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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
What are the pharmacokinetic and physiological effects of antagonists?
- 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
26
Describe bioavailability of a drug
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
27
What are the factors affecting bioavailability of a drug?
- SA of membrane - PH of site - mesenteric blood flow (reduced blood to intestines) - Gastric emptying - Presence of food - Efflux transporters in membrane
28
Describe the permeability coefficient
``` Speed of drug crossing the membrane dependent on permeability function of lipophilicity of drug, ionisation state, size and difusability ```
29
Describe drug distribution
``` 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 ```
30
Describe plasma protein binding of drugs
- 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
Describe the elimination of drugs
- renal excretion - liver metabolism - chemical transformation
32
Describe the metabolism of lipophilic drugs
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
Describe the importance of the liver in metabolising drugs
Packed with drug metabolising enzymes - lots of endoplasmic reticulum where microsomes form alongside many enzymes including microsomal enzymes e.g. cytochrome P450
34
Describe phase 1 of drug metabolism
Functionalisation reactions | Addition of unmasking of functional polar group - principal reactions = oxidation, reduction and hydrolysis
35
Describe phase 2 of drug metabolism
Conjugation reactions | addition of a group or groups to drug molecule (polar) so they can't move through the membranes
36
What are the properties of drug metabolising enzymes?
- 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
Describe microsomal drug metabolism
- competitive between substrates - Inhibition of enzymes by drugs - induction of enzyme systems - age, nutritional status, liver disease and genetic polymorphisms
38
Describe dosage choice of drugs
- 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
What is cancer?
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
What is hyperplasia?
increased growth of cells
41
What is a carcinogen?
agent with the ability to produce a genetic change resulting in the production of a genetically unstable cell
42
Describe the multifaceted nature of cancer
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
Describe the cancer progression
Normal cells, atypical, benign, malignant, metastatic
44
Describe oncogenes
Aberrant activation of genes that drive cell cycle and inhibit apoptosis
45
Describe DNA repair genes
Genes that protect cells from genetic damage thus allowing accumulation of mutations that may affect TSG or Onco genes
46
Describe tumour suppressor genes
Genes that inhibit cells cycle or that promote apoptosis
47
Describe cancer pathogenesis
``` Normal epithelium Hyperproliferative epithelium Early adenoma ( glandular origin or characteristic) Intermediate adenoma Late adenoma Carcinoma ```
48
Describe cervical tumour progression
HPV, squamous epithelia hyperplasia, koliocyte undergone structural changes
49
Describe the genetic evolution of cancer
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
Describe the difference between benign and malignant tumours
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
Describe tumour grade
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
Describe tumour stage
``` 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
Describe tumour naming
``` Oma = bengin sarcoma = cancerous ```
54
What is angiogenesis ?
Formation of vascular system in tumour
55
Describe hallmarks that given the transformation of normal cells to cancerous cells
- 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
Describe the growth factor signalling cascade
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
Describe tumourgenesis
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
Describe inhibition of anti growth signals during tumour genesis
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
Describe P53 tumour suppressor
- 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
Describe evasion of apoptosis
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
Describe the apoptosis pathway
- Extrinsic mediator for extrinsic pathway - Mitochondria mediator for intrinsic pathway - Caspase mediated (enzymes) executioner - Apoptosis bodies recognised by phagocytes and removed without inflammation
62
Describe the extrinsic signal in apoptosis pathway
- 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
Describe the intrinsic pathway of apoptosis
- 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
Describe the limitless replication potential
- 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
Describe how tumours avoid senescence
- 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
Describe sustained angiogenesis
- 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
Describe tumour dissemination
- 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
What is the basement membrane?
Thin extracellular matriculates of tissue that separates the lining of internal or external body surface from underlying connective tissue
69
Describe chronic myelogenous leukaemia
-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
Describe cervical cancer
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
Describe breast cancer
Lobular or ductal epidermal growth factor receptor (EGER, HER2) over expressed Treatment = surgery, radio/chemo therapy Herceptin- monoclonal antibody against HER2 receptor
72
Describe melanoma
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
Describe Retinoblastoma
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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