Pharma 9: Infections of CNS Flashcards
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
Penicillin’s access to brain normally and in bacterial meningitis
NORMALLY→ must be given IT
Meningitis→IV
98% of low mw drugs
((<400Da)) DO NOT CROSS BBB
Large mw drugs
CANT ENTER BBB
these include anticancer,bacterial, monoclonal ab, gene therapies
To cross BBB drug must be
- lipid soluble
- mw <400Da
- <8-10 hydrogen bonds with solvents in water
Relationship between lipid solubility and accessibility to BBB
NOT LINEAR because:
if highly lipid soluble→ it will be better distributed peripherally→less for CNS
Which lipohilic drugs cross BBB
SMALL
antidepressants, anxiolytic/hypnotics, antiepileptics, opioids (except the ones that target GI)
Glucose GLUT 1
D-glucose
Monocarboxylic acid MCT1
L-lactic acid
Neutral amino acid LAT1
L-phenylalanine
L-DOPA, Gabapentin→high affinity for BBB carrier mediated transporters
Basic amino acid CAT1
L-arginine
Purine nucleoside CNT2
Adenosine
Principles of improving CNS drug delivery
- Enhance BBB permeability
- Chemical alterations to drug
- Transcranial drug delivery→intracerebral polymer implants
Method of enhancing BBB permeability
chemically induced osmotic sock
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)
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
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
How does rabies reach the brain
thru the nerves
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
treatment of abscess
surgical and pharmacological
drugs and their concentrations in CSF
Penicillin→ 5% Vancomycin→ 10% Ampicillin→15% Cefotaxime→15% Gentamycin→20% Chloramphenicol→30%
direct administration of gentamycin
very risky
directly injected into ventricles with gram -ve→ increased mortality
Acyclovir MOA
Synthetic nucleoside analog
Guanosine’→monophosphorylated by viral thymidine kinsae→incorporated into viral dna→chain termination→inhibit dna replication
nuceloside analogues
acyclovir valacyclovir peniclovir famciclovir ganciclovir cidofovir
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
