Drug Therapy and Disorders of Cell Growth Flashcards
What are the main stages of a drug life cycle in the body?
Absorption
Distribution
Metabolism
Excretion
What is meant by absorption?
The movement of a drug from the area of administration to the circulation
What is the definition of CMax?
Maximum concentration a drug can reach in the circulation
What is the definition of TMax?
The time it takes for a drug to reach CMax (maximum concentration in circulation)
What are some of the common sites of administration of a drug?
Oral sublingual topical IV IM pessary suppository inhalation
What is the therapeutic range of a drug?
The optimal dose at which a drug is effective without being toxic
Which is a constant and which is variable, TMax or CMax, and why?
TMax is constant - increasing dose doesn’t speed up the absorption process
CMax variable - increasing dose increases concentration in circulation
What are the main factors affecting absorption of a drug?
physiological/membrane barriers
GI activity
food/alcohol
disease
What is bioavailability?
The amount of blood in circulation available for use
What is first pass metabolism?
Metabolism of a drug before it reaches its target
What are the biochemical properties that affect drug absorption?
- lipid solubility
- ionisation
- particle size
What determines the lipid solubility of a drug?
The lipid-water partition coefficient
What determines the degree of ionisation of a drug?
The Henderson-Hasselbalch equation
What causes different rates of drug absorption in children?
Different pH levels
Gastric emptying
Metabolic rate
What are some advantages of IV drug administration?
bypass first pass metabolism
100% bioavailability
quick
What are some advantages of inhalation drug administration?
bypasses first pass metabolism
can be metabolised in lungs
avoid oral administration side effects
What are some advantages of rectal drug administration?
slow absorption
avoid stomach irritation
bypass first pass metabolism
What are some advantages of subcut/IM drug administation?
bypass first pass metabolism
only need small dose
effect can be modulated with formulation
What are some advantages of transdermal drug administation?
bypass first pass metabolism
can be used for slow release
What are some advantages of sublingual drug administation?
bypass first pass metabolism
What are the differences between pharmacokinetics and pharmacodynamics?
pharmacodynamics - drug mechanism of action
pharmacokinetics - drug movement in the body
What is the definition of drug distribution?
The ability of a drug to reach the target tissue from the circulation
What is the definition of volume of distribution?
It is the theoretical volume of plasma required to detect the total concentration of drug in the body
What is the definition of drug clearance?
The time it takes for a drug to be eliminated from the circulation
What are the main organs involved in drug clearance?
Kidneys
Liver
What are the mechanisms of drug clearance from the kidneys?
Glomerular filtration rate
Active secretion
Distal reabsorption
What is the biliary system?
It’s a mechanism used by the liver to expel drug into the intestine through bile
What happens to a drug when it goes through the biliary system?
It is bound to a conjugate which renders it inactive
What is the importance of plasma proteins in drug administration?
They bind drug molecules, only unbound drug is active
What half-life of drug is best used in acute situations and why?
Short half life.
Long half life takes longer to take effect
What properties of a drug are associated with higher volume of distribution?
Drugs which are lipophilic and non ionised, crossing barriers quicker
What factors can affect how much drug is bound in the circulation?
OTHER DRUGS
pregnancy
kidney failure
hypoalbuminaemia
What is the definition of half life?
The length of time after which the concentration of a drug in the circulation has halved
What factors affect half life of a drug?
Volume of distribution
Clerance rate
What are the mechanisms of excretion of drugs from the kidneys, and what types of drugs do they excrete?
GFR - most unbound drugs
active secretion - ionised drugs (acids/bases)
passive reabsorption - small non-ionised drugs
What properties of a drug affect its volume of distribution?
Ionisation
Lipid solubility
What happens to drugs metabolised in the liver?
Rendered polar and water soluble, then excreted in bile
In which organs do drugs have to be actively transported across membranes?
BBB
ovaries
testes
In which organs do drugs tend to build up during distribution?
Eyes bone kidneys lung spleen fat
Why can drug metabolism cause toxicity?
Because drug breakdown products can be toxic metabolites
What are the main changes that occur to a drug during metabolism, and why are they important?
drug made polar
drug mate water soluble
polar and watersoluble compunds can be excreted, whereas nonpolar and lipid soluble compounds are reabsorbed by circulation
What are the main steps involved in drug metabolism in the liver?
Phase 1 - oxidation, reduction, hydrolysis = make compound polar
Phase 2 - glucouronidation = make compound water soluble
What is the class of enzymes responsible for drug metabolism in the liver?
