Pharmacological aspects of Immunology Flashcards
1
Q
What are the NSAIDs groups?
(6)
A
- Aspirin
- Propionic acid derivatives - e.g. ibuprofen, naproxen
- Arylalkanoic acids – e. g indometacin, diclofenac
- Oxicams - e.g. piroxicam
- Fenamic acids - e.g. mefanamic acid
- Butazones - e.g. phenylbutazon
2
Q
Explain the Eicosanoid pathways
- what are their end products and their clinical relevance? (4)
A
- Leukotrienes: bronchial constriction
- Thromboxanes: platelet aggregation, vasoconstriction
- Prostaglandins: bronchial tone, vascular tone, hyperalgia
- Prostcyclins: vasodilation
3
Q
What effect does NSAID’s have on the Eicosanoid pathway
A
- NSAID’s are non-specific inhibitors of the cyclooxygenase pathway
- this irreversibly binds the enzymes to prevent prostaglandin synthesis
- therefore the tissue-specific synthases are not produced
4
Q
What is the mechanism of action of NSAIDs?
(3)
A
- All inhibit cyclo-oxygenase
- Three isoforms
-
COX-1 - Constitutive expression – all tissues
- Stomach, Kidney, Platelets, Vascular endothelium
- Inhibition → anti-platelet activity, also side effects
-
COX-2 – Induced in inflammation (IL-1)
- Injury, infection, neoplasia
- Inhibition → analgesia and anti-inflammatory actions
-
COX-3 – CNS only?
- May be relevant to paracetamol
-
COX-1 - Constitutive expression – all tissues
5
Q
What are the indications for NSAID therapy?
A
- Short-term management of pain (and fever)
As mild analgesics (orally and topically)
- mechanical pain of all types
- minor trauma
- headaches, dental pain
- dysmenorrhoea
As potent analgesics (orally, parenterally, rectally)
- peri-operative pain
- ureteric colic
6
Q
Where is NSAID useful as an anti-inflammatory agent?
A
- Gout
- Inflammatory arthriitis: ankylosing spondylitis, rheumatoid arthritis
7
Q
What are the indications for Aspirin?
- why might the use be limited?
A
- Limited in use for pain and inflammation limited by
- GI toxicity
- Tinnitus – mechanism obscure, usually reversible
- Reye’s syndrome (fulminant hepatic failure in children)
- Mainly used for its Anti-platelet effect
- Primary and secondary prevention eg stroke and MI
- Treatment of acute MI and stroke
8
Q
Explain how NSAID produces GI toxicity (3)
- what are the presenting effects?
A
- In the GI tract prostaglandins E2 and I2
- Decrease acid production
- Increase mucus production
- Increase blood supply
- as NSAID’s inhibit this, all the above is reversed
- NSAID inhibition in stomach and duodenum
- Irritation
- Ulcers (gastric 15-30%, duodenal 10%)
- Bleeding
- Similar effect in the colon
- Colitis – esp with local preps e.g. rectal diclofenac
9
Q
What is the risk of NSAID GI toxicity
A
- Upper GI bleeding
- Relative Risk 4.7 all users
- Azapropazone = 23.4
- Piroxicam = 18.0
- Small differences between others…
- Biggest risk factor for GI bleed = previous GI bleed
- Age
- Chronic disease (e.g.rheumatoid disease)
- Steroids
10
Q
Explain how NSAIDs cause nephrotoxicity
- contraindications to avoid this
A
- Primarily related to changes in glomerular blood flow
- Decreased glomerular filtration rate
- Sodium retention
- Hyperkalaemia
- Papillary necrosis
- Acute renal failure 0.5-1%
- Avoid or dose adjust in renal failure
- Avoid in patients likely to develop renal failure
11
Q
What is the relationship between asthma and Aspirin?
A
- About 10% of asthmatics experience bronchospasm following NSAID
- perhaps because of arachidonic acid is shunted down the 5LPO pathway when COX is inhibited so more leukotrienes are produced
- leukotrienes cause bronchial constriction
12
Q
How can NSAID toxicity be prevented?
