dependent fashion
Efficacy of drug supported by clinical trials using agreed outcome measures

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3
Q

Describe the logic model - mechanistic understanding of drug action

A
  • Consumption of drug
  • Binding of drug to receptors
  • Intracellular changes resulting in desired response
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4
Q

Describe drug activity

A

For drugs to be active the minimum concentration required are in nano molar (1x10^-9) - macromolar range (1x10^-6)

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5
Q

Describe drug receptor types

A
  • Enzymes
  • Transporters
  • Receptor - drug specific receptors that have not alternative function
  • Ion channels
  • G-Protien coupled receptors
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6
Q

Describe G-protein coupled receptors

A

Topology - shape prediction, domain defined by 3D shape/function.
Domain position depends on what will bind, each evolved for different specific functions

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7
Q

Describe G-Protein binding

A

Agonist binds with receptor bound to Gprotein - 3 domains alpha beta and gamma, binding to the effector protein to stimulate a response
Hydrolysis of Gprotein by GTPase inactivates
-effector is no longer activated
- alpha subunit rejoins the gamma subunit

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8
Q

Describe the types of G alpha proteins

A

G alpha S - Stimulates
G alpha I - inhibits
G alpha q - stimulates turnover of membrane phospholipid inositol phosphate

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9
Q

Describe the role of inositol phosphate

A
  • InsP3 bind to endoplasmic receptors and open endoplasmic Ca2+ channels
  • allows Ca2+ release into cytosol where it interacts with many targets
    Second messenger initiates cascade of intracellular signalling events
    e.g. GProtein to phosphatase C to cAMP to protein kinases to effector
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10
Q

Describe drug tolerance and desensitisation

A

Uncoupling - over time G proteins are not activated as receptor changes shape with increased stimulli
Cells control environment, increased exposure becomes less sensitive

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11
Q

Describe enzyme linked receptors

A
  • Ligand binding
  • Receptor dimerisation
  • Activation of catalytic domain, tyrosine residues become phosphorylated
  • Accessory proteins bind to complex
  • Intracellular pathways activated -kinase cascade
  • Transcription factors are activated
  • Transcription factors enter nucleus and bind at promoter regions
  • Activation or suppression of the synthesis of RNAfor specific genes which contain transcription factor binding sites in promoter region
  • Effects of receptor binding can last for hours/days/weeks
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12
Q

What are the 4 classes of enzyme linked receptors?

A
  • Receptor tyrosine kinase
  • Serine/ threonine kinases
  • Cytokine receptors - ligand binding cause receptor activation of cytosolic tyrosine kinases
  • Guanylyl cyclase linked - similar to RTK but intrinsic enzyme activity causes cGMP formation
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13
Q

Describe nuclear receptors

A
  • Ligand activated transcription factors not associated with membranes
  • ligands have to be freely permeable across cell membranes
  • ligand bind receptors
  • receptors enter nucleus
  • Initiate gene transcription and/or repress gene transmission
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14
Q

Describe drug selectivity/specificity

A

The ability of a drug to produce a particular effect, precise molecular interactions between drug and receptor affinity.
low selectivity/specificity = drug/ receptor can bind to multiple

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15
Q

Describe potency of a drug

A

Dosage of drug needed to produce effect - how well it binds - dependent on affinity of drug to receptor
Uses 50% of maximum response

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16
Q

What is EC50?

A

against concentration that induces 50% of maximal response relating to potency

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17
Q

What is Emax?

A

maximum response of drug is reached by increasing drug concentration, relating to efficacy of the drug

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18
Q

Describe drug efficacy

A

The ability of a drug to induce effect
Full agonist -induces full physiological effect
Partial agonist - cannot induce a maximal response good for producing therapeutic effect without overdose risk

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19
Q

Describe toxic effects of drugs

A

Median lethal dose (LD50) lethal dose for 50% of users
or
Medial toxic dose (TD50) toxic dose for 50% of users

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20
Q

What is the therapeutic index?

A

TI = LD50 or TD50 / ED50

wider therapeutic range = safer as more of the drug is needed to produce toxic effect

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21
Q

What is an antagonist?

