bimm118 drugs targeting the cns parkinson epilepsy hypnotics general anesthetics anxiolytics...
TRANSCRIPT
BIM
M11
8
Drugs Targeting the CNS
• Parkinson
• Epilepsy
• Hypnotics
• General Anesthetics
• Anxiolytics
• Antidepressants
BIM
M11
8
Diabetes mellitus
Pancreas:• Islets of Langerhans: site of hormone production
– A (alpha) cells – produce Glucagon– B (beta) cells – produce Insulin
– D (delta) cells – produce Somatostatin
Insulin and Glucagon are the major regulators of blood glucose
BIM
M11
8
Selective toxicity
• Injure target organism without affecting the host• Can accomplish this by attacking processes that critical to microbial well-being,
but that don’t affect mammals• Bacterial cell wall• Inhibition of an enzyme unique to bacteria• Disruption of bacterial protein synthesis
BIM
M11
8
classification
• Susceptible organism• Narrow spectrum, broad spectrum• Antibacterial• Antiviral• antifungal
BIM
M11
8
• Mechanism of action• Cell wall• Cell membrane permeability• Lethal inhibition of bacterial protein synthesis• Nonlethal inhibition of bacterial protein synthesis• Drugs that inhibit bacterial synthesis of nucleic acids
BIM
M11
8
Microbial drug resistance
• Organisms – staphylococcus aureus, enterococcus faecalis, enterococcus faecium, pseudomonas aeruginosa and mycobacterium tuberculosisi
BIM
M11
8
• Microbes may increase manufacture of drug-metabolizing enzymes (penicillins)
• Microbes may cease active uptake of certain drugs (tetracyclines)
• Changes in receptors which decrease antibiotic binding and action
• May synthesize compounds that antagonize drug actions
BIM
M11
8
• Antibiotic use promotes the emergence of drug-resistant microbes – especially the use of broad-spectrum antibiotics
• The more the use – the greater the chance
BIM
M11
8
Delaying the emergence of resistance
• Prescribed only when needed• Narrow-spectrum• Limit use of newer drugs• Minimize giving antibiotics to livestock
BIM
M11
8
selection
• Identify the infecting organism• Drug sensitivity of the infecting organism• Host factors – site of infection, host defenses, allergies, inability
of drug of choice to penetrate the site of infection, unusual susceptibility of the patient to toxicity
BIM
M11
8
• Cultures must be obtained prior to initiation of therapy• Drug sensitivity may or may not be done
BIM
M11
8
Antibiotic combinations
Severe infection
Mixed infections
Prevention of resistance – tuberculosis
Decreased toxicity
Enhanced antibacterial action
BIM
M11
8
Inappropriate uses
• Viruses• Treat FUO• Improper dosage• Inadequate information• Omission of surgical drainage
BIM
M11
8
Weaken bacterial cell wall
• Penicillins – cause the bacterial wall to weaken and take up water and burst
• Mechanisms of resistance – inability to reach targets and inactivation of penicillins by bacterial enzymes
BIM
M11
8
classification
• Narrow spectrum – penicillinase sensitive• Narrow spectrum – penicillinase resistant• Broad spectrum penicillins• Extended-spectrum penicillins
BIM
M11
8
Penicillin G
• Against most gram positive, gram negative cocci and nonpenicillinase-producing strains of Neisseria gonorrhoeae, anaerobic bacterial and spirochetes
BIM
M11
8
• Sodium penicillin• Potassium penicillin• Procaine penicillin • Benzathine penicillin – highly sensitive• Not given orally• IM usually• Only sodium and potassium given IV
BIM
M11
8
allergy
• Most common cause of drug allergy• Prior exposure required but may not be known• May have cross-sensitivity to cephalosporins
BIM
M11
8
Penicillinase-resistant penicillins
• Resistant to inactivation by beta-lactamases• Naficillin• Oxacillini• Cloxavillin• Dicloxacillin• Methycillin – resistant strains – respond to vancomycin and/or
rifampin
BIM
M11
8
Broad spectrum penicillins
• Ampicillin – strep, pertussis, proteus, e.coli, salmonella, shigella and h influenzae
• Diarrhea and rash – most common side effects
BIM
M11
8
• Amoxicillin – more acid resistant• Less diarrhea• Amoxicillin with clavulanate – augmentin (inhibits bacterial beta-
lactamases)
BIM
M11
8
Extended spectrum penicillins
• Ticarcillin• Carbenicillin indanyl• Mezlocillin• Pipercillin• Pseudomonas, enterbacter, proteus, klebsiella• Given with aminoglycoside for pseudomonas