(4)
A
- Is an NSAID the answer (paracetamol, opioids, COX2 inhibitor, non-pharmacological?)
- Consider risk factors eg age, renal impairment, previous peptic ulcer disease
- Avoid or dose adjust in renal impairment
- Consider co-administration of gastroprotection with proton pump inhibitor
13
Q
How is Paracetamol metabolised?
A
- Phase 1 oxidation reaction (induced by enzyme inducers e.g alcohol)
- NAPQI
- Phase 2 conjugation reaction (following phase 1)
- NAPQI-glutathione –> excreted
- these pathways can easily be oversaturated leading to overdose after a few extra pills
- Direct Phase 2 conjugation
- paracetamol sulphate and glucuronide –> excreted
14
Q
What is the treatment for paracetamol overdose?
A
-
N-acetylcysteine (glutathione precursor) used in paracetamol poisoning
- enables NAPQI to be harmlessly removed
15
Q
What are Selective COX-2 Inhibitors?
- what are they used for
- risk/indication
A
- Selective inhibition of COX-2 in vitro and in vivo
- Anti-inflammatory and analgesic in humans
- Objective evidence of selectivity (GI, platelets) at > anti-inflammatory doses
- Comparable efficacy (not superior) to non-selective NSAIDs in
- Acute pain
- Dysmenorrhoea
- Inflammatory joint disease
- Controversy due to apparent increased risk of MI – but may have been a result of an absence of antiplatelet effect
- Currently only recommended in high-risk patients and after a cardiovascular risk assessment
16
Q
What are the side effects of COX-2 Inhibitors?
A
- has GI-side effects but has a relatively lower risk compared to NSAIDs
17
Q
What are corticosteroids?
- example
- action (6)
A
Cortisol (hydrocortisone) – predominant endogenous glucocorticoid
- Carbohydrate and protein metabolism
- Fluid and electrolyte balance (mineralocorticoid effects)
- Lipid metabolism
- Psychological effects
- Bone metabolism
- Profound modulator of immune response
18
Q
What is the biological effect o corticosteroids?
A
- Steroids reduce immune activation by altering gene expression in numerous cell types,
- including T cells, B cells and cells of the innate immune system.
- Their onset of action is delayed and they must be taken regularly
19
Q
What are the immunomodulatory effects of steroids?
- cell trafficking (2)
- cell function (7)
- don’t effect (2)
A
- Cell trafficking
- Lymphopenia, monocytopenia (redistribution)
- Neutrophilia and impaired phagocyte migration
- Cell function
- T cell hyporesponsiveness
- Inhibited B cell maturation
- Decreased IL1, IL6 and TNFa production (monocytes)
- Widespread inhibition of Th1 and Th2 cytokines
- Inhibition of COX - prostaglandins
- Impaired phagocyte killing
- ↓collagenases, elastases etc
- Don’t effect
- Immunoglobulin levels
- Complement
20
Q
What is the clinical use/ indication cor corticosteroids?
- types of preparations
A
- To suppress inflammation of all kinds, particularly in acute disease but also in maintenance therapy
- Asthma, Crohn’s / UC, Eczema, Multiple sclerosis, Sarcoid, allergy, rheumatoid arthritis, systemic lupus erythematosus etc etc
-
Replacement therapy in hypoadrenalism
- __hydrocortisone used
- Myriad preparations, and also routes
- Systemic (oral and parenteral)
- Topical (skin, joint injections, inhaled, enteric-coated, rectal)
21
Q
What are the five key Corticosteroid drugs to remember?
- what are their potency
- lipid solubility
- systemic vs topical use
A
22
Q
What are the Early side effects of steroid therapy?
(4)
A
- Weight gain
- Glucose intolerance
- Mood change
- Suppression of ACTH release
23
Q
What are the Late side effects of steroid therapy?
(7)
A
- Proximal muscle weakness
- Osteoporosis
- Skin changes
- Body shape changes
- Hypertension
- Cataracts
- Adrenal suppression
24
Q
How do corticosteroids affect the adrenal system?
- How is this managed?
