Brainscape's Knowledge GenomeTM

Browse over 1 million classes created by top students, professors, publishers, and experts.


See full index

Pharmacology > Arthritis Drugs > Flashcards

Arthritis Drugs Flashcards

1
Q

What is arthritis?

A

Joint inflammation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

Osteoarthritis

A 
Osteo - bone
Primary
 “Wear and tear”
 Related to aging
Secondary
 Trauma
 Disease or obesity
Pain through inflammation
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

Rheumatoid arthritis

A 
Rheum - flowing in a stream
 Systemic auto-immune disorder
 May affect other tissues
 Pain through inflammation
tends to affect small joints first, such as in hands and feet but can affect any connective tissues (skin, CV system, lungs, muscles). Occurs because antibodies are targeted towards normal proteins in the connective tissue of joints, with the result that pro-inflammatory chemicals called cytokines are released. 
Causes joint inflammation, especially:
Synovial membrane
Tendon sheaths
Bursae
Leads to proliferation of synovial membrane + erosion of cartilage/ bone
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Osteoarthritis is a disease affecting synovial joints

A

Characterised by loss of cartilage and bone from articulating surfaces
Alteration in cartilage structure
cartilage gets worn away and there are changes in the protein structure of the cartilage. As a result, the cartilage layer becomes thin and the bone underneath grows to fill the space where the cartilage was. The result is that bone spurs develop. The ends of the bone rub together and the shape of the joint changes, causing deformities. Fragments of cartilage end up in the synovial fluid, reducing its lubricant capacity. Often affects multiple joints in sufferers

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

Type I collagen

A

location- bone

function- Osteoblast differentiation from bone marrow

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

Type II collagen

A 
location - cartilage
function - Maintains integrity of cartilage
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

Aggrecan

A

Location - synovial membrane

Function - Maintains integrity of cartilage

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Matrix metalloproteinases

A

Location - Synovial Tissue

Function - Degrade extra cellular matrix proteins to enable growth

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

Why is cartilage degraded?

A

Upregulation of cytokines
IL-1β inhibits type II collagen synthesis of hyaline cartilage
Destroy environment surrounding cartilage cells → changes to cartilage structure
Cathepsin-B can cleave aggrecan
↑Matrix metalloproteinases → breakdown of collagen → cartilage degradation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Risk factors

A 
Age 
Gender - more common in women thought to be due to a decrease in oestrogen after menopause
Previous joint injury/ disease
Genetic (e.g. collagen gene mutations)
Obesity
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

The Inflammatory Response

A 
Phospholipase A2
(PLA2)
--->
Arachidonic acid
--->
COX
---> 
Blood vessels/ local tissues/ Mast cells 
PGE2               PGI2               PGE2
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Arachidonic acid

A

Arachidonic acid is a constituent of the cell membrane, derived from linoleic acid in the diet (found in vegetable and nut oils and butter).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Eicosanoids

A

Eicosanoids are 20 carbon fatty acids derived from the cell membrane.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

PGI2

A

PGI2 (prostacyclin) synthesized in vascular endothelial cells
PGD2/ PGI2 → vasodilation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

PGE2

A

PGE2 – mast cells/ macrophages and many other tissues, including those surrounding hypothalamus. i.e. blocking COX enzymes leads to a reduction in prostaglandins E2 and I2 and also thromboxanes such as TxA2.
PGE2 → vasodilation, pyrogenic + (under certain conds.) anti-inflammatory effects

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

COX

A

Cyclo-oxygenase (COX) enzymes found throughout the body
Three isoforms - COX1, COX2, COX3
All catalyse the same reaction (i.e. arachidonic acid → PGs and Txs)
‘Housekeeping’ responsibilities include regulation of blood flow/ clotting and renal function.
COX also known as Prostaglandin H synthase.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

poteential effects of histamine/ bradykinin

A

Increased permeability of venules → oedema

Increased sensitivity of C fibres (PAIN!)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Tx

A

Thromboxane

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

COX 1

A 
Constitutive
Expressed in most tissues including platelets
house keeping enzyme
protects GI mucosa
control of renal blood flow
initiation of labour
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

