Pharmacolgy S6 Flashcards

Question

Anticholinergic give examples

Answer 1

Iprotropium bromide ( ATROVENT ) A quaternary anticholinergic agent Bronchodilation develops more slowly and less intense than adrenergic agonists. Response may last up to 6 hours. Useful add-on in actute severe asthma not responding to high dose b2-agonists

Answer 2

1. Oxygen, high flow 2. Nebulised salbutamol – continuous if necessary, oxygen driven 3. Oral prednisolone ~40 mg daily for 10-14 days - can be stopped without tailing down 4. If not responding, add nebulised ipratropium bromide 5. Consider i.v. magnesium sulphate 1.2-2.0 g over 20 min 6. Consider IV aminophylline if no improvement and life threatening features not responding to above treatment (BEWARE if taking oral theophylline ).

Answer 3

* Corticosteroids * Azathioprine * Ciclosporin * Tacrolimus * Mycophenolate mofetil

Answer 4

* Methotrexate * Sulphasalazine * Anti-TNF agents * Rituximab * Cyclophosphamide (cytotoxic)

Answer 5

* prevent interleukin (IL)–1 and IL-6 production by macrophages * inhibit all stages of T-cell activation

Answer 6

* SLE & vasculitis -as maintenance therapy * RA - weak evidence for efficacy * Inflammatory bowel disease * Bullous skin disease * Atopic dermatitis * Many other uses as ‘steroid sparing’ drug

Answer 7

* Cleaved to 6-mercaptopurine (6-MP) | * functions as an anti-metabolite to decrease DNA and RNA synthesis

Answer 8

6-MP is metabolized by thiopurine methyltransferase (TPMT) * TPMT gene highly polymorphic * Individuals vary markedly in TPMT activity * Those with low or absent TPMT levels are likely to develop myelosuppression * Therefore test this before prescribing

Answer 9

• Bone marrow suppression – Monitor FBC • Increased risk of malignancy – Esp transplanted patients -NHL * Increased risk of infection * Hepatitis All immunosuppressants – Monitor LFT

Answer 10

Ciclosporin & tacrolimus

Answer 11

calcineurin inhibitors

Answer 12

* active against helper T cells, preventing the production of IL-2 via calcineurin inhibition * Ciclosporin binds to cyclophilin protein * Tacrolimus binds to tacrolimus-binding protein * Drug/protein complexes bind calcineurin * Calcineurin normally exerts phosphatase activity on the nuclear factor of activated T cells. This factor then migrates to the nucleus to start IL-2 transcription

Answer 13

* Widely used in transplant medicine * Also indicated for atopic dermatitis and psoriasis * Pimecrolimus only available as topical formulation use in atopic dermatitis * Not commonly used in rheumatology -concerns about toxicity * Ciclosporin useful in RA/SLE patients with cytopenias as it has no clinical effect on bone marrow * Monitor for toxicity -check BP and eGFR

Answer 14

* Nephrotoxicity * Hypertension * Hyperlipidemia * Nausea, vomiting, diarrhea * Hypertrichosis, gingival hyperplasia, * Hyperuricemia. * Multiple drug interactions are possible, primarily with agents affecting the cytochrome P-450 system

Answer 15

* Is a prodrug derived from fungus Penicillium stoloniferum * inhibits the enzyme inosine monophosphate dehydrogenase (required for guanosine synthesis) * impairs B- and T-cell proliferation * spares other rapidly dividing cells (because of the presence of guanosine salvage pathways in other cells)

Answer 16

Most common include nausea, vomiting, diarrhea • Most serious ismyelosuppression

Answer 17

Primarily in transplantation * Good efficacy as induction and maintenance therapy for lupus nephritis * In transplantation medicine drug levels of the active metabolite mycophenolic acid (area under the curve) may be monitored * Toxicity may be precipitated by both renal and liver disease

Answer 18

Alkylating agent -cross links DNA so that it cannot replicate • Many immunological effects: – suppresses T cell activity – suppresses B cell activity • Indications: – lymphoma, leukaemia – lupus nephritis – Wegener’s granulomatosis – Polyarteritis nodosum

Answer 19

* It is a prodrug * Converted in the liver (mixed function oxidase enzymes, cytochrome P450) to active forms that have chemotherapeutic activity.. * The main active metabolite is 4-hydroxycyclophosphamide * 4-hydroxycyclophosphamide exists in equilibrium with its tautomer, aldophosphamide. Most of the aldophosphamide is oxidised to make carboxyphosphamide. A small proportion of aldophosphamide is converted into phosphoramide mustard (main active metabolite)

Answer 20

Cyclophosphamide is excreted by the kidney * Acrolein, another metabolite is toxic to the bladder epithelium and can lead to hemorrhagic cystitis * This can be prevented through the use of aggressive hydration and/or Mesna.

