1
Q
What are the differences between tumour cells and their surrounding stroma?
A
Tumour cells are neoplastic cells and is autonomous (i.e. response to physiological stimulus is lost/abnormal, allowing unregulated growth)
- have self sufficiency in growth signals
- are insensitive to anti-growth signals
- invade tissue & metastasise
- have limitless replicative potential
- sustained angiogenesis
- avoid apoptosis
Their surrounding stroma is anything that is not a cancerous cell
- e.g. connective tissue, blood vessels, inflammatory cells.
2
Q
What are the general characteristics of benign and malignant tumours?
A
BENIGN:
- well circumscribed
- slow growth
- no necrosis
- non-invasive
- no metastasis
MALIGNANT:
- poorly circumscribed
- rapid growth
- often necrotic
- invasive
- metastasises
3
Q
What are the four ways in which malignant tumours spread?
A
- Directly invade locally
- Via the lymphatics
- Via the bloodstream (haematological)
- Through body cavities (transcoelomic)
4
Q
Why is a benign tumour not always clinically benign?
A
- Have space occupying effects
- obstruction
- epilepsy
- conduction abnormalities - Cause haemorrhage
- pulmonary
- GI - Cause hormone production
- pituitary
- adrenal
- endocrine production
5
Q
The seed and soil hypothesis explains that not all tumours behave the sae. What are some of the common areas that certain tumours metastasise to? (HINT: there’s 4 examples)
A
- Prostate (tends to metastasise to) -> bones
- Lung -> brain, adrenals
- Breast -> lung, liver, bone, brain
- Ovary -> peritoneal cavity
6
Q
What are the macroscopic features of benign and malignant tumours?
A
BENIGN:
- intact surface
- exophytic growth
- homogenous cut surface
- circumscribed/encapsulated edge
MALIGNANT:
- alterated surface
- endophytic growth
- heterogenous cut surface due to necrosis
- irregular infiltrative edge
- endophytic growth
7
Q
What are the microscopic features of benign and malignant tumours?
A
BENIGN:
- resemble tissue fo origin
- well circumscribed
- well differentiated
- minimal nuclear polymorphism
- mitotic figures normal
- no necrosis
MALIGNANT:
- variable resemblance
- poorly circumscribed
- variable differentiation
- variable pleomorphism (may be anaplastic)
- mitotic figures abnormal
- necrotic
8
Q
What do the terms grade and stage mean in relation to tumours? Give examples of how staging is used clinically.
A
GRADE = the degree of resemblance to the tissue of origin
- correlates broadly with clinical behaviour
- e.g. a grade 1 malignant neoplasm = well differentiated whereas a grade 4 malignant neoplasm = nearly anaplastic
STAGING = the extent to which a cancer has developed by spreading
- e.g. TNM staging : T = tumour size
N = degree of lymph node involvement
M = extent of distant metastases
- e.g. Dukes’ staging system for colorectal cancer (A, B, C, D)
9
Q
How are benign and malignant tumours named? (for both epithelial and connective tissue tumours)
A
BENIGN:
- epithelial = papillomas or adenomas
- connective tissue = begin with the term denoting the cell of origin e.g. lipoma
MALIGNANT:
- epithelial = carcinomas
- connective tissue = sarcomas
10
Q
Give examples of (i) epithelial (ii) mesenchymal (iii) miscellaneous tumours.
A
(i) Benign = squamous cell papilloma, transitional cell papilloma, adenoma
Malignant = squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma
NOTE: epithelial tumours may be associated with a non-invasive precursor (e.g. carcinoma in situ, intraepithelial neoplasia)
(ii) Benign = lipoma, haemangioma etc
Malignant = liposarcoma, haemangiosarcoma
NOTE: not usually associated with a non-invasive prescursor
(iii) melanoma, teratoma, lymphoma, blastomas, carcinoid tumours, cysts
11
Q
What is a teratoma?
A
- contains elements of all three embryonic germ cell areas
- is of germ cell origin
- is both benign and malignant forms
- ovarian = almost always benign
- testicular = almost always malignant
12
Q
What are tumour stem cells?
