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Pharma 3 > Antituberculotic drugs. Anti-Leprosy drugs > Flashcards

Antituberculotic drugs. Anti-Leprosy drugs Flashcards

1
Q

Reasons for spreading of TBC

A

Appearance and spreading of MDR Mycobacteria
Appearance and spreading of hypersusceptibles
Insufficient or lacking th in developing countries

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2
Q

Tuberculin reactors with high risk

A

DM

Immunosuppression

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3
Q

Problems in treating TBC

A

M. Tuberculosis is resistant to bodys natural defence
system (survives in cells)
M. Tuberculosis is resistant to most general ABs
Few bacilli with genetic resistance to any single antiTBCs
is always present

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4
Q

Isoniazide
Mechanism of Action
Spectrum
Mechanism of Resistance

A

Mechanism of Action
Inhibits mycolic acid (cell wall component) synthesis
Mycolic is unique to M.Tuber; has high molecular weight

Is a prodrug: requires enzymatic activation by M.Tuber
enzyme: catalase peroxidase
Active Metabolite: Isonicotinoyl NAD(P) adduct
Main target of isonicotinyl NAD(P) adduct: enoyl ACP
reductase–> inhibition

Spectrum
Selectively active against M.Tuber
Bacteriostatic for resting, bacteriocidial for dividing

Mechanism of Resistance
Mutation of catalase peroxidase
Overexpression of enoyl APC reductase

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5
Q

Isoniazide

Pharmacokinetics
Side Effects

A

Pharmacokinetics
Rapid and complete GIT absorption
Minimal PPB, readily diffuses into all compartments
CSF conc= plasma conc
Vd=0.7l/kg–> distributed in total body water
Elimination: Biotransformation: acetylation
speed dep on whether slow or fast acetylators

Side Effects (increase with slow acetylators)
HSR
Neurotoxicity: pyridoxine depletion (increase glutamate,
decrease GABA) . Pyridoxine= cofactor!
Prev. by giving pyridoxine (B6)
Hepatotoxic: post acetylation–> hydrolysed to MAH and
hydroxylated to N hydroxy MAH–> unstable–>
spontaneous decomposition into toxic radical
formation

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6
Q

Other Drugs which also react with Pyridoxine

A

Dapsone
Penicillamine
Boric Acid

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7
Q

Rifampin/Rifampicin
Mechanism of Action
Spectrum
Mechanism of Resistance

A

Mechanism of Action
Inhibits bacterial DNA dep RNA polymerase
—> inhibition of transcription

Spectrum: Broad; bacteriostatic
M. Tuber
M. Avium/ M. Leprae
Most G+: staphylococcis aureus, clost. difficile
Several G-: Enterobacteriacae, pseudomonas, H
Influenzae, Neisseria Meningitis, Legionella

Mechanism of Resistance
Mutation in DNA dep RNA polymerase –> decreased
binding
Monotherapy

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8
Q

Rifampin/Rifampicin
Pharmacokinetics
SE

A 
Pharmacokinetics
   incompletely absorbed orally
   Vd=0.7l/kg
   elimination: biotransformation: deacetylation--> fecal 
         excretion
   biliary excretion with EHC
SE
   Allergic symptoms
   Hepatitis
   GIT: nausea
   Discolouration of body fluids as a coloured compound

CYP INDUCER

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9
Q

Ethambutol
Chemistry
Mechanism of Action
Spectrum

A

Chemisty: 2 alcoholic OH groups, 2 secondary amino
groups–> basic compound

MoA
Inhibits synthesis of arabinogalactan (cell wall compo.)
Target enzyme: arabinosyl transferase

Spectrum
Selective for M. Tuber and other Mycobac. strains

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10
Q

Ethambutol
Pharmacokinetics
SE

A 
Pharmacokinetics
   70% oral absorption
   Even distribution, low PPB
   Elimination: mainly urinary excretion via renal tubular as 
        organic cations (OCT2--> MATE1)

SE
Ocular toxicity–> ocular neuritis
Hyperuricaemia: compet. inhibits secretion of uric acid

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11
Q

Pyrazinamide

Mechanism of Action
Spectrum

A

Mechanism of Action
Inhibits mycolic acid synthesis
Active form: pyrazinic acid, hydrolised upon entering M.
then exported, if environment acidic–> protonated–>
now lipophilic–> rediffuses into M

Spectrum:
M. Tuber
Ineffective against M. Avium (like INH)

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12
Q

Pyrazinamide

Pharmacokinetics
SE
A

Pharmacokinetics
Well absorbed
Vd: 0.6-0.7l/kg
eliminated: tubular secretion of pyrazinic acid
xanthine oxidase partially metabolises it at =N

SE
Hepatic Injury (cholestatic)
Hyperuricemia: secreted in exchange for uric urate at
luminal OAT4–> reabsorption of urate

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13
Q

First Line Agents: M. Tuber

A

Isoniazide
Rifampicin
Ethambutol
Pyrazinamide

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14
Q

Typical Treatment Regimens for M. Tuber

A 
1st 2 months:
   INH+rifampicin+ethambutol
Months 2-6
   INH+rifampicin
Months 6-12
   Maintenance therapy with INH