A
- High-dose exogenous corticosteroids suppress endogenous production within 1 week
- __clinical effects not seen until later
- After prolonged therapy adrenal cortex begins to atrophy and endogenous production takes some time to recover upon cessation
- Abrupt withdrawal below replacement dose reduces the ability to deal with physiological stress – eg infection – and may precipitate an adrenal crisis
- Steroid warning card
- Tail dose slowly
- Increase dose during acute illness and prior to surgery
25
Link between infection and corticosteroid use
* Risk is related to cumulative dose
* Phagocytic defects (risk occurs early on)
* Bacterial infection – *S. aureus*, enteric bacteria etc
* Fungal infection – **candida,** aspergillus
* candida using inhalers - rinse mouth after use
* Cell-mediated defects (risk occurs later on)
* Intracellular pathogens
* TB
* Varicella
* Listeria
* Pneumocystis
26
What are Disease-modifying anti-rheumatic drugs (DMARDS)?
* diverse group of drugs that target the immune system
* Derive name from use in _rheumatoid arthritis_, but also used in
* _transplantation and myriad other autoimmune and inflammatory disorders_
* __chronic urticaria, eczma, psoriasis
* also sometimes (in higher doses) for _cancer chemotherapy_
27
How are Disease-modifying anti-rheumatic drugs (DMARDS) distinguished from other drug classes
- NSAID
- Steroids
- Biologics
* NSAIDS: despite name, not disease-modifying
* Steroids: the idea of DMARDS is that they’re ‘steroid-sparing’
* Biologics: newer class of drugs resembling naturally-occurring molecules
28
Give examples of Disease-modifying anti-rheumatic drugs (DMARDS)
(3)
- what are their actions, indications
* **Methotrexate**: competitive inhibitor of dihydrofolate reductase (DHR)
* anti-folate action which is needed for purine synthesis in DNA
* reduces T cell activity
* used in Rheumatoid arthritis, Psoriasis, Chrons disease
* **Azathioprine**: Inhibits thiopurine S methyltransferase (TPMT)
* also inhibits purine synthesis
* similar indications to methotrexate, more widely used in transplantation
* **Ciclosporin**: Inhibits calcineurin which in turn reduce T lymphocyte activity
* similar indications to aza/metho
* used in more dermatology and transplantation
29
What is Ciclosporin?
- action
- indication
- toxicity
* Inhibits calcineurin, which in turn reduces T lymphocyte activity
_Main indications_
* more widely in dermatology and transplantation
* Rheumatoid arthritis, Psoriasis, Crohns disease
_Main toxicities_
* Hepatotoxicity
* Nephrotoxicity
* Gum hyperplasia
* Hirsutism
NOTE **tacrolimus** (newer formulation) is easier to take and tolerate, and available for _topical use (esp eczema)_
30
What is Azathioprine?
- action
- indication
- toxicity
* Inhibits thiopurine S methyltransferase (TPMT), also inhibits purine synthesis
* Folate needed for purine synthesis in DNA
* This reduces T cell activity
_Main indications_
* more widely in transplantation
* Rheumatoid arthritis, Psoriasis, Crohn's disease
_Main toxicities_
* GI upset very common when starting
* Hepatotoxicity
* Leucopenia
* Pulmonary fibrosis
* Teratogenic
31
What is Methotrexate?
- action (4)
- indication
- toxicity
* Competitive inhibitor of dihydrofolate reductase (DHR), therefore anti-folate action
* Folate needed for purine synthesis in DNA
* This reduces T cell activity, and also (in higher doses) tumour synthesis
* Increases adenosine level (anti-inflammatory)
* Reduces the production of damaging polyamines
* Induces apoptosis of activated CD4+ and CD8+ T-cells
_Main indications_
* Rheumatoid arthritis
* Psoriasis
* Crohns disease
_Main toxicities_
* Hepatotoxicity
* Leucopenia
* Pulmonary fibrosis
* Teratogenic
NOTE weekly dosing; errors have caused major toxicity
32
What are therapies for rheumatoid arthritis (RA)
- most effective?