A
- the cells which can repopulate the tumour
example = basal and squamous cell carcinoma
13
Q
What does the statement “many tumours have a clonal origin” mean?
A
- gene coded for by the X chromosome
=> in females one X is randomly switched off - The enzyme G-6PD can be separated by chromotography into an A and a B form
- normal tissue = a 50:50 ratio of A and B enzyme markers
- If the tumour arises from a single cell (i.e. clonal) then all the cells have the same enzyme marker (all A or all B)
14
Q
What are the changes in bone structure and function that occur with osteoporosis?
A
- decreased size of osteons
- thinning of trabeculae
- enlargement of haversian and marrow spaces
15
Q
What is the incidence of osteoporosis in the UK?
A
Affects 3 million people in the UK
Affects 1 in 3 women and 1 in 12 men
- at the age of 50, the chances of fragility fractures are: In woman all fractures = 40% chance, for hip fractures in woman = 18% and in men = 6% chance.
16
Q
What are the risk factors for osteoporosis?
A
- GENETIC/GENDER: females more prone than men due to menopause (change in oestrogen regulation)
- LIFESTYLE & NUTRITIONAL: smoking, excess alcohol, prolonged immobilisation, sedentary
- MEDICAL CONDITIONS: many are related to hormone imbalances. Examples include; anorexia nervosa, rheumatoid arthritis, early menopause, hyperthyroidism
- DRUGS that lead to OP: chronic corticosteroid therapy, excessive thyroid therapy, anticoags, anticonvulsants, chemotherapy, gonadotrophin releasing hormone agonist OR antagonist
- RISK OF ANOTHER FRACTURE AFTER A PREV FRAGILITY FRACTURE: Fragility fracture = low energy trauma - mechanical forces that wouldn’t normally cause a fracture
A previous wrist fracture: doubles risk of future hip fracture & triples risk of future vertebral fracture
17
Q
What are the most common sites for osteoporotic fractures ? Appreciate the morbidity associated
A
Distal radius, neck of femur, vertebral body, spine, proximal humerus
- hip fractures are: fatal in 20-30% of cases
only 30% fully recover
permanently disables 50%
18
Q
List the modifiable and non modifiable risk factors for osteoporosis.
A
MODIFIABLE: NON MODIFIABLE
- oestrogen deficiency - gender
- smoking - age
- alcohol - previous fracture
- low calcium - family history
- low BMI - long term steroids
- vit D deficiency - race
- inacitvity
19
Q
How is osteoporosis diagnosed?
A
- blood tests, FBC, serum biochemistry, bone profile
- thyroid function tests
- testosterone & gonadotrophin levels (men)
- x-ray of lumbar and thoracic spine ( BUT >30% bone loss is required to be visible)
- BMD measurement using DEXA
20
Q
How is osteoporosis treated?
A
- BIPHOSPHONATES: e.g. alendronate, risedronate
- disrupt the activity of osteoclasts => OC end up dying as they inhibit part of the mevalonate pathway
- potential side effects = oesophagitis, mandibular necrosis - ANABOLIC AGENTS e.g. strontium ranelate, intermittent PTH.
- stimulate bone production (OB activity increase)
- this may be more effective than the above as it’s replacing wasted bone rather than simply halting the wasting - Ca2+ supplements
- HRT - this carries an increased risk of breast cancer
- INCREASE EXERCISE
21
Q
What are the types of osteoporosis?
A
TYPE 1: POST MENOPAUSAL - affects cancellous bone - vertebral & distal radius fractures common - related to oestrogen loss - F:M = 6:1 TYPE 2: AGE RELATED IN >75 y.o - affects cancellous AND cortical bone - hip & pelvic fractures common - related to poor calcium absorption - F:M = 2:1 DISUSE OSTEOPOROSIS - resulting from conditions resulting in prolonged immobilisation, typically in neurological or muscle disease
22
Q
Explain the scoring for DEXA.