A

effect of one hormone, neurotransmitter is reduced or abolished by second drug

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22
Q

What are the 4 antagonist mechanisms?

A
  1. receptor antagonism - competitive
  2. receptor antagonism - non competitive
  3. pharmacokinetic antagonism
  4. physiological antagonism
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23
Q

Describe competitive antagonists

A

Maximal effect of agonist is unchanged by presence of antagonist but more of the agonist is needed for maximal effect - right shift on concentration response curve

Antagonist competes for receptor site, and has affinity for receptor and binds in equilibrium
low affinity = reversible competitive
High affinity = irreversible

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24
Q

Describe non competitive (allosteric )antagonist

A

Drug binds to allosteric site and prevents activation converting full agonist to partial agonist

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25
Q

What are the pharmacokinetic and physiological effects of antagonists?

A
  • antagonist drug acts to increase clearance, reduce plasma concentration and affects half life
  • interaction between 2 drugs that initiate opposing effects via different receptors in the same target tissue
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26
Q

Describe bioavailability of a drug

A

Amount of active drug in the blood stream

Determined first by efficiency of absorption and presentation to circulation of a drug administered by enteral route

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27
Q

What are the factors affecting bioavailability of a drug?

A
  • SA of membrane
  • PH of site
  • mesenteric blood flow (reduced blood to intestines)
  • Gastric emptying
  • Presence of food
  • Efflux transporters in membrane
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28
Q

Describe the permeability coefficient

A 
Speed of drug crossing the membrane dependent on permeability 
function of lipophilicity of drug, ionisation state, size and difusability
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29
Q

Describe drug distribution

A 
Distribution to other compartments depends on molecular size, ability to cross membrane and extent of binding to plasma membrane. 
Compartments =
 Intracellular fluid (ICF)
Extracellular fluid (ECF)
Blood
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30
Q

Describe plasma protein binding of drugs

A
  • Loose electrostatic bonding albumin for acidic drugs and acid glycoprotein for basic drugs
  • equilibrium established between bound and free form
  • reduces drug concentration available in plasma to reach site of action
31
Q

Describe the elimination of drugs

A
  • renal excretion
  • liver metabolism
  • chemical transformation
32
Q

Describe the metabolism of lipophilic drugs

A

extensively metabolised, if it didn’t occur lipophilic drugs would endlessly circulate and be recycled in the body and be reabsorbed through glomerular or enterohepatic reabsorption

33
Q

Describe the importance of the liver in metabolising drugs

A

Packed with drug metabolising enzymes
- lots of endoplasmic reticulum where microsomes form alongside many enzymes including microsomal enzymes e.g. cytochrome P450

34
Q

Describe phase 1 of drug metabolism

A

Functionalisation reactions

Addition of unmasking of functional polar group - principal reactions = oxidation, reduction and hydrolysis

35
Q

Describe phase 2 of drug metabolism

A

Conjugation reactions

addition of a group or groups to drug molecule (polar) so they can’t move through the membranes

36
Q

What are the properties of drug metabolising enzymes?

A
  • low substrate specificity
  • low reaction specificity
  • lower catalytic rates but may be present in high concentrations
  • usually lipophilic
  • enzymes inducible - one drug can induce enzyme which induces another reaction of second drug
37
Q

Describe microsomal drug metabolism

A
  • competitive between substrates
  • Inhibition of enzymes by drugs
  • induction of enzyme systems
  • age, nutritional status, liver disease and genetic polymorphisms
38
Q

Describe dosage choice of drugs

A
  • Bioavailability
    -volume of distribution - volume off body fluid needed to dissolve total drug concentration in plasma to total drug in body
    -clearance of drug- drug cleared per unit time
  • half life
    the right dose has correct therapeutic use and avoids any toxic effects
39
Q

What is cancer?

A

Group of diseases characterised by uncontrolled cell division leading to growth of abnormal tissue
-Results from accumulation of many genetic alterations that disrupt the function of many different genes

40
Q

What is hyperplasia?

A

increased growth of cells

41
Q

What is a carcinogen?