COX 2

A

Inducible
Inflammatory cells – induced by injury, infection, cytokines
COX-2 is produced ‘when needed’. The products of COX-2 have roles in inflammation, fever, pain and also ovulation and uterine contraction during labour.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

COX 3

A

Found in CNS of some species

COX-3 may be produced from the same gene as COX-1.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

NSAIDs

A

target COX enzymes
Non-Steroidal Anti-Inflammatory Drugs (~ 50 on global market)
Aspirin
Ibuprofen
Diclofenac
Meloxicam
Indomethacin
Many are available OTC
Most widely prescribed drugs for arthritis
Diff formulations (e.g. tablets, suspensions, gels, injections)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

Actions of NSAIDs

A

Antipyretic
inhibit actions of PGs on hypothalamus
Analgesic
reduce sensitivity of neurons to bradykinin
effective against pain of muscular/ skeletal origin
Anti-inflammatory
reduce vasodilation and decrease permeability of venules
May scavenge oxygen radicals → ↓ tissue damage
Aspirin – inhibits NFκB expression → ↓ transcription of genes for inflammatory mediators
Celecoxib, diclofenac and ibuprofen - ↓ IL-6 and TNF-α in SF

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

NSAID response

A

Variation in individual responses/ tolerance to drugs
~ 60% people respond to any NSAID
Others usually respond to certain NSAIDs
Pain relief almost immediate → full analgesic effect within a week (anti-inflamm. effect takes longer)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

Problems with NSAIDs

A

Risk of gastric ulcers
Impair coagulation
Use with caution in elderly (GI bleeding can be serious/ fatal)
Risk of CV events in patients with cardiac disease/ hypertension
May induce asthma attack, angioedema, urticaria or rhinitis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

angioedema

A

rapid swelling of dermis, subcutaneous tissues;

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

Urticaria

A

skin rash (hives)

28
Q

Why do NSAIDs create complications?

A

Many inhibit COX1 as well as COX2
PGs produced by COX1 are involved in many beneficial processes:
Production of GI mucus (protective)
Blocking ↑ risk of ulcer
Cardiovascular function : PGs (e.g. PGI2) inhibit platelet aggregation
COX also generates TXA2, which promotes platelet aggregation.

29
Q

How to solve the problem that NSAIDs create

A 
COX1 and COX2 differ in structure
Should be possible to produce selective drugs
Observed that best tolerated (GI) drugs had some COX2 selectivity
E.g. meloxicam
But rofecoxib (early COX-2 inhibitor) withdrawn, as some patients died from CV complications (↓ PGI2 → platelet aggregation?)
30
Q

Meloxicam

A

Meloxicam – appears to concentrate in synovial fluid – free concentration higher than in plasma (why? Lower albumin content) At therapeutic concentrations, less GI effects than other NSAIDs and does not affect platelet function. CV complications – i.e. MI and stroke. Also problems with wound healing, angiogenesis and resolution of inflammation + more expensive than NSAIDs.

31
Q

COX2 Inhibitors

A

E.g. celecoxib, etoricoxib
Used mainly in patients at high risk of serious GI side effects (but with little CV risk*)
Common side-effects: headache, dizziness, skin rash, peripheral oedema

32
Q

Misoprostol (synthetic Prostaglandins)

A 
Given alongside NSAIDs
Preserves mucous lining of GI tract
Protects against ulceration
Other uses?
Side-effects: diarrhoea (can be severe), vaginal bleeding
 N.B. Precautions in women of childbearing age!
Proton Pump Inhibitors (e.g. omeprazole)
Reduce acid secretion
33
Q

Aspirin

A

Rapidly absorbed in stomach (i.e. weak acid)
Displaces warfarin bound to plasma proteins
i.e. ↑ plasma warfarin + potentiates warfarin’s anticoagulant activity!!

34
Q

Paracetamol

A

Paracetamol is NOT an NSAID
Why?
It has no anti-inflammatory effect
But…
It is analgesic, antipyretic
It suppresses PG production
Actions may involve COX, but in CNS (COX3?)
May stimulate serotonergic pathways involved in inhibition of pain sensation
Often grouped together with NSAIDs
Used as a safer (long-term) alternative to NSAIDs/ COX-2 inhibitors BUT recent studies (NICE Guideline Development Group) have queried the effectiveness of paracetamol in treating OA.

