Pharmacology P&I Flashcards
Define pharmacokinetics.
What your body does to the drug.
Define pharmacodynamics
What the drug does to your body.
Define bioavailability.
Fraction of the administered dose of the drugs that reaches systemic circulation. Expressed as F.
What factors affect bioavailability?
Molecular weight of drug
gastric pH
First pass metabolism (hepatic)
Define apparent volume of distribution.
total amount of drug in the body divided by drug blood plasma concentration
Define clearance.
Volume of plasma cleared of drug per unit time.
Define half-life.
Time required for plasma concentration of drug to decrease by half. Determined by clearance and volume of distribution.
Define volume of distribution.
The volume in which the amount of drug would need to be uniformly distributed to produce observed blood concentration.
How many half lives to reach steady state?
4-5 half lives.
Define steady state.
The concentration of the drug in the plasma has reached a therapeutically effective level and as long as regular doses are administered to balance the amount of drug being cleared the drug will continue to be active.
Non-linear pharmacokinetics.
Concentration not proportional to dose. Rate of elimination constant regardless of amount of drug administered.
Describe non-linear pharmacokinetics.
Concentration not proportional to dose. Rate of elimination constant regardless of amount of drug administered.
Can the bioavailability of drugs differ with different routes of administration?
Yes.
Define loading dose.
A loading dose is an initial higher dose of a drug that may be given at the beginning of a course of treatment before dropping down to a lower maintenance dose. Depends on concentration you wish to achieve.
How do you work out the time taken for a drug to reach steady state?
5 times the half-life.
Define drug receptor.
A macromolecular component of a cell with which a drug interacts to produce a response.
Name a common therapeutic target.
Enzymes.
Name 4 different types of drug receptors.
Enzyme linked - multiple actions
ion channel linked - fast
G protein linked - amplifiers
Nuclear (gene linked) receptors - long lasting
Define affinity
measure of propensity of a drug to bind to its receptor. Attractiveness of drug and receptor.
Different types of bond
Covalent
Efficacy
Ability of the bound drug to change the receptor in a way that produces an affect.
Potency
Relative position of the dose effect curve along the dose axis.
When is low potency an issue?
If the dose you have to give is so large its hard to administer.
Can competitive antagonists be overcome?
Yes.
What is a partial agonist?
Has affinity but less intrinsic activity. Bind to a receptor and stimulate a response but has less than maximal efficacy.
Therapeutic index.
The higher the TI, the better the drug. Low dose to produce effect, high dose to produce death.
Name some common drug drug interactions in the elderly.
Statins and erythromycin /other antibiotics.
Verapamil and beta blockers
warfarin and multiple drugs including aspirin
ACE inhibitors increase hypogylcaemic effect on sulfonylureas.
What increases the more drugs a patient is on?
Risk of drug-drug interactions
Risk of poor adherance
What are the two hallmarks of malignancy?
Invasion (local)
Metastasis
Define metastasis.
Spread of a tumour to and growth at ectopic sites via blood, lymphatics, intra-epithelial route or transcoelomic.
Define carcinoma. What percentage of human cancers do carcinomas make up?
Malignant tumour derived from epithelial cells.
80%
Define sarcoma.
Malignant tumour derived from mesenchymal cells.
Define melanoma.
Malignant tumour derived from neural crest cells.
Define leukaemia.
Malignant tumour derived from circulating white blood cells.
Define Lymphoma.
Malignant tumour derived from the lymphatic system.
What is the ECM of epithelial tissues? What is it made up of?
Basement membrane.
Fibronectin, collagen 4, laminin.
Outline the different steps of the metastatic cascade.
- Local invasion
- Neovascularisation
- Detachment
- Intravasation (enter into blood or lymph)
- Transport
- Lodgement/arrest
- Extravasation (leaves blood/lymph at ectopic site)
- Growth at ectopic sites
What is the correlation between E-cadherin expression and malignancy? Explain this phenomenon.
Less malignant, more likely to express E-cadherin.
E-cadherin is expressed on cell surface of all epithelial cells. It binds cells together.
For cells to become malignant, E-cadherin must be disrupted.
Describe the ways in which E-cadherin expression can be disrupted.
- Exon-skipping (lacking exons that encode calcium binding domain)
- ECD promoter methylated (inactivated)
- Mutations in proteins that interact with ECD (beta-catenin)
- mutations in transcription factors that regulate E-cadherin (snail, slug, twist)
Name a specific integrin and receptor that promotes invasion and metastasis.
Vitronectin receptor and integrin alpha-v-beta-3.
What effect does HGF have on epithelial cells? How does it have this effect?
Induces them to dissociate and scatter.
Binds to cmet (on tumour surface), increases tyrosine phosphorylation of beta-catenin, disrupting ECD-mediated adhesion.
What kind of cells may be present in the tumour microenviroment? What may these cells secrete?
cancer-associated fibroblasts (CAFs) immune cells that have infiltrated the tumour * myofibroblasts tumour-associated vasculature pericytes
Growth factors, chemokines, enzymes.
Give an example of how tumour stromal interaction lead to MMP expression.
Breast carcinoma cells produce transforming growth factor. This causes host stromal cells to produce the MMP stromelysin 3.
Discuss how HIF (hypoxia-inducible factor) can cause neovascularization of a tumour. What chemotherapy drug’s mechanism of action targets this process?
If a tumour cell is in a place where it is hypoxic - HIF is produced, causing upregulation of VEGF, causes blood vessels to grow towards tumour.
Bevacizumab (avastin).
What are the four steps of WBC extravasation?
Rolling
Activation
Adhesion
Diapedesis
What are the principal sites of metastasis for breast cancer?
Bone, lungs, liver, brain
What are the principal sites of metastasis for lung adenocarcinoma?
Brain, bones, adrenal gland, liver
What are some of the different hypothesis regarding metastasis?
Seed and soil - ectopic sites must have a similar microenvironment to the site of the primary neoplasm.
Mechanical hypothesis - metastasis occurs purely by anatomic and mechanical routes.
What is the 5 year survival rates like for localized, regional and metastatic disease?
Localized - excellent
Regional - decreased
Metastatic - poor. Fewer than 20% of patients survived after 5 years for half of the cancer sites.
