Pharma 9: Infections of CNS Flashcards by Ahmed Alyaseen

The effect of inflammation on the permeability of BBB

Bacterial meningitis, encephalitis→ inflammation→disrupt BBB integrity→ allow substances into the brain which normally would not have been able to penetrate

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Penicillin’s access to brain normally and in bacterial meningitis

NORMALLY→ must be given IT

Meningitis→IV

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98% of low mw drugs

((<400Da)) DO NOT CROSS BBB

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Large mw drugs

CANT ENTER BBB

these include anticancer,bacterial, monoclonal ab, gene therapies

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To cross BBB drug must be

lipid soluble
mw <400Da
<8-10 hydrogen bonds with solvents in water

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Relationship between lipid solubility and accessibility to BBB

NOT LINEAR because:

if highly lipid soluble→ it will be better distributed peripherally→less for CNS

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Which lipohilic drugs cross BBB

SMALL

antidepressants, anxiolytic/hypnotics, antiepileptics, opioids (except the ones that target GI)

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Glucose GLUT 1

D-glucose

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Monocarboxylic acid MCT1

L-lactic acid

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Neutral amino acid LAT1

L-phenylalanine

L-DOPA, Gabapentin→high affinity for BBB carrier mediated transporters

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Basic amino acid CAT1

L-arginine

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Purine nucleoside CNT2

Adenosine

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Principles of improving CNS drug delivery

Enhance BBB permeability
Chemical alterations to drug
Transcranial drug delivery→intracerebral polymer implants

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Method of enhancing BBB permeability

chemically induced osmotic sock

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Methods of chemically inducing osmotic shock

Hyperosmolar MANNITOL infusion in IC artery
Vasocative agents transiently increase BBB permeability like histamine (plasma albumin enters as well→ASTROGLIOSIS→not used clinically)

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Chemical alterations made to the drug

Prodrug→activated in CNS eg. LEVODOPA

Lipidization→make drug more lipid soluble→downside: loss of pharmacological activity

Imitate endogenous ligands→transported by natural receptors, transporters and carries across BBB eg. LEVODOPA

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Transcranial drug delivery process

open cranium
insert intracerebral polymer implant (GLIADEL) (up to 8) which are loaded with CARMUSTINE→anticancer
The drug is released as the wafer is slowly degraded

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How does rabies reach the brain

thru the nerves

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Principles of treatment of CNS infections

eliminate the microorganism with the use of a drug toxic to the microorganism administered at a sufficient concentration at the site
treat responses secondary to the infection ie treat seizures with antiep and inflammation with gc

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treatment of abscess

surgical and pharmacological

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drugs and their concentrations in CSF

Penicillin→ 5%
Vancomycin→ 10%
Ampicillin→15%
Cefotaxime→15%
Gentamycin→20%
Chloramphenicol→30%

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direct administration of gentamycin

very risky

directly injected into ventricles with gram -ve→ increased mortality

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Acyclovir MOA

Synthetic nucleoside analog

Guanosine’→monophosphorylated by viral thymidine kinsae→incorporated into viral dna→chain termination→inhibit dna replication

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nuceloside analogues

acyclovir
valacyclovir
peniclovir
famciclovir
ganciclovir
cidofovir

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ACV uses

prophylaxis and treatment of HSV and VZV infections even immunocompromised patients

ACV administration

IV/orally→cross BBB via nucleoside transporter topically

ACV side effects

well tolerated BUT nephrotoxic and neurotoxic (dose adjeusted in pt with renal failure ad drug excreted by kidneys) reversible after discontinuation

ACV administration

SLOW IV fast iv bolus→crystalluria and elevated serum creatinine→ACV crystals→obstruct renal tubular lumen

Ara-A/foscarnet use

acyclovir resistant HSV-1 encephalitis

Sorivudine use

VZV infections

Ganciclovir use

CMV encephalitis

Caution with gancyclovir

Bone marrow toxicity | Excreted by kidney→check renal function

In HIV

treat according to etiology

Bacterial meningitis according to age

<1 month→gram -ve and group B 1 month - 15 years→ H. influ, N.meningiditis, S. pneumo .15yrs→N. menin, S pneumo, staph

``` Antibiotic therapy for: S pneumo streptooccus groups A and B L. monocytogens N. meningiditis, ```

penicillin G

B lactamase -ve H influenza

Ampicillin

B lactamase +ve H influenza

Cefotaxime

E. coli Kliebsella Proteus

Cefotaxime/Ceftriaxone with Gentamycin

Penicillins, Cephalosprins classification

B lactams

Penicillins, Cephalosporins MOA

BACTERICIDAL (MAINLY) inhibit peptidoglycan cross linking by binding to PBP→bacterial cell wall lysis

Penicillins | ADMIN

Orally or parentally depends on stability of acid

Penicillins distribution

Throughout body tissues and fluids

Penetration of penicillins across BBB

once meninges inflamed→readily penetrates to reach therapeutic retractions at CSF

Penicllins | elimination

by kidney primarily by tubular secretion

Penicillins side effects

HYPERSENSITIVITY→benign rash to anaphylaxis N/V diarrhea CROSS ALLERGY WITH OTHER PENICILLINS or CEPHALOSPORINS

Cephalosporin

Cefatoxime

Cephalosporins similar to penicillins in terms of

MOA, chemistry, toxicity

Cephalosporins advantage over penicillins

more resistant to b lactamases→broader spectrum

Cephalosporins are ineffective against

Enterococci L monocytogenes

Aminoglycosides

Gentamycin

Gentamycin MOA

Bactericidal binds IRReversibly to 30s subunit→inhibit bacterial protein synthesis

Gentamycin adminstered

IV INFUSION OVER 15-30 MINUTES BECAUSE IT ISNT ABSORBED ORALLY

Gentamycin CNS penetration

Poor but effective

Gentamycin elimination

glomerular filtration

Gentamycin side effects

LOW TI nephrotoxicity, ototoxicity, NM blockade

Fungal CNS infections are common in?

Immunocompromised patients eg AIDS

Similarity between fungal infections and M. TB

inhaled to affect lungs and sometimes CNS

Amphoterecin B use

life threatening fungal infection such as histoplasmosis, coccidiomycosis

Amphoterecin B MOA

Binds ergosterol of cell wall→ forms pores in cell membrane→hydrophilic core forms and ion channel→unregulated leakage of ions and metabolites

Amphoterecin B adminstration

IV→reaches therapeutic levels in CSF with a risk of toxicity

Amphoterecin side effects

Nephrotoxicity→sever kidney damage

Preventing amphoterecin B toxicity

giver water IV and monitor kidney function

Which form of Amphoterecin B has less side effects

Lipid formulations like liposomal amphoterecin B

Flucytosine MOA

inhibits fungal DNA synthesis by disrupting function of RNA in protein synthesis

Amphoterecin B and flucytosine synergic action

Amphoterecin B makes the cell more permeable to flucytocsin→effective against C. neoformans meningitis

Flucytosine side effects

RARE gi disturbances anemia neutropenia thrombocytopenia USUALLY causes the drug to be discontinued

Pharma 9: Infections of CNS Flashcards

(66 cards)