35
Q

Paracetamol – side effects

A 
Few side-effects
Chronic use of large doses → kidney damage
Toxic doses (10 – 15g) → potentially fatal liver damage (occurs 24 – 48hr after O.D.)
36
Q

Osteoarthritis – treatment options

A 
Exercise – strengthens core muscles/ improves aerobic fitness
Suitable footwear + pacing
Weight loss
Joint supports/ braces
Thermotherapy/ TENS devices
37
Q

Drugs used to treat osteoarthritis

A

Paracetamol – regular dosing ± oral NSAID (with PPI*)
Topical NSAID or capsaicin (esp knee/ hand)
Opioid analgesic – for further relief
Intra-articular corticosteroid injection → temporary benefit
Joint replacement surgery (hip, knee, ankle)

38
Q

Strontium ranelate

A

promotes osteoblast differentiation/ inhibits osteoclast activity*
reduces pain*
Indicated for prevention of fractures in severe osteoporosis (OP)
BUT
- found to ↑ risk of MI and thrombotic events so use restricted to treatment of severe OP**

39
Q

Glucosamine sulphate

A

major constituent of ECM
Present in cartilage + synovial fluid
Demonstrated positive effects both in vitro + in vivo (animal models)
Differing results from clinical trials – measured pain and structural improvement
Overall no sig benefit but poss long-term side effects
Not recommended by NICE!

40
Q

Diagnosis of Rheumatoid arthritis

A

Symptoms presented – usually a throbbing andaching sort of pain. Often worse in the mornings and after resting, not after activity.
Stiffness - especially in the morning. Rheumatoid arthritis morning stiffness usually lasts longer than half an hour (i.e. longer than O.A.) Warmth and redness – affected joint hot, tender to touch and painful + inflammation around the joints, such as tear glands and salivary glands.
Important to diagnose RA asap.
Refer to specialist (rheumatologist) to confirm diagnosis, assess progression of disease, prescribe DMARDs to limit joint damage.* urgent referral if small joints are affected or >1 joint affected.
Diagnosis – physical examination of joints, blood tests – markers of inflammation, FBC for anaemia (associated with RA), Rheumatoid factor – present in 8/ 10 with RA but may not show up early in disease + also in some unaffected individuals; imaging – x-rays, ultrasound, MRI.
Disease progression/ control assessed by measuring levels of C-reactive protein (CRP) in the blood.

41
Q

Rheumatoid arthritis treatment options

A 
NSAIDs/ opioid analgesics
Glucocorticoids
---> treatment of pain
Immunosuppressants
Disease Modifying Antirheumatic Drugs (DMARDS)
Anticytokines
----> Limitation of joint damage 
*Treatment should be started within 3months of the onset of persistent symptoms
42
Q

Maintenance of a healthy joint

A

Osteoblasts – bone formation
Expression of anti-inflammatory cytokines (IL-10, IL-11, IL-1RA)
Chondrocytes synthesize collagen matrix (anabolic)
maintenance of a healthy joint requires the correct balance of cells and chemicals (N.B. the cells present in the joint are influenced by cytokines present in the synovial fluid). If this balance is disrupted (e.g. by an enhanced immune response) then the joint will start to break down.

43
Q

Destruction of a joint

A

Osteoblasts – bone resorption
Expression of pro-inflammatory cytokines (TNF, IL-1, IL-6)
Chondrocytes/ synovial fibroblasts secrete MMPs – break down collagen (catabolic)

44
Q

Glucocorticoids

A

Naturally produced in the body
Used short-term – to manage flare-ups (rapidly reduce inflammation) in patients with recent-onset or established disease
Long-term – if other treatment options failed - must discuss complications
Used short-term to manage flare-ups in patients with recent-onset or established disease to rapidly reduce inflammation. Long-term treatment offered if complications have been discussed and other treatment options have failed.