Alternatively:
INH + Rifampicin for 9 months

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15
Q

Second Line Agents for M Tuber

A 
Ethionamide
Cycloserine
P-Aminosalicyclic Acid
Aminoglycosides
Fluoroquinolone
Capreomycin
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16
Q

Ethionamide
Mechanism of Action
Spectrum

A

MoA
Inhibition of mycolic acid synthesis
Prodrug; activated in M. by FAD containing enzyme
that oxidises–> sulfinic acid intermediate
Target enzyme: enoyl APC reductase

Spectrum
M. Tuber
M. Leprae

17
Q

Ethionamide
Pharmacokinetics
SE

A

Pharmacokinetics
Lipophilic –> readily absorbed and distributed
Elimination: biotransformation; metabolites–> urine

SE: Numerous therefore 2nd line
   GIT distrubance
  CNS: depression, drowsiness
   Endocrine disturbances--> gynecomastia, hypothyroid.
   Hepatitis
   Phototoxic
18
Q

Cycloserine
Chemistry
MoA
Spectrum

A

Chemistry
analogue of D Alanine; contains free amino group–>
reacts with pyridoxal like INH

MoA
Inhibits incorporation of D Alanine into Cell Wall–>
decreases peptidoglycan synthesis

Spectrum
Not M. Tuber specific
G+: staph aureus, enterococci, nocardia
G-: E Coli

19
Q

Cycloserine

Pharmacokinetics
SE

A 
Pharmacokinetics
   Readily absorbed and distributed
   Excreted into urine 50% unchanged--> toxic in renal 
      insuff
   Biotransformation
SE
  CNS (pyridoxine)
20
Q

P Aminosalicylic Acid (PAS)

MoA
Spectrum

A

MoA
May impair folic acid synthesis; is a folic acid analogue
with an extra hydroxy group–> inhibition of DHF R

Spectrum
Specific for M. Tuber

21
Q

P Aminosalicylic Acid (PAS)

Pharmacokinetics
Spectrum

A

Pharmacokinetics
Readily absorbed and distributed
Acetylation (NAT1–> therefore no slow or fast
acetylation as with NAT2)and Urinary excretion
unchanged

SE
GIT irritation due to large daily dose
HSR

22
Q

Aminoglycosides

A

Amikacin
Kanamycin
Streptomycin: SE vestibular dysfunctions

23
Q

Fluoroquinolones

A

Moxifloxacin

broad spectrum ABs

24
Q

Capreomycin

A

Not AG but similar
Can show cross resistance; also oto and nephrotoxic
Must be given IV

25
Q

General Concept: Leprosy

A

Caused by Mycobacterium Leprae
Also known as Hansens Disease
Long incubation time (decades)
Neurons are destoryed

26
Q

Main Types of Lebrosy

A 
Tuberculoid Type (benign)
Lepromatous Type
27
Q

Tuberculoid Type: Leprosy

A

Leprosy with few bacilli
Characterised by skin macules with clear centers and
well defined margins
Good cellular immune response is present (HSR4)
Therapy duration: 6 months
Dapsone daily+rifampicin monthly

28
Q

Lepromatous Type: Leprosy

A

Multibacillary Leprosy
Diffuse or ill defined local infiltrations in skin; become
thickened and glossy
Atrophy, absorption of small bones, ulcerations –> spont.
amputation
Cellular immune response deficient
Therapy duration: at least two years
Dapone daily+ rifampicin+ clofazimine(last two monthly)

29
Q

First Line Agents: Leprosy

Drug Names

A

Dapsone
Rifampicine
Clofazimine

30
Q

First Line Agents: Leprosy

Dapsone

A

Chemically related to sulphonamide

MoA:
Inhibits folate synthesis

Resistance increases–> combined therapy recommended

Pharmacokinetics
Well absorbed orally and well distributed
Elimination: acetylation–> urine; glucuronidation–> bile;
hydroxylation–>formation of free radicals–> SE
T1/2: 24-48 hrs; but remains in certain tissues for longer

SE
   Haemolysis
   Methemoglobinemia
   Nausea/vomiting
   Fever
   Neuropathy
31
Q

First Line Agents: Leprosy

Clofazimine

A

MoA
inhibits template function of DNA via binding (GC rich=
characteristic for Mycobacteria)
Antiinflammatory activity–> prev of erythema nodosum

Pharmacokinetics
Well absorbed orally, tendency to accumulate in body
anti leprotic effect delayed 6-8 weeks
T1/2 = 8 weeks!

SE
Blue black skin lesions
Nausea/Dizziness/Headache–> dose related

32
Q

Second Line Agents: Leprosy

Drug Names

A

Thalidomide
Ethionamide
Fluoroquinolones
Clarythromycin

33
Q

Second Line Agents: Leprosy

Thalidomide

A

Effective for th of erythema nodosum leprosum

SE: Neuropathy
–> generally not given to females

34
Q

Second Line Agents: Leprosy

Ethionamide

A

Also antituberculotic

Pharma 3 (14 decks)

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