A

agent with the ability to produce a genetic change resulting in the production of a genetically unstable cell

42
Q

Describe the multifaceted nature of cancer

A

Intrinsic - within our body little control over, random errors in genetic replication
Extrinsic -
Endogenous - biological ageing, inheritance, genetic susceptibility - partially modifiable
Exogenous - Radiation, chemical carcinogens, tumour causing virus - modifiable

43
Q

Describe the cancer progression

A

Normal cells, atypical, benign, malignant, metastatic

44
Q

Describe oncogenes

A

Aberrant activation of genes that drive cell cycle and inhibit apoptosis

45
Q

Describe DNA repair genes

A

Genes that protect cells from genetic damage thus allowing accumulation of mutations that may affect TSG or Onco genes

46
Q

Describe tumour suppressor genes

A

Genes that inhibit cells cycle or that promote apoptosis

47
Q

Describe cancer pathogenesis

A 
Normal epithelium 
Hyperproliferative epithelium 
Early adenoma ( glandular origin or characteristic) 
Intermediate adenoma 
Late adenoma Carcinoma
48
Q

Describe cervical tumour progression

A

HPV, squamous epithelia hyperplasia, koliocyte undergone structural changes

49
Q

Describe the genetic evolution of cancer

A

Identification of abnormal cells at defined points in pathological progression
- some biological mutations can bypass others therefore some early pre cancer stages are not clear

50
Q

Describe the difference between benign and malignant tumours

A

Structure - Well differentiated / Undifferentiated - anaplastic
Growth - Slow/rapid invasive
Duration - May stop growing/Rarely stop growing
Metastasis - None / frequent
Effect - slight harm due to locations/ significant harm

51
Q

Describe tumour grade

A
  1. small uniform glands
  2. more storm between glands
  3. distinctly inflictive margins
  4. irregular masses of neoplastic glands
  5. only occasional gland formation
52
Q

Describe tumour stage

A 
Includes looking for lymph node involvement, important in prognosis 
0 - carcinoma in situ 
1 - localised 
2 - early locally advanced 
3 - late locally advanced 
4 - metastasised
53
Q

Describe tumour naming

A 
Oma = bengin 
sarcoma = cancerous
54
Q

What is angiogenesis ?

A

Formation of vascular system in tumour

55
Q

Describe hallmarks that given the transformation of normal cells to cancerous cells

A
  • evading apoptosis
  • self sufficiency in growth signalling
  • intensity of anti growth signals
  • tissue invasion and metastasis
  • limitless replicative potential
  • sustained angiogenesis
  • Deregulating cellular energetics
  • avoiding immune destruction
  • tumour promoting inflammation
  • genome instability + mutation
56
Q

Describe the growth factor signalling cascade

A

Growth Factor in extracellular fluid binds to receptor
Activation of intracellular protein signals transduction cascade
Activates transcription of growth promoting genes
Activated cyclins and CDKs drive cell cycle progression

57
Q

Describe tumourgenesis

A
  1. Begins to secrete growth factor, autocrine loop self stimulation, interaction between growth factors, cytokines and target cells
  2. Components of signal transduction pathway is muttered and become constitutively activated
    - Ras oncogene - family of G proteins if activated drives signal transduction inactive bound to GDP and active bound to GTP
  3. Transcription factors controlling cyclin expression are mutated and become constitutively activated - myc oncogenes promoted myc = transcription factor expressed that activates several growth promoting genes
  4. Cyclin and CDK protein complexes that drive the cell cycle become over expressed
58
Q

Describe inhibition of anti growth signals during tumour genesis

A

Expression of cell cycle inhibitors is disrupted

  • mutation or loss of Rb - retinoblastoma protein
  • mutation or loss of P53
  • mutation or loss of CDK inhibitors
59
Q

Describe P53 tumour suppressor

A
  • transcription to activate P21 gene
  • P21 protein inhibits cyclin/CDK function
  • loss of P53 removes inhibition of cell growth
  • P53 mutated/ deleted in 70% of all cancers
60
Q

Describe evasion of apoptosis

A

Normal cells removed by apoptosis, cancer cells evade apoptosis signals

  • expression of gene promoting apoptosis is disrupted
  • mutation or loss of P53
  • Dysregulated components of intrinsic/extrinsic pathways
  • Reduction of CD95 expression reducing cytochrome c from mitochondria due to raised BCL-2 or BCL-XL
61
Q