Answer 21

Developed in 1940s (ALL) * Gold standard treatment for RA * Other indications – malignancy – psoriasis – Crohn’s disease • Also unlicensed roles: inflammatory myopathies, maintenance therapy in vasculitis, steroid-sparing agent in asthma

Answer 22

Methotrexate competitively and reversibly inhibits dihydrofolate reductase (DHFR) * The affinity of methotrexate for DHFR is 1000X that of folate for DHFR. * Dihydrofolate reductase catalyses the conversion of dihydrofolate to the active tetrahydrofolate the key carrier of one-carbon units in purine and thymidine synthesis * Methotrexate, therefore inhibits the synthesis of DNA, RNA and proteins * Methotrexate acts specifically during DNA and RNA synthesis, and thus it is cytotoxic during the S-phase of the cell cycle. It therefore has a greater toxic effect on rapidly dividing cells (such as malignant and myeloid cells, and GI & oral mucosa), which replicate their DNA more frequently

Answer 23

Mechanism of action in non-malignant disease e.g. RA, psoriasis is not clear * Mechanism is not via anti-folate action * Possible mechanisms include – inhibition of enzymes involved in purine metabolism, leading to accumulation of adenosine, a purine nucleoside that is elaborated at injured and inflamed sites. Adenosine is a regulatory autocoid that is generated as a result of cellular injury or stress, interacts with specific G protein-coupled receptors on inflammatory and immune cells to regulate their function. – the inhibition of T cell activation activation – suppression of intercellular adhesion molecule expression by T cells

Answer 24

Mean oral bioavailability is 33% (13- * Mean intramuscular bioavailability is 76% * Administered PO, IM or S/C * In patients taking PO with partial response or with nausea then swap to s/c * WEEKLY NOT DAILY DOSING, metabolized to polyglutamates with long half lives * 50% protein bound -NSAIDs displace * Renal excretion

Answer 25

mucositis • marrow suppression both respond to folic acid supplementation * hepatitis, cirrhosis, * pneumonitis (a hypersensitivity reaction) * infection risk * Highly teratogenic, abortifacient

Answer 26

Well tolerated * 50% of patients continue the drug for >5 years, longer than any other DMARD * Improved QOL * Retardation of joint damage * Anchor drug for DMARD combinations

Answer 27

A conjugate of a salicylate (5aminosalicylic acid, 5ASA) and a sulfapyridine molecule * Developed in 1940s * RA or ‘rheumatic polyarthritis’ believed to be infectious * Designed to relieve pain & stiffness (5-ASA = anti-inflammatory) * And to fight infection (sulfapyridine = sulfonamide)

Answer 28

• T cell – inhibition of proliferation – possible T cell apoptosis – inhibition of IL-2 production • Neutrophil – reduced chemotaxis – reduced degranulation

Answer 29

• Mainly due to sulfapyridine moiety – myelosuppression – hepatitis – rash • Milder side effects – nausea – abdo pain/vomiting

Answer 30

adalimumab infliximab Etanercept

Answer 31

 Inflammation Cytokine cascade Recruitment of leukocytes to joint elaboration of adhesion molecules production of chemokines  Angiogenesis VEGF and IL-8 levels  Joint destruction MMPs and other destructive enzymes Bone resorption and erosion Cartilage breakdown “Decrease”

Answer 32

anti-TNF therapy does not appear to increase the overall risk of malignancy in RA * but BSBR data shows increased risk of new malignancy in those anti-TNF treated patients with prior malignancy * risk of serious infections is similar to that from other DMARDs * Anti-TNF increases risk of skin/soft tissue infections * TB reactivation and other intracellular bacterial infections post marketing surveillance

Answer 33

Rituximab binds specifically to a unique cell-surface marker CD20, which is found on a subset of B cells but not on stem cells, pro-B cells, plasma cells or any other cell type Rituximab: 3 key mechanisms for B cell depletion: * activation of complement mediated B cell lysis * initiation of cell mediated cytotoxicity via macrophages * induction of apoptosis

Answer 34

development of hypogammaglobulinaemia and increased risk of infection development of hypersensitivity or blocking immune responses e.g HACA

Answer 35

Inhibit PDE increase cAMP so no Ca influx no contraction ——-> bronchodilation

Answer 36

theophylline, aminophylline) Antagonise adenosine receptors Inhibit phosphodiesterase – increase cAMP relevant in vivo

Answer 37

Narrow therapeutic window (10-20 mmol/L) Frequent side-effects – nausea, headache Potentially life-threatening toxic complications Important drug interactions – levels increased p450) inhibitors eg erythromycin, ciprofloxacin

Answer 38

Oral steroids • Step 5+, Anti-IgE – Strict criteria for use, very expensive. Potentially reduces exacerbation rates in patients not controlled on oral steroids

Answer 39

10 micron particles – deposited in the mouth and oropharynx 1-5 micron particles – most effective as they settle in small airways 0.5 microns – too small. Inhaled to alveoli and exhaled without being deposited in the lungs

Answer 40

1. Unable to complete sentences 2. Pulse > 110 beats / min 3. Respiration > 25 / min 4. Peak Flow 33-50% of best or predicted

Answer 41

Previous plus any one of: * PEF <33% * sPO 2 <92 * PaO 2 <8 kPa * PaCO 2 >4.5 kPa * Silent chest * Cyanosis * Feeble respiratory effort * Hypotension, bradycardia, arrhythmia * Exhaustion, confusion, coma Near-fatal: PaO 2 >6 kPa, mechanical ventilation

Answer 42