Cytochrome P450
What are the effects of enzyme inhibition on drug metabolism?
Drug metabolism slowed = higher level of drug in bloodstream
What is the effect of enzyme induction on drug metabolism?
Drug metabolised faster - lower levels of drug in bloodstream
Which genetic modification of Cytochrome P450 causes a lack of response to codeine?
CYP2D6
Which types of Cytochrome P450 are the most important in drug metabolism?
CYP3A4
CYP2D6
CYP1A2
Which class of Cytochrome P450 is important in smokers and why?
CYP1A2 - metabolises theophylline, smoking induces enzyme so higher level of theophylline required
Which classes of Cytochrome P450 present genetic polymorphisms?
CYP2D6
CYP2C9
CYP2C19
What factors can affect drug metabolism?
Age Pregnancy Gender Other drugs Liver disease Ethnicity Genetics
In which phase of drug metabolism is a conjugate added to the drug, and what is this called?
Phase 2 - glucouridation
What are the different phenotypic types of metabolises?
Poor metabolisers (PM Intermediate metabolisers (IM) Extensive metabolisers (EM) Ultra rapid metabolisers (UM)
List some factors which induce drug metabolism
Alcohol
Smoking
Other drugs
Pregnancy
What are the main three considerations when deciding on a treatment regime?
Dosage of drug
Timing of administration
Frequency of administration
What are the functions of enteric coating on tablets?
protect GI tract from drug
protect drug from GI acids
What are advantages of solutions and suspensions?
quick absorption
palatable (especially children)
easy for people with swallowing problems
can be given NG
What are advantages of tables/pills?
easy to mass produce
easy to take
reproducible effect
reliable pharmacological effect
What are advantages to sustained release formulations?
Better compliance
less frequency of administration
maintains drug at therapeutic level
What are some advantages of rectal formulations?
good for patients who can’t swallow
bypasses first pass metabolism
What are some of the advances in drug delivery methods?
nanoparticles
monoclonal antibodies
viral carriers
What are the common factors considered for adverse drug reactions?
Onset and severity
What are the classifications of adverse drug reaction onset?
Acute (<60mins)
subacute (1-24 hours)
latent (>24hrs)
What are the classifications of adverse drug reactions severity?
mild
moderate
severe
What are the categories of adverse drug reactions and their main properties?
Augmented effect - predictable, primary or secondary
Bizarre effect - rare, non reversible, nonrelated
Chronic effect - after long term drug use (eg steroids)
Delayed effect - teratogenic/carcinogenic drugs
End of treatment effect - withdrawal/rebound symptoms
Failure of treatment effect - common, dose not high enough
What is the mechanism used for reporting adverse reactions?
Yellow Card system
What percentage of ADRs could potentially be avoided?
about 65%
What percentage of hospitalised patients will develop an ADR?
10-20%
What are some risk factors for ADR?
Age multiple conditions multiple medications kidney/liver disease gender (women more likely) genetics prior history of ADR
What percentage of ADRs leads to death in the UK?
up to 3%
How common is death resulting from ADR in terms of leading causes?
4th leading cause
What are the common mechanisms of drug interactions?
Pharmacodynamic
Pharmacokinetic
In what way can drug interactions affect pharmacokinetics of other drugs?
they can affect Absorption, Distribution, metabolism and excretion
How can drug-drug interactions affect drug absorption?
affect local pH
affect GI motility
affect gut flora
forming complexes with other molecules
How can drug-drug interactions affect distribution of a drug?
affect plasma protein binding = alter bioavailability
How can drug-drug interactions affect metabolism of a drug?
induce/inhibit cytochrome P450 function in the liver = increase/reduce drug metabolism and breakdown
How can drug-drug interactions affect elimination of a drug?
can affect kidneys
can affect GFR
= slow down elimination
What are the pharmacodynamic effects of drug interactions?
Direct/indirect effects
agonistic/synergistic effects
antagonistic effects
What are examples of indirectly agonistic drug interactions?
warfarin + NSAIDS
benzo’s + alcohol/trycyclics
verapamil + atenolol
What are examples of indirect antagonistic drug interactions?
NSAIDs + hypertensives/heart failure drugs
which types of drugs are more likely to cause drug interactions?
drugs which are normally highly protein bound
drugs with a steep dose/response curve
What is the best approach when dealing with drug interactions?