A
T-SCORE: comparison with a young adult of the same gender who has peak bone mass
>-1 = normal
-1 to -2.5 = osteopenia
less than -2.5 = osteoporosis
Z-SCORE: comparison of pt with data from the same age/sex/size
23
Q
What is X-chromosome inactivation? Give an example.
A
Because females = XX and males = XY
- females need to silence one X chromosome (= chromosome inactivation)
- mechanism of silencing is initiated by Xist
{ X inactive specific transcript “marks” the inactive X, it is only expressed from inactive x-chromosome & codes for RNA. No protein product or RNA remains in the nucleus}
- this is then followed by DNA methylation
E.g. Calico cats; whether paternal or paternal X depends whether express orange or black coat (white = autosomal)
24
Q
What is the difference between heterochromatin and euchromatin?
A
HETEROCHROMATIN:
- highly condensed in interphase
- transcriptionally inactive (contains few genes)
- replicates LATE in S phase
EUCHROMATIN:
- organised in 30nm fibre during interphase
- transcriptionally active
- replicates EARLY in S phase
25
What is DNA methylation?
- inhibits gene transcription
- prevents binding of transcription factors to promoter & inhibits transcription by converging chromatin from an open to a closed conformation
- methyl CpG proteins contain a methyl binding domain that specifically recognises methylated CpGs
- it recruits other proteins (e.g. histone deacetylases) that remove acetyl groups and => favouring compact chromatin
26
What are the two ways in which the methyl tags can silence genes?
1. Can block transcription machinery from binding to the DNA
| 2. Can recruit proteins that bind to methylated DNA, which then block the transcription machinery from binding
27
What is uniparental disomy? Name and explain certain diseases which result from uniparental disomy.
Chromosome imbalances
- both chromosomal copies are inherited from the same parent
Meiosis I = uniparental heterodisomy
Meiosis II = uniparental isodisomy
chr 11 = Wilms' tumour
chr 15 = PWS/AS
PWS and AS are 2 v. different disorders but are both linked to the same imprinted region of chr 15. Some of the genes in this region are silenced in the egg & at least one is silenced in the sperm => someone who inherits a defect on 15 is missing different active genes, depending on whether the chromosome came from mum OR dad
28
What is genomic imprinting? State the mechanism and the evidence for imprinting.
Imprinted genes only expressed from one allele, dependent on parental origin
- imprinting resets on passage through germline
MECHANISM: must be somatically stable
must be reversible during gametogenesis
=> DNA methylation = best candidate
EVIDENCE: human tumours: hydatidiform mole (2xF) ovarian teratoma (2xM)
Mouse chimeras: normal + androgenetic (2xM) = growth enchanced. normal + gynogenetic (2xF) = growth retarded
29
Give examples of diseases arising from abnormal epigenetic regulation. (HINT: there's 6)
```
Beckwith-Wiedmann (BWS) Syndrome [overgrowth]
Fragile X Syndrome
Myotonic Dystrophy (congenital)
Prader-Willi Syndrome
Angelman Syndrome
Wilms' Tumour [overgrowth]
```
30
What is the epidemiological time triad?
= Time - place - person
Time:
- long term = secular
- epidemic = temporary increase
- periodic = cyclical
- seasonal
Place:
- geographical, local, workplace, community, home, social gatherings
Person:
INTRINSIC = genetics, sex, age, marital status, ethnic group
EXTRINSIC = lifestyle, behaviour, occupation, migration, socio-economic
31
Give examples of potential (i) exposures (ii) outcomes.
(i) infectious disease, sanitation, medical technology (e.g. antibiotics, transplants, radiotherapy etc)
(ii) life expectancy, mortality, quantity of life, inequality, morbidity etc
32
What is (i) incidence (ii) prevalence? Know the necessary calculations to calculate the rates of each.
(i) the rate at which new cases occur in a population during a specific period
rate = no. new ppl w. outcome over a time period / total no. ppl in group at risk *100,000
(ii) proportion of a population that are cases at a point in time
- point prevalence = at one point in time
- period prevalence = over a time period
rate = no. ppl w. outcome at point in time / total no. ppl in group * 100
33
What is an ecological population case series?
In ecological studies, the unit of observation is the population or community. Common types of ecological study are geographical comparisons, time trend analysis or studies of migration.
Studies of risk-modifying factors on health or other outcomes based on populations defined either geographically or temporally.
-> Both risk-modifying factors and outcomes are averaged for the populations in each geographical or temporal unit and then compared using standard statistical methods.
34
What is a case-control study?
Compares patients who have the disease/outcome of interest (cases) with patients who don't have the disease/outcome (controls), and looks back retrospectively to compare how frequently the exposure to a risk factor is present in each group to determine the relationship between the risk factor and the disease.
Is observational as no intervention is attempted & no attempt is made to alter the course of the disease.
GOAL= to retrospectively determine the exposure to the risk factor of interest from each of the two groups of individuals: cases and controls.
These studies are designed to estimate odds
35
What is a cohort study? What two subtypes is there?
This study identifies a group of people and follows them over a period of time to see how their exposures affect their outcomes. This type of study is normally used to look at the effect of suspected risk factors that cannot be controlled experimentally, for example the effect of smoking on lung cancer.
Retrospective = looking back
Prospective = looking forward
36
What is a RCT?
Randomised controlled trial
= study where people are randomly allocated to receive (or not receive) a particular intervention (this could be two different treatments or one treatment and a placebo).
This is the best type of study design to determine whether a treatment is effective.
37
What is a case series?
A case series is a descriptive study of a group of people, who usually receive the same treatment or who have the same disease. This type of study can describe characteristics or outcomes in a particular group of people, but cannot determine how they compare with people who are treated differently or who do not have the condition.
38
What is a cross-sectional study?
Study that describes characteristics of a population.
It is ‘cross sectional’ because data is collected at one point in time and the relationships between characteristics are considered.
Importantly, because this study doesn’t look at time trends, it can’t establish what causes what.
39
What are the four main criteria of ADME?
```
A = absorption
D = distribution
M = metabolism
E = excretion
```
40
What are the major routes of drug administration? List their benefits and drawbacks. (HINT: there's 7 routes)
ORAL
- A: convenient
- DA: first-pass effect, many variables & barriers
SUBLINGUAL
-A: no first pass effect
- DA: inconvenient, small dose limit, taste
INHALATION
- A: fast, rapid delivery to blood
- DA: requires special properties of drug (e.g. atomised, vaporised)
TOPICAL
- A: convenient, localised
- DA: only local
TRANSDERMAL
- A: prolonged release
- DA: skin=v.effective barrier
INTRAMUSCULAR
- A: rapid for aqueous solutions, slow for oil
- DA: painful, requires trained personnel
INTRAVENOUS
- A: direct, total dose, rapid
- DA: requires a professional, infection risk, rapid response
41
What is bioavailability?
the fraction of unchanged drug that reaches the systemic circulation
- IV gives 100% bioavailability
- Oral gives less than 100%
42
What are the four ways that small molecules cross the cell membranes?
(1) DIFFUSING DIRECTLY THROUGH THE LIPID
- lipid solubility is => highly important
(2) DIFFUSING THROUGH AQUEOUS PORES
- more likely for diffusion of gases i.e. very small molecules
(3) TRANSMEMBRANE CARRIER PROTEINS
- e.g. solute carriers. This can be done actively OR passively
(4) PINOCYTOSIS
- mostly macromolecules (v.large molecules) and not drugs.
43
What is the difference between hydrophilic and lipophilic drugs?
Hydrophilic: soluble in aqueous and polar media (e.g .blood plasma, cytosol & interstitial fluid)
Lipophilic: soluble in fats & non polar solutions (e.g. interior of lipid bilayer & fat)
NOTE: lipophilic is more readily absorbed than hydrophilic
44
What does the ionised:unionised ratio depend on?
pH
45
What is the relationship between ionisation and lipid solubility?
ionised drugs have low lipid solubility
46
What factors affect distribution?