* _Anti-inflammatory drugs:_ *Symptoms relief*
* Non-steroidal anti-inflammatory drugs (NSAIDs)
* Steroidal anti-inflammatory drugs (glucocorticoids)
* _Disease-modifying anti-rheumatic drugs (DMARDs)_: *Slow the clinical and radiographic progression of RA*
* Synthetic DMARDs: **MTX, sulfasalazine, hydroxychloroquine, leflunomide**
* Targeted synthetic DMARDs: **JAK inhibitors- tofacitinib, baricitinib**
* Biologic agents (biologicals): TNF-blockers (most effective)
* Drugs targeting IL-1, IL-6 , B-cells and T-cells
33
Give more detail on the clinical use and action of Methotrexate
* “Anchor drug” in combination therapies
* Reduces inflammation quickly and keeps it under tight control
* Reduces the risk of death from cardiovascular disease in people with RA
* Taking supplements of folic acid reduces side-effects caused by folic acid depletion
34
What are the adverse effects of synthetic DMARDs
- what is a synthetic DMARD
* - Methotrexate, Hydroxychloroquine, Leflunomide are synthetic DMARDs
* Hydroxychloroquine: accumulation of a drug in the eye --\> retinopathy
* Leflunomide- hypertension
* Nausea, Loss of appetite
* Diarrhoea
* Rash, allergic reactions
* Headache
* Hair loss
* Risk of infections (pneumonia)
* Hepatotoxicity (metabolism), Nephrotoxicity (route of elimination)
35
Give examples of targeted synthetic DMARDs (2)
- action
- indication
used in moderate-to-severe active RA in patients who have had an inadequate response to, or are intolerant to one or more DMARDs (as monotherapy or in combination with MTX): _more effective_
* **Tofacitinib**
* selectively inhibits the JAK1 and JAK3
* also used in _psoriatic arthritis and UC_
* **Baricitinib**
* selectively and reversibly inhibits JAK1 and JAK2
36
What are adverse effects of targeted synthetic DMARDs?
* **Tofacitinib**
* Anaemia, cough,
* diarrhoea,
* fatigue, fever,
* gastrointestinal discomfort, increased risk of infection
* **Baricitinib**
* Dyslipidaemia, herpes zoster,
* increased risk of infection,
* nausea,
* oropharyngeal pain,
* thrombocytosis
37
What are biologics?
- give an example of biologics treatment
* therapeutic treatment derived or synthesised from biological sources
* **Anti-TNF-alpha antibody:** in treating Rheumatoid Arthritis
38
What is the role of TNF in the inflammatory cascade of Rheumatoid Arthritis?
* TNF hyperactivity
* results in high-levels IL-1
* TNF blockers reduces these effects
39
What are the targets of biologic agents in RA?
40
When are biological therapies indicated?
* Patient has failed to respond to treatment with at least two standard (synthetic) DMARDs,
* one of which must be MTX (unless the patient cannot take MTX for medical reason)
* Patient’s RA _disease activity score (DAS 28) is measured as 5.1 o_r over, on two occasions, one month apart
41
What are the currently licensed biologics for the treatment of RA in the UK?
(4)
* **TNF-blockers:** infliximab, etanercept, adalimumab, golimumab, certolizumab pegol
* **Monoclonal antibody against B cells**: rituximab
* **T cell co-stimulation inhibitor:** abatacept
* **Monoclonal antibodies against IL-6R:** tocilizumab, sarilumab
42
What are the TNF-blockers? (5)
- how are they best applied
* **Infliximab** – partially humanized mouse monoclonal anti-hTNF-a antibody
* **Etanercept** – soluble TNF receptor dimer
* **Adalimumab** – human IgG1 monoclonal anti-TNF-a antibody
* **Golimumab** – human IgG1 monoclonal anti-TNF-a antibody
* **Certolizumab pegol** – PEGylated anti-TNF-a monoclonal antibody fragment
- combined with MTX, they give excellent joint protection
43
What is Infliximab
- mechanism
- used in?
- NICE
* Partially humanized mouse monoclonal anti-human TNF-a antibody
* chimeric antibody
* Neutralizes free, membrane and receptor-bound TNF-a → _antibody-dependent cell-mediated cytotoxicity (ADCC)_
* Treats RA and
* Also used for the _treatment of Crohn’s disease, ulcerative colitis, plaque psoriasis, ankylosing spondylitis_
* NICE only approves infliximab, if combined with MTX
44
What is Etanercept
- mechanism
- used in?