Describe the apoptosis pathway

A
  • Extrinsic mediator for extrinsic pathway
  • Mitochondria mediator for intrinsic pathway
  • Caspase mediated (enzymes) executioner
  • Apoptosis bodies recognised by phagocytes and removed without inflammation
62
Q

Describe the extrinsic signal in apoptosis pathway

A
  • Binding of CD95 - death protein attaches to transmembrane receptor fas/death receptor
  • Adaptor molecule Fadd associated death domain = bridge between Fas and procaspase 8 leading to formation of death inducing signal
  • DISC = death inducing signalling complex
63
Q

Describe the intrinsic pathway of apoptosis

A
  • cells respond to DNA damage
  • leads to tumour suppressor activation CP53, activates BCL2 family protein BAX (anti apoptotic) and BAK ( proapoptotic) leading to cytochrome C pushing cell into apoptosis
64
Q

Describe the limitless replication potential

A
  • Normal cells divide from 50-70 times
  • Due to erosion of telomeres in each round of replication
  • Loss of telomeres creates double strand breaks in DNA that allow chromosome rearrangement
  • P53 and Rb recognise these breaks and induce senescence or apoptosis
65
Q

Describe how tumours avoid senescence

A
  • many cancers lose P53 and Rb function
  • raging cells with shortened telomeres undergo chromosome rearrangement - dicentric or abnormal
  • Dicentrics fragment in division and should induce apoptosis - mitotic catastrophe
  • Activation of telomerease gene allows cell restoration of telomeres
  • crucial event for cells to survive during tumourgeneis
66
Q

Describe sustained angiogenesis

A
  • tumours cannot grow more than 1-2mm without being vascularised
  • due to extent of oxygen, nutrients and waste through tissues
  • create new blood vessels - neoangiogenesis
    in hypoxic conditions cells secrete VEGF- vascularised endothelial growth factor
  • activated Was and Myc oncogenes to regulate VEGF
67
Q

Describe tumour dissemination

A
  • Detachment of tumour cells from neighbouring cells
  • Degrading of ECM
  • Attachment to novel ECM components
  • Migration of tumour cells
    Cell proliferation and remodelling of surrounding matrix, stimulate new blood vessel growth and produce new secondary site
68
Q

What is the basement membrane?

A

Thin extracellular matriculates of tissue that separates the lining of internal or external body surface from underlying connective tissue

69
Q

Describe chronic myelogenous leukaemia

A

-WBC cancer, myeloid growth in bone marrow
- Chromosomal translocation C9 (ABL1 gene) end 22 BCR gene end changes
-Philadelphia chromosome - fused protein BCR-ABL1 -ABL1 tyrosine kinase switch on fusion with BCR results in deregulation of gene expression by increased division
Treatment includes ABL kinase inhibitor - imatinib

70
Q

Describe cervical cancer

A

HPV 16/18
Cervical epithelial neoplasia - koliocyte formation
Virus carries 2 oncogenes - E6 (inactivates P53) + E7 (competes for pr binding freeing EzF to transactivate targets)
Treatments = vaccination

71
Q

Describe breast cancer

A

Lobular or ductal
epidermal growth factor receptor (EGER, HER2) over expressed
Treatment = surgery, radio/chemo therapy Herceptin- monoclonal antibody against HER2 receptor

72
Q

Describe melanoma

A

Skin cancer
- occurs spontaneously
- mutation of Raf oncogene p16 -tumour suppressor
- initial radial growth followed by vertical growth VGP cells target for metastases
Treatment = surgery, chemo/radio therapy, immunotherapy - interferon alpha / interleukin 2

73
Q

Describe Retinoblastoma

A

Heritable and non heritable two hit hypothesis
-pRb1 gene mutations
- can be single gene mutation
- cancer of juveniles
Treatment = chemo/radio therapy , enucleation, laser photocoagulation, cryotherapy, thermo therapy and bratty therapy

Clin Sci IMS, Respiratory, Renal, Cardiovascular, Nutrition & Energy (17 decks)

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