- try changing the frequency of the administration
- try alternative drug
- modify dose and monitor closely
what are risk factors for drug interactions?
being on many drugs having multiple prescribers/self prescribing age diabetes asthma surgery
what are the names given to a drug which is interacted with by another drug, and the drug causing the changes?
object drug
precipitant
What is the incidence of drug interactions in hospital and primary care?
up to 30%
up to 70%
What are common causes for medication errors?
tiredness depression inexperience heavy workload unfamiliarity with drug
What is meant by medication error?
potentially harming a patient as a result of wrong medication being given
What is meant by prescription faults and errors?
faults - wrong decision on what drug to prescribe
error - mistake in writing up prescription
When are medication errors most likely to occur?
on admission
on discharge
What are the different classifications of errors in clinical practice?
error: wrong decision but not acted on
mistake: wrong decision, acted on
slip: task executed incorrectly
lapse: task executed correctly but omitted
What are the 6 R’s to avoid prescription writing errors?
Right patient Right drug Right dose Right route Right time Right formulation
are teratomas malignant or benign in ovaries?
benign
are teratomas malignant or benign in testes?
malignant
what is the leading type of cancer in men?
prostate cancer
what is the leading type of cancer in women?
breast cancer
what is the second most common type of cancer both men and women?
lung cancer
what type of cancer is most common overall?
breast cancer
what kind of cancers can occur in epithelial tissue?
glandular adenocarcinomas
squamous cell carcinomas
what kind of cancers can occur in connective tissue?
osteosarcoma, liposarcoma, fibrosarcoma
which cancers have the best, and worst, 5year survival rate?
best - melanoma
worst - lung cancer
what are germ cell tumours known as?
teratomas
what are the main two genetic mechanisms which contribute to cancer?
loss of tumour suppression genes
gain of oncogenes
what are some of the main factors which promote tumour growth?
increased angiogenesis
reduced apoptosis
how can cancer spread through the body?
via circulation
via lymphatics
local invasion
transcoelomic
where is breast and prostate cancer likely to spread to?
bone
where is ovarian cancer likely to spread to?
omentum
what are some common sites for tumour metastasis?
liver
bone
lung
brain
what are biomarkers and why are they useful?
proteins and molecules secreted by tumour cells
can be detected and used for diagnostic/prognostic and treatment purposes
what are some types of biomarkers used clinically and for which cancer type?
alpha-feto protein (AFP) - testicular and liver cancer
oestrogen receptor - breast cancer
prostate specific antigen - prostate cancer
carcino-embryonic antigen (CAE) - colorectal cancer
what is the difference between local invasion and transcoelomic spread?
transcoelomic spread moves through body cavities
it’s faster than local invasion
what is a feature of cancer cells which allows them to form metastases?
loss of cell-cell adhesion
alteration of cell-matrix adhesion
What can be some of the local effects of cancer?
obstruction pressure pain bleeding (anaemia/haemorrhage) infection/ulceration
What can be some of the systemic effects of cancer?
weight loss (cachexia)
paraneoplastic syndromes (unexplained symptoms)
effects of treatment
hormone secretion ("normal" or abnormal)in what ways can cancer affect hormone secretion in terms of systemic effects?
- normal: tumour cells induce higher levels of hormone from organs which normally secrete that hormone
- abnormal: tumour cells induce production of hormone from the organ which doesn’t normally produce that hormone
what are the stages of a cell life cycle during mitosis?
G0 - cell not in active division G1 - cell getting ready for DNA replication S - DNA replication occurs G2 - cell getting ready for mitosis M - mitosis occurs
what are the two different sets of factors which control cell division?
extrinsic - growth factors, hormones etc
intrinsic - checkpoints/restriction point
What is the role of cyclin dependent kinases?
they area checkpoints during cell cycle, when cyclin is present
What is pRb?
Retinoblastoma gene, tumor suppressor gene
target for CDKs, controls function of E2F transcription factor:
- hypophosphorylated –> active: inactivates E2F, so cell cycle stops
- phosphorylated –> inactive: E2F remains active, so no break applied to cell cycle
What is E2F transcription factor?
a molecule which strongly induces cell cycle division
What is the restriction point (P) during mitosis?
the checkpoint at G1 when the cell stops relying on external factors for progression of division process
What is P53?
It’s a gene which is activated when there are errors in the cell cycle, to repair error or induce apoptosis through activation of p21
What are the main genetic pathways which are disrupted during cancer?
- P53 pathway
- Cyclin D –> pRb –> E2F pathway
at which stage of cell cycles does cancer normally occur?
G1
which are the main genes which become abnormal during cancer?
pRb
Cyclin D
CDK4
p16
what are the mechanisms of chemical and radiation carcinogenesis?
chemical - nucleotides damaged, carcinogenic adducts bind to DNA
radiation - nucleotides damaged by radiation (xray, UV, gamma)
what are the two versions possible in the “two hit hypothesis” of carcinogenesis, and what do they involve?
somatic - both copies of gene in same cell mutated over time
inherited - one gene in cell DNA already mutated, other one gets a somatic mutation later on
both lead to inactivation/loss of both genes in one cell, causing cancer
what are proto-oncogenes, and how are they related to cancer development?
normal growth-promoting genes
structural or expression alteration can mutate them to become oncogenes
how do oncogenes contribute to cancer?
they promote production of oncoproteins like growth factors and growth factor receptors
what genetic changes normally lead to sporadic cancers?
several genetic mutations which occur over time
what are the main three genetic causes of cancer?
- chemical
- physical (radiation)
- viral
what is PDL1 and what is its function in cancer?
checkpoint inhibitor
it binds to PD1 receptors on T cells, therefore “blinding” the T cells from recognising cancer cells as foreign
how do barium studies show up on a scan?
white
what types of barium studies are used for which types of cancer?
barium meal/swallow - upper GI/duodenum
barium enema - lower GI/large bowel
what is the radiation for barium meal and barium enema?
barium meal - 1.5mSv
barium enema - 7mSv
what is the difference between a pixel and a voxel?
pixel is 2D (x-rays)
voxel is 3D (CT)
how do CT scans reconstruct the image?
analysing how many photons are sent back (not absorbed)
uses the Hounsfield attenuation coefficient
What is the Hounsfield attenuation coefficient?
a measure which compares the attenuation level of tissues with that of water
what are the radiation doses for chest, abdomen and pelvic CT scans?
chest - 8mSv
abdomen - 10mSv
pelvis - 10mSv
What is the principle of ALARA?
as low as reasonably possible
only schedule CT scans when really necessary to avoid unnecessary radiation
how do MRIs form an image?
magnetic frequency to align H+ protons
building image from how long it takes for them to return to normal alignment
what should be the main properties of cancer screening?
- early detection to allow for treatment
- test shouldn’t cause harm
- test should have reasonable cost/benefit ratio
- test should be sensitive and specific
what are the main classes of chemotherapy drugs?
antimetabolites
antimitotic antibiotics
alkylating agents
vinca alkaloids/taxanes
what is an example of an alkylating agent in chemotherapy, and how does it work?
cisplatin
activated when added to water, it impairs DNA replication
how do cancer cells resist alkylating agents?
- alter its entry/exit into and out of the cell
- inactivate it with enzymes once it enters
- repair DNA that has been affected by drug
what is the mechanism of action of anti-metabolites in chemotherapy, and what is an example of one?
methotrexate
mimic metabolites and bind to cell structures to stop DNA synthesis (S) in cell cycle
what is the mechanism of action of vinca alkaloids and taxanes in chemotherapy?
- vinca alkaloids prevent spindle formation prior to mitosis
- taxanes promote spindle formation but cycle goes no further
what is the mechanism of action of antimitotic antibiotics in chemotherapy, and what is an example of them?
anthracyclines and non-anthracyclines
act in different ways at mitotic stage to stop it from happening
What are the considerations of multidrug therapy for chemotherapy?
- prevent resistance
- synergistic action to increase response
- different mechanisms to increase chance of response
- different side effects to prevent neurotoxicity
how do chemotherapy drugs cause nausea and vomiting?
through activation of the enterochromaffin cells, which release serotonin, causing nausea
what is the basis PDL1 and Chimeric Antigen Receptor therapies in cancer immunotherapy?
PD1/PDL1 - unblinding T cells so they recognise cancer cells as foreign
CAR - modifying own T cells so they attack cancer cells)
what are some other types of chemotherapy drugs apart from the cytotoxic agents and immunotherapy?
hormonal drugs
drugs targeting growth factors
what are the systemic treatment options for cancer used?
chemotherapy
immunotherapy
targeted therapy
hormonal therapy
what are the principles of adjuvant and neoadjuvant therapy in cancer?
neoadjuvant - prior to surgery, maximise surgical success
adjuvant - post surgery
what are the benefits of radiotherapy?
- can treat inoperable tumours
- can reduce size of tumour to make it operable
- can maintain structure/function of organ
- responsible for 40% of cured cancers
what are the prevention mechanisms for cancer?
behavioural/environment change diet change screening vaccination/prophylactic treatment genetics
what is the percentage of cancers treated with chemotherapy?
3%