45
Q

Actions of Adrenal Steroids

A 
Two main types of action:
Glucocorticoid
metabolic effects
anti-inflammatory
immunosuppressive    
Mineralocorticoid
water & electrolyte balance 
Metabolic - Increase breakdown of protein and fat to release glucose. Where does this happen? (liver/ adipose tissue) Also proteins broken down – amino acids released into blood; anti-inflammatory – inhibit prod of inflammatory mediators (reminder later); immunosuppressive – inhibit NF-B which is necessary for activation of immune cells (B cells) and synthesis of cytokines.
46
Q

Natural steroids

A

Hydrocortisone/ corticosterone
show both (MC + GC) activities
enzyme in MC-sensitive tissues (e.g. kidney) converts these to MC-inactive compounds – why?

Aldosterone
mineralocorticoid only
Aldosterone – increased reabsorption of Na and H2O in collecting duct/ DCT – inc bp.

47
Q

Synthetic steroids

A

Modification of natural steroids gives:
Different split of activities/potencies
Varying duration of action

48
Q

Duration of action of steroids

A 
Short-acting (1 -12 hrs)
Cortisone/ hydrocortisone
Twice daily cream or intra-articular injection 
Intermediate-acting (12 – 36 hrs)
Prednisolone
Daily oral or intra-articular injection
Long-acting (36 – 55 hrs)
Dexamethasone
Intra-articular injection every 3 - 21 days
49
Q

Nuclear receptors and steroids

A

Steroids must enter the cell before causing a response. They are able to do this because they are lipid (fat) soluble and are therefore able to cross the cell membrane. Once in the cytoplasm, steroids bind to free receptors to form a complex. 2 complexes join together, enabling them to enter the nucleus. Once inside the nucleus, the complex binds to DNA. This results in genes being either switched on (e.g. lipocortin-1) or switched off. When genes are switched on messenger RNA is produced, which is used to make particular proteins. Many well-used steroids work by switching off genes. These are often genes which code for proteins involved in inflammation.
i.e. takes time for steroids to have an effect.

50
Q

Glucocorticoid actions in Rheumatoid arthritis

A

anti-inflammatory, immunosuppressant actions:
↓ transcription of pro-inflammatory cytokines (e.g. IL-2)
↓ circulating lymphocytes
inhibit phospholipase A2 → ↓ release of arachidonic acid…………….
↑ synthesis of anti-inflamm. proteins (e.g. protease inhibitors)

used for asthma and ARTHRITIS….
beclomethasone, budesonide, prednisolone – stabilise mast cells (so ↓ histamine rel.)

51
Q

Unwanted effects of oral corticosteroids

A 
Buffalo hump 
Moon face 
increased abdominal fat 
thinning of skin 
increased risk of infection
poor wound healing 
hypertension
muscle wasting 
osteoporosis
52
Q

Danger of stopping steroid treatment abruptly

A

Patients on course of steroid therapy > 1 month must not suddenly stop treatment
Patients on long-term therapy advised to carry card
Cause suppression of normal steroid synthesis
due to excessive negative feedback
may precipitate acute adrenal failure
if exogenous steroids withdrawn abruptly, gradual reduction needed

53
Q

Disease Modifying Antirheumatoid Drugs (DMARDs)

A

Drugs with unrelated structures + diff mechanisms of action
Therapy started upon definite diagnosis of R.A. → slow onset of disease
Most important examples:
Sulfasalazine, gold compounds, penicillamine, immunosuppressants (e.g. methotrexate, ciclosporin, azathioprine, leflunomide), anticytokines

54
Q

Sulfasalazine

A

Common 1st choice DMARD in UK
Complex of salicylate (NSAID) + sulphonamide (antibiotic)
Thought to act by scavenging free radicals prod by neutrophils
Causes remission in ‘active’ R.A.
Given as enteric-coated tablets (poorly absorbed orally)
Side-effects: GI upset, headache, skin reactions, leukopenia

55
Q

Penicillamine

A

Prod by hydrolysis of penicillin
75% patients respond but therapeutic effects take weeks
Thought to ↓ IL-1 generation + ↓ fibroblast proliferation → ↓ immune response
Given orally – peak plasma conc → 1-2 hrs
Side-effects: rashes, stomatitis (40% patients); anorexia, taste disturbance, fever, n & v
Should not be given with gold compds – metal chelator!
Penicillamine also thought to prevent maturation and cross-linking of newly synthesized collagen (useful in scleroderma, a disease in which hard fibrous plaques occur in the skin.