BIM
M11
8
Drugs that weaken bacterial cell wall II
• Cephalosporins, imipenem, astreonam, vancomycin, teicoplanin, fosfomycin
BIM
M11
8
cephalosporins
• Most commonly used antibiotic• Similar to penicillins• Bactericidal• First generation highly susceptible – to beta-lactamases
BIM
M11
8
generations
• 1-4• Increasing in activity against gram-negative bacterial and
anaerobes• Increasing resistance to destruction by beta-lactamases• Increasing ability to reach cerebrospinal fluid
BIM
M11
8
First generation
• Prophylaxis against infection in surgical patients• Gram positive infection
BIM
M11
8
Third generation
• Menigitis• Gram negative bacilli• Gonorrhea, proteus, salmonella, klebsiella
BIM
M11
8
imipenem
• Broadest antimicrobial spectrum of any drug – good for mixed infections – always given in conjunction with cilastatin to inhibit destruction of imipenem by renal cells
• Carbapenems – new class of beta-lactam antibiotics• Only given – IV, IM• Nausea, vomiting, diarrhea, rash
BIM
M11
8
Vancomycin
• Pseudomembranous colitis• MRSA• Other serious infections• Oral for GI infection• Mostly given slow IV• Ototoxicity, hypotension (with rapid IV infusion),
thrombophlebitis
BIM
M11
8
Bacteriostatic inhibitors of protein synthesis
• Tetracyclines, macrolides, clindamycin, chloramphenicol, spectinomycin and dalflopristin/quinupristin
• Suppress bacterial growth and replication but do not kill• Second-line agents
BIM
M11
8
tetracyclines
• Broad-spectrum• Inhibit protein synthesis – suppress bacterial growth• Gram-positive and gram-negative bacterial – rickettsia,
spirochetes, brucella, chlamydia, myocoplasma, helicobacter pylori and vibrio cholerae
BIM
M11
8
• Due to use – has increasing bacterial resistance• Infectious diseases, acne, PUD, periodontal disease,
rheumatoid arthritis
BIM
M11
8
Adverse effects
• GI• Bones and teeth• Suprainfection• Hepatotoxicity• Renal toxicity• Photosensitivity• Orally, IV, and IM
BIM
M11
8
macrolides
• Inhibit bacterial protein synthesis• Azithromycin, erythromicin, clarithromycin, dirithromycin • Effective against most gram-positive bacterial as well as some
gram-negative bacterial• May be good alternative to those allergic to PCN
BIM
M11
8
Therapeutic uses
• May be used as an alternative patients allergic to penicillins – respiratory tract infections
• Legionella• Pertussis• Diphtheriae• Mycoplasmic pneumoniae• strep
BIM
M11
8
• Oral, IV• Adverse effects - GI, Liver, suprainfection of the bowel,
thrombophlebitis• Clarithromycin – not as much nausea (h. pylori), respiratory tract
BIM
M11
8
• Adverse effects – GI, dizziness, h/a restlessness• Candida infections• Tendon rupture – not for children under 18 yrs. • Should not be taken with milk or food• Watch for bleeding – elevates warfarin levels
BIM
M11
8
clindamycin
• Cleocin – given for specific conditions• Causes pseudomembranous colitis• Inhibits protein synthesis• Anaerobic bacteria – streptococci, some pelvic and abdominal
infections• Given orally, IV, IM
BIM
M11
8
aminoglycosides
• Bactericidal inhibitors of protein synthesis• Narrow-spectrum – aerobic gram-negative bacilli• Gentamycin, tobramycin, amikacin
BIM
M11
8
• Amikacin – least susceptible to resistance• E.coli, Klebsiella pneum., serratia, proteurs mirabilis,
pseudomonas• Reserved for serious infections due to aerobic gram-negative
bacilli• Most given IM or IV
BIM
M11
8
• Binds tightly to renal tissue – easily causes nephrotoxicity• Ototoxicity• Reduce dosage in patients with renal disease• Narrow therapeutic range – peak and trough levels (avoid high
trough levels) – not greater than 2mcg/ml
BIM
M11
8
• Neomycin – often given topically, eye, ear, skin• Also given – orally prior to surgeries of the bowel, suppress
bowel flora
BIM
M11
8
Sulfonamides and trimethoprim
• Broad-spectrum – disrupt synthesis of tetrahydrofolic acid – inhibits synthesis of folic acid
• Doesn’t hurt our cells because our cells take up folic acid from our diet
• Bacterial cells make their own and sulfonamides disrupt this process
BIM
M11
8
• Resistance – prevalent –
• Works on gram positive cocci, gram negative bacilli, actinomycetes, chlamydiae, some protozoa
• Primary usage – urinary tract infections, mostly due to