* Extracellular domain of the hu p75 TNFR fused with the Fc domain of hu IgG1
* Binds free and membrane-bound TNF, reducing the accessible TNF in Rheumatoid Arthritis → ADCC
* it's a soluble TNF receptor dimer
* Used in RA
* Also used for the _treatment of juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis_
45
What are the two fully human anti-TNF-alpha mAbs?
- used in?
**_Adalimumab_**
* treating RA
* Also used in juvenile idiopathic arthritis, plaque psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn’s disease
**_Golimumab_**
* treating RA
* In combination with MTX
* Also used in psoriatic arthritis, ankylosing spondylitis
* Longer half-life
46
What is Certolizumab pegol?
- mechanism
- used in?
- what is peg?
* PEGylated Fab’ fragment of humanized anti-TNF-a mAb – no Fc portion
* used to treat RA
* Also used for the treatment of Chron’s disease
**Polyethylene glycol:** When covalently attached to drugs, it reduces antigenicity/ immunogenicity prolongs the circulatory time of the drug
47
What is considerations made before anti-TNF therapy?
- what are the side effects?
- course of treatment
* Patients screened before starting treatment to exclude an increased risk of side effects, in particular for
* a past history of tuberculosis (TB),
* multiple sclerosis,
* recurrent infection,
* leg ulcers
* and a past history of cancer
* Chest X-ray to be taken to exclude signs of previous TB and to exclude signs of heart failure
* Increased risk of infections, reactivation of TB
* cancer can be worsened
* Live vaccines, against e.g. yellow fever or polio, should be avoided
* Anti-TNF therapy can be administered for as long as 10 years.
* Patients can stay on the drug for as long as they continue to respond well to it
48
What is Rituximab
- mechanism
- used in
* partially humanized anti-CD20 mAb
* Rituximab opsonized B-cells are attacked and killed by three mechanisms:
* 1)Complement mediated cytotoxicity
* 2-3) Antibody-dependent cell-mediated cytotoxicity (ADCC) – FcgR or CR mediated opsonic phagocytosis
* 4) Apoptosis of B cell
* used to treat RA and in the treatment of SLE
49
What is Abatacept
- mechanism
- used in?
* CTLA-4/ hu IgG1 soluble receptor fusion protein
* acts as a T-cell co-stimulation inhibitor
* Competitive inhibitor of CD28
* Increases threshold for T-cell activation
* Suppresses the proliferation of synovial recirculating T cells
* Reduces the level of inflammatory mediators
* used in treating RA
50
What are two IL-6R inhibitors?
- mechanism
- used in?
* **Tocilizumab**: humanized anti-IL-6 receptor monoclonal antibody
* Also used in systemic juvenile idiopathic arthritis
* Intravenous infusion 8 mg/kg of body weight
* **Sarilumab**: fully human monoclonal antibody against IL-6Ra
* 200 mg once every two weeks, administered as a subcutaneous injection
- used in patients with critical covid-19 infection
51
What is Anakinra?
- mechanism
- used in
* Recombinant IL-1ra- acts an IL-1R antagonist
* Differs from native human IL-1ra: it has the addition of a single methionine residue at its amino terminus
* In RA:
* Reduces bone erosion
* Decreases osteoclast production
* Blocks IL-1-induced MMP release from synovial cells
* _Not used in the UK to treat RA, but licensed in the US_
52
What are the adverse effects of biological therapies?
- contraindications?
* Increased risk of infections:
* Upper respiratory tract infections (nasopharyngitis)
* Pneumonia
* Urinary tract infections
* It is recommended to receive influenza and pneumococcal vaccines before embarking on biological therapy
* Avoid live vaccines
* Nausea
* Headache
* Hypertension
* Allergic reactions
_Contraindicated in pregnancy and while breastfeeding (rituximab, tocilizumab, sarilumab, abatacept, anakinra)_
53
Review the biologics used in Rheumatoid Arthritis
