Pharmacology: Antimicrobials (Sulfonamides, Quinolones, & Uti Drugs)

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Sulfonamides: Classification?

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(1) Rapidly absorbed:
Short acting [4-8hr] --> Sulfisoxazole, Sulfadiazine,
Intermediate acting [12-18hr] --> Sulfamethoxazole
Lng acting --> Sulfadoxine

(2) Poorly absorbed [active in intestinal lumen] --> Sulfasalazine

(3) Sulfonamides for special uses --> Sulfacetamide, Mafedine, Silver sulfadiazine

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Sulfasalazine: AE?

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SULFONAMIDE ANTIBIOTIC [poorly absorbed]

Reversible infertility due to changes in count and morphology

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Pentasa: Use?

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SULFONOMIDE [Poorly absorbed] ANTIBIOTIC --> Sulfazolaide derivative for IBD & Rheumatoid arthritis

Controlled release formulation delivering to entire GIT including small bowel

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Asacol: Use?

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SULFONOMIDE [Poorly absorbed] ANTIBIOTIC --> Sulfazolaide derivative for IBD & Rheumatoid arthritis

Delayed formulation delivering drug to terminal ileum and beyond

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Olsalazine: Use?

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SULFONOMIDE [Poorly absorbed] ANTIBIOTIC --> Sulfazolaide derivative for IBD & Rheumatoid arthritis

Prodrug [coupled 5-ASA --> split by intestinal bacteria]

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Rowasa use: Use?

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SULFONOMIDE [Poorly absorbed] ANTIBIOTIC --> Sulfazolaide derivative for IBD & Rheumatoid arthritis

Rectal enema and suppositories used for procosigmoiditis

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Sulfasalazine: Use?

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SULFONOMIDE [Poorly absorbed]

For IBD & Rheumatoid arthritis

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Sulfasalazine: MOA/PD?

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SULFONOMIDE [Poorly absorbed] for IBD & Rheumatoid arthritis

Converted to 5-aminosalicylate & sulfapyridine in GIT

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Sulfacetamide: Use?

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SULFONOMIDE ANTIBIOTIC
Management of ophthalamic infections like TRACHOMA [Sulfisoxasole - short acting also available for same purpose]

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Mafenide:
Use?
AE?

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SULFONOMIDE ANTIBIOTIC
Use: Treatment of BURNS

AE: Carbonic anyhdrase inhibition leads to
(1) Metabolic acidosis
(2) Treat by stopping and bicarbonate infusion

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Silver sulfadiazine:
Use?
AE?

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SULFONOMIDE ANTIBIOTIC [Sulfadiazine is short acting]
Use: Prevents infection of BURNT surface & chronic ulcers

AE: Well tolerated w/ limited [rash itch & allergy minimal]

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Sulfmonamides:
MOA/PD?
Resistance?

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MOA/PD:
(1) Bacteriostatic
(2) Inhibitors of dihydropteroate synthase [no or defective folic acid synthesis]

Resistance:
(1) Lowered affinity/sensitivity to dihydropteroate synthase
(2) Increase production PABAfrom external sources
(3) Decreased permeability
(4) Increased inactivation [rapid-acetylation] --> May lead to toxic products

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Sulfmonamides:
Absorbtion?
Distribution?
Metabolism?

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Absorbtion: W/ excpetion of sulfasalazine all well absorbed from GIT

Distribution:
(1) Moderate tissue penetration
(2) Bind plasma proteins VERY strongly [displace most other drugs and molecules including billirubin], Can get into breast milk

Metabolism: Biotransformed in liver and excreted in kidney, Inactivated by acetylation

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Sulfadiazine: DOC in what condition?

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SULFONAMIDE ANTIBIOTIC [short acting]
Toxoplasmosis

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Sulfisoxazole: Use?

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SULFONAMIDE ANTIBIOTIC [short acting]
(1) Uncomplicated UTI
(2) Cystitis

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Sulfadoxine + Pyrimethamine: Use?

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SULFONAMIDE ANTIBIOTIC [long acting] + Pyrimethamine

Malaria prophylaxis

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Short acting sulfonamides: Use

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Sulfisoxazole & Sulfadiazine
(1) TRACHOMA
(2) LGV
(3) Nocardia

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Sulfonamides: DI?

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(1) Displacement of many drugs bound to albumin increasing serum levels: E.g. Oral hypoglyceimic and warfarin effects can be potentiated
(2) Methenamine --> Releases formaldehyde in acid media of urine forming complexes w/ sulfonamides

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Sulfonamides: AE?

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(1) Hypersensitivity like rxn [Stevens-Johnson Syndrome] can lead to liver necrosis
(2) Cross sensitivity between sulfonamides and possibly other derivatives [thiazides, oral, hypoglycemic agents]
(3) Crystalluria: more w/ sulfadiazine and rare w/ sulfisoxisole
(4) Acute hemlytic anemia [G6PD], RARELY AGRANULOCYTOSIS, APLASTIC ANEMIA, MYELOTOXIC EFFECT
(5) Kernicterus [billirubin displacement]

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SMX-TMP [Co-trimoxazole]: MOA/PD?

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BACTERIOCIDAL [either on own is only bacteriostatic]
Sulfamethoxazle is a rapidly absorbed intermediate acting sulfonamide [dihydropteroate synthase inhibitor] while trimethoprim is a dihydrofolate reductase inhibitor. They act in concert to prevent to consecutive steps of folate syntesis [dihydroolic acid & tetrahydrofolic acid]

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SMX-TMP [Co-trimoxazole]:
Route?
Distribution

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Oral, Rapidly absorbed

Sulfonamides are concentrated in the urine

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SMX-TMP [Co-trimoxazole]: What group of bacteria DOESN'T it cover?