56
Q

Stomatitis

A

inflammation of mucous membranes in the mouth (gums, cheeks, etc)

57
Q

Gold compounds (sodium aurothiomalate/ auranofin)

A

Auranofin (oral) → inhibits induction of IL-1 + TNF-α → ↓ pain + joint swelling
Sodium auranofin – deep i.m. injection
Concentrate in synovial cells, liver cells, kidney tubules, adrenal cortex & macrophages
Effects develop over 3 – 4 months
Side-effects: skin rashes, flu-like symptoms, mouth ulcers, blood disorders (33%)
Serious side-effects: encephalopathy, peripheral neuropathy + hepatitis (10%)

58
Q

Anti-malarials (chloroquine/ hydroxychloroquine)

A

↑pH of intracellular vacuoles → interferes with antigen-presenting
Induces apoptosis in T-lymphocytes
Usually used when other treatments fail
Therapeutic effects take a month
~ 50% patients respond
Side-effects: n+v, dizziness, blurring of vision – requires screening

59
Q

Anticytokine Drugs

A

Engineered recombinant antibodies → v. expensive!
Use restricted to patients who don’t respond well to other DMARDs
Can be given with methotrexate
E.g. adalimumab, etenercept, infliximab – target TNF; rituximab, abatacept, natalizumab – target leukocyte Rs; tocilizumab - blocks IL-6 Rs → disrupt immune signaling
Given by s.c. or i.v. injection
Some patients do not respond
Side-effects: may develop latent disease (e.g. TB, hep B, herpes zoster, etc) + opportunistic infection; also, nausea, ab pain, worsening heart failure, hypersensitivity
Act as decoy receptors, mopping up naturally present TNF-alpha. i.e. TNF-alpha and interleukins released in the joints of sufferers – these chemicals (cytokines) induce COX-2 expression. Have less effect on normal immune response.
Abatacept used in combination with MTX in patients who have failed to respond to 2 DMARDs

60
Q

Immunosuppressants

A

Rheumatoid arthritis is an AUTOIMMUNE disorder

Suppressing the immune system will therefore suppress (but not cure) disease

61
Q

Ciclosporin

A

1st discovered in fungus
Potent immunosuppressant but no effect on acute inflammation
Inhibits IL-2 gene transcription → ↓ T cell proliferation
Poorly absorbed orally – special formulations (capsules/ oral solutions)
Accumulates in high conc in tissues (i.e. remains for some time)
Given to patients who have received transplants. Thought to inhibit gene transcription of the cytokine IL2.
side effects -Nephrotoxicity*
Hepatotoxicity
Hypertension
Also: nausea/ vomiting, gum hypertrophy, GI problems

62
Q

Azathioprine

A

Cytotoxic: interferes with purine metabolism → ↓ DNA synthesis
Depresses cell-mediated + antibody-mediated immune reactions
i.e. targets cells in induction phase of immune response
Main specific effect: suppression of bone marrow
Purines are bases found in DNA which are necessary for synthesis of DNA during cell proliferation. Depresses antibody-mediated immune reactions by interfering with production of B cells and presentation of antigen to T cells (i.e. reduces proliferation of these cells).

63
Q

Methotrexate

A

Folic acid antagonist → inhibits DNA synthesis
Blocks growth and differentiation of rapidly dividing cells
Inhibits T cell activation
Patients often continue treatment for > 5 years
Side-effects: possibility of blood dyscrasias (abnormalities) + liver cirrhosis (requires monitoring), folate deficiency – why is this a problem?
Often prescribed with a DMARD

64
Q

Leflunomide

A

Specific inhibitor of activated T cells
Well absorbed orally; long t½
Side-effects: diarrhoea, alopecia, ↑ liver enzymes → risk of hepatotoxicity

65
Q

Cyclophosphamide

A

Only used when other therapies have failed
Prodrug – can be administered orally → activated in liver to phosphoramide mustard + acrolein
Acrolein → haemorrhagic cystitis (can be prevented by administering large volumes of fluid)

Pharmacology (13 decks)

Brainscape helps you reach your goals faster, through stronger study habits.
© 2024 Bold Learning Solutions. Terms and Conditions