```
degree drug ionisation
lipid solubility
pH of compartments
cardiac output & blood flow
capillary permeability
plasma protein binding
```
47
What is the relationship between biphosphates and bone?
- phosphate groups have a high affinity for calcium
- they are quickly absorbed to the skeleton
ORAL alendronate: given daily/weekly
IV zoledronate: given yearly (it has a huge affinity for bone)
48
What are the effects of protein binding upon the distribution and availability of drugs within the body?
A drug must be free to distribute widely OR bind to its receptor
Many drugs bind to plasma proteins (albumin, alpha1 acid glycoprotein, lipoproteins, globulin)
- the fraction of unbound drug can be as low as 1%
=> the competition for binding sites can cause big increases in free drug concentrations.
E.g. warfarin & aspirin. Normally 98% of warfarin is bound to albumin but this is lower in the presence of aspirin as aspirin also has a high affinity for albumin
49
Give an overview of (i) Drug Absorption and (ii) Drug Distribution.
- the route of administration is affected by both drug & patient factors
- unless drugs are injected directly into the systemic circulation, then there are barriers to absorption
- the main drug properties that affect absorption are lipophilicity & ionisation
- body water is distributed into 4 main compartments (plasma water, intracellular, interstitial, transcellular - and fat)
specialised compartments exist and factors such as perfusion, influence distribution
- the degree of distribution between these compartments depends on tissue and drug dependent factors
- side effects of some drugs can be minimised by limiting their distribution via the route of administration
50
What is a genetic disease?
One caused by a change in the genes
51
What are the various mutation types? Use this sentence "the cat sat on the mat" to explain what each type does.
STOP - the cat
MISSENCE - the car sat on the mat
INSERTION - the cat spa to nth ema t
DELETION (out of frame) - the cas ato nt hem at
DELETION (in frame) - the cat on the mat
TRIPLET EXPANSION - the cat cat sat on the mat
52
What is the difference between mendelian and non-mendelian inheritance?
Mendelian Inheritance
- change in a single gene sufficient to cause clinical disease
- it is inherited in a fashion predicted by Mendel's laws
Non-mendelian inheritance
- everything else, including common 'multifactorial' diseases
53
What is autosomal dominant? Give an example disease. Give definitions for (i) allelic heterogeneity (ii) locus heterogeneity.
1 faulty copy of the gene causes disease
E.g. Marfan's syndrome (fibrillin 1 mutation)
25% = new mutations 75% = inherited in AD pattern
(i) different mutations in the same gene can cause the same disease (HHT 1 and HHT 2)
(ii) the same disease might be caused by mutations in one of several genes
54
What is autosomal recessive? Give an example disease. In what families is this most common?
2 faulty copies of the gene cause disease
E.g. sickle cell anaemia (A->T, glutamate->valine)
increased likelihood in consanguineous families
55
Discuss X linked inheritance, making sure to mention X linked recessive.
X linked recessive = gene fault lies on X chromosome
- for a female carrier: half of male kids will be affected & half of female children will be carriers
- if an affected male has children: all of the male children will be normal and all of the female children will be carriers
56
What are the complications of the basic pedigree pattern? (HINT: there's 2)
NON PENETRANCE:
- failure of genotype to manifest (i.e. carrying mutation but don't show characteristics of the disease)
VARIABLE EXPRESSION:
- different family members may show different features of a disorder
- both are seen more often in dominant conditions due to the influence of other genes and environment, as well as chance
57
What are the various features of mitochondrial DNA? Discuss mitochondrial inheritance.
16,559 base pairs
- many copies (because of many mitochondria) in a cell
- contains important genes for mitochondrial metabolic pathways & rRNAs
- inherited almost exclusively maternally
- point mutations & deletions occur
- rare
- maternal transmission only
- both sons and daughters are equally affected
58
What are the two phases of drug metabolism?
PHASE 1
- generally oxidation, reduction or hydrolysis
- usually introducing/revealing a reactive chemical group
- products are often more reactive
PHASE 2
- synthetic, conjugative reactions
- hydrophilic, inactive compounds usually generated
59
Explain how paracetamol is metabolised.