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Anaerobic

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SMX-TMP [Co-trimoxazole]: Spectrum?
Alternative to doxycycline + streptomycin in?

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Spetrum: NOCARDIA, NO ANAEROBIC COVERAGE
T - Tree [resp] S. pneumoniae, H. influenzae, Klebsiella

M - Mouth [GIT] E. COLI, SALMONELLA, Shigella, Diptheria

P - Pee [UTI] - E. COLI

SMX - Syndrome [AIDS] - PCP, & Toxoplasmosis

Alternative to doxycycline + streptomycin in: Brucellosis

NOCARDIA

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SMX-TMP [Co-trimoxazole]:
AE?
More common AE in older pts?

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(1) Megoloblastic anemia in folate deficient, Leucopenia, Thrombocytopenia
(2) Transient jaundice may be due to allergic cholestatic hepatitis
(3) OLDER PTS -->. Skin rashes, Exfoliative dermatitis, Fever, SJS

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Quinolones:
MOA/PD?
Resistance?

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MOA/PD: Inhibit DNA gyrase by blocking the A subunit and inducing the formation o a relaxation complex analogue. DNA gyrase mediates relieves tension in DNA by introducing -ve supercoils.

Resistance: (1) Change in porins (2) Efflux pumps (3) Target enzyme mutation

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Quinolones:
AE?
Prolong QT Interval?
Hepatotoxic potential?

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AE:
(1) GIT Irritation, Skin rashes
(2) Headache, Hallucination, Delirium & Trigger seizures
(3) Sparfloxa

Prolong QT Interval: Sparfloxacin [3rd gen]

Hepatotoxic potential: Trovafloxacin

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Quinolones: Contra?

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Children & Pregnant --> B/C ARTHRALGIA & JOINT SWELLING

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Quinolones: DI?

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Increase plasma concentrations of theophylline [anti asthma drug, phosphodiesterase inhibitor]

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Quinolones:
Route & Inhibitors?
Distribution?
Elimination & Inhibitors [Most]?
Moderate excretion through hepatic?

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Route: PO/IV, PO MAY BE INHBITED BY ANTACIDES

Distribution: Very high in urine, kidney, lungs, PROSTATE, stool, bile, higher than CSF & bone

Elimination: Tubular secretion, Can be reduced w/ PROBENICID

Moderate excretion through hepatic: Trovafloxaxin, Moxifloxacin, Sparfloxacin

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Quinolones: Generations?

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1st --> Nalidixic acid, Norfloxacin
2nd --> Ciprofloxacin, Ofloxacin
3rd --> Lomefloxacin, Gatifloxacin, Sparfloxacin
4th --> Moxifloxacin, Trovafloxacin

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Quinolones: 1st gen spectrum/use?

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1st --> Nalidixic acid, Norfloxacin:
Narrow, UTI pathogens only

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Quinolones: 2nd gen spectrum/use?

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2nd --> Ciprofloxacin, Ofloxacin: BROAD SPECTRUM
(1) Greater activity against gram-ve when compared to 1st [GONOCOCCAL]
(2) Mycbacterium, Mycoplasma pneumoniae

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Quinolones: 3rd gen spectrum/use?

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3rd --> Lomefloxacin, Gatifloxacin, Sparfloxacin: BROAD SPECTRUM
(1) Greater activity against gram +ve but reduced against gram -ve when compared to 2nd gen
(2) Good against some MRSA & enterococci

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Quinolones: 4th gen spectrum/use?

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4th --> Moxifloxacin, Trovafloxacin: BROADEST SPECTRUM
(1) Active against ANAERPBIC as well

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Quinolones: 4th gen spectrum have what type of coverage that the other generations don't have?

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ANAEROBIC

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Methenamine mandelate: MOA/PD?

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Formaldehyde liberation in pH less than 5.5 antibacterial

NO antibacterial activity @ alkaline pH

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Methenamine mandelate: Use?

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UTI

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Methenamine mandelate: DI?

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Forms insoluble complex w/ sulfonamides resulting in mutual antagonism

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Methenamine mandelate: AE?

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(1) CHEMICAL CYSTITIS
(2) Gastritis
(3) Hematuria & Frequent micturation @ higher doses

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Nitrofurantoin: MOA/PD?

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Unkown, possibly reactive intermediates that are formed and seem to be responsible for damaging DNA [bacteria reduce drug more rapidly than mammilian]

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Nitrofurantoin: Elimination?

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Urine by filtration & excretion

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Nitrofurantoin: AE?

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(1) PULMONARY REACTION AS PNEUMONITS
(2) HEMOLYSIS in G6-PD
(3) BROWN URINE
(4) IPF
(5) Gastritis, Periperal neuritis, Photosensitivity, Hepatocellular damage

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Phenopyridine: Use?

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(1) NO ANTIBACTERIAL ACTION
(2) Urinary analgesic that relieves symptoms of urgency, frequency, & dysuria

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Phenopyridine: AE?

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(1) RED/ORANGE Colored urine
(2) OD can cause methemoglobinemia

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Quinolones: Used in treatment of TB?
Leprocy?

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TB:
(1) 2nd Gen: OFLOXACIN & Ciprofloxacin
(2) Sparfloxacin [3rd gen]

Leprocy: Ofloxacin

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Metronidozole:
Spectrum?

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Anaerobic bacteria, Some parasites

Front 47

Metronidozole:
MOA/PD?

Back 47

Partially reduced by oxidoreductase, which causes the break-up/fragmentation of DNA in an as yet undefined way