Majority of paracetamol is conjugated by either sulphate or glucoronide groups (phase 2 only)
- a small amount undergoes phase 1 by cytochrome P450 enzymes, producing a toxic metabolite
- if normal doses are taken then there is normal glutathione levels so it can combine with glutathione, then it can be conjugated and excreted
- if an excess if taken then glutathione levels are depleted, resulting in the toxic metabolite combining with hepatic proteins => hepatotoxicity
60
Give an overview of drug metabolism.
The aim is to produce metabolites that can be excreted
- it mainly occurs in the liver and metabolites can be active or toxic
- genetic variability in metabolic enzymes occurs & expression of metabolic enzymes can be induced and/or inhibited
- competition for metabolic enzymes occurs & metabolic pathways can be saturated
- metabolism can affect the bioavailability of drugs
61
Explain the metabolic examples and relevance to bioavailability of (i) warfarin and phenobarbital and (ii) Grapefruit juice & statins.
(i) Phenobarbital: increases the expression of CYP450s
warfarin: is metabolised by CYP450s
=> if you take them at the same time, then there's a decreased effectiveness of warfarin
(ii) simvastatin is metabolised by CYP3A4 in the gut wall & liver
- it has a high 1st pass metabolism => about 5% reaches the circulation
- BUT grapefruit juice blocks CYP3A4
=> they compete and more simvastatin reaches the circulation
(NOTE: statins do have side effects and these aren't usually an issue due to the small % within the circulation)
62
What is the function of drug elimination? What are the major routes of drug elimination?
- drugs are eliminated either unchanged or as metabolites
( hydrophilic drugs are eliminated more readily than lipophilic drugs - except in the liver)
Possible sources of excretion = breath, faeces, urine, milk, saliva, bile, hair, perspiration
- the kidneys are the most important organs involved in the elimination of drugs and their metabolites
63
What factors affect pharmacokinetic parameters?
```
age
sex
diet
pregnancy
disease
genetic variability
ethnicity
body weight
other medications
```
64
What is (i) Cmax (ii) Tmax?
(i) the peak plasma concentration
| (ii) time to the peak plasma concentration
65
What is the relationship between the absorption half life and the length of time within the therapeutic window?
The longer the absorption half life, the longer the drug stays within the effective therapeutic window
66
What is the main action of NSAIDs? State their primary action.
(1) Anti-inflammatory
(2) Analgesic
(3) Anti-pyretic
Main action is to inhibit prostaglandin biosynthesis by direct action of cyclo-oxygenase (COX) enzymes
67
What is the mechanism of action os NSAIDs? There is 2 main mechanisms, state what these are and give examples of drugs which follow each mechanism.
NSAIDs all inhibit COX, but they do so by 2 main mechanisms:
(1) an irreversible, time-dependent inhibition of the enzyme
E.g. APIRIN
- it inactivates the enzyme by acetylating the alpha-amino group of the terminal serine of the enzyme forming a covalent bond
- further synthesis of prostaglandins requires synthesis of new enzyme
(2) A rapid, reversible competitive inhibition of the enzyme
E.g. IBUPROFEN
- binds reversibly to the enzyme and competes with the natural substrate, arachidonic acid.
68
What are the physiological mechanisms that give rise to prostaglandin synthesis? (Name and describe the 2 main enzymes)
```
Generated in tissues from a precursor (arachidonic acid) by cyclo-oxygenase enzymes
- thromboxanes, leukotrienes & prostaglandins are all products of arachidonic acid metabolism
The 2 main COX enzymes:
COX-1:
- constitutive
- important in maintaining GIT integrity
COX-2:
- inducible
- involved in inflammatory response
- implicated in cancer development
```
69
What is the role of prostaglandins in inflammation?
Inflammation is always accompanied by the release of prostaglandins
- predominantly PGE2, but also PGI2
- PGD2 from mast cells
PGE2, PGI2 and PGD2:
- act as potent vasodilators
- they also synergise with other inflammatory mediators (e.g. histamine, bradykinin)
- they potentiate histamine & bradykinin actions on postcapillary venule permeability & pain sensory nerves
70
What is the (i) Anti-inflammatory action (ii) Anti-pyretic effect (iii) Analgesic effect of NSAIDs?
(i) prostaglandins are important inflammatory mediators (particularly in vasodilation & resultant oedema, they have less of an effect on cellular accumulation or migration)
=> NSAIDs only affect the aspects on inflammation in which prostaglandins play a significant part. NSAIDs can reduce many of the local signs & symptoms of inflammation (i.e. redness, heat, swelling, pain)
(ii) body temp is regulated by the hypothalamus
- fever occurs when the 'set point' is raised
- bacterial endotoxins cause release of factors (IL-1) from macrophages. IL-1 causes generation of PG in hypothalamus and PG increase the thermostat 'set point'
=> NSAIDs act by preventing the formation of PG & prevent the increase in temp
(iii) Inflamed regions are painful due to bradykinin & histamine release:
- activate nociceptive afferent nerve terminals
- register a painful stimulus
PG sensitise nociceptive nerves to these compounds
=> by preventing PG production, NSAIDs prevent sensitisation to pain-producing compounds
71
Describe the salicylates. What is the function of them? What are the unwanted side effects of aspirin?
Asprin = a prodrug (acetylsalicylic acid), it can directly acetylate COX enzyme
- it is also metabolised to the active compound (salicylic acid) by plasma & tissue esterases (NOTE: this is about 70% of it)
- salicylates are found in the plasma w/in 30 mins
- peak plasma concentration is reached w/in 1-2 hrs
SIDE EFFECTS:
Stomach - bleeding, ulcers
Systemic - tinnitus, dizziness, impaired hearing, nausea, vomiting, hypersensitivity
Metabolic changes - acid/base balance affected
Haemostasis - blood coagulation affected through (and action on) platelets
CNS effects - stimulation initially, ultimately coma & respiratory depression
Renal - insufficiency in susceptible patients & with chronic use & overdose
72
Give examples of propionic acids and fenamates.
```
Propionic acids
- e.g. ibuprofen, naproxen
- they aren't prodrugs
- well absorbed
- last for 4-6 hrs
Fenamates
- e.g. mefenamic acid
```
73
What is the function of paracetamol (acetaminophen)? Describe its mechanism of action.
- has good analgesic & anti pyretic activity, but is a poor anti inflammatory
- is well tolerated in GIT
- weak COX inhibitor (researched that it may be a selective inhibitor of the CNS specific COX-3
- given orally and is well absorbed
- reaches peak plasma conc in 30-60 mins and its half life in plasma = 2-4 hrs
- it has fewer side effects than other NSAIDs (perhaps dut to COX selectivity)
MAJOR ISSUE = hepatotoxicity due to overdose ( it is normally inactivated in the liver by glucoronate & sulphate conjugation. When these enzymes are saturated, toxic metabolites are formed - which can result in HEPATIC NECROSIS
74
What are selective COX-2 inhibitors?
Coxibs
- e.g. celecoxib
- used for osteoarthritis and rheumatoid arthritis
- restricted for when traditional NSAIDs produce too severe GIT side effects
- CV risk also has to be assessed
75
What are the clinical uses for NSAIDs? (Analgesic, anti-inflam and anti-pyretic uses)
ANALGESIA: headache, dysmennorhea, backache, bony metastases of cancer, post-op pain.
- short term analgesia = paracetamol, ibuprofen & aspirin
- long term (chronic) analgesia = naproxen, diclofenac
ANTI-INFLAMMATORY
- chronic or acute inflammatory conditions
- dosage for chronic is higher
=> a low incidence of side effects is important e.g. ibuprofen
- coxibs are sometimes used for OA & rheumatoid arthritis
ANTI-PYRETIC
- to lower temp
- paracetamol is preferred as it lacks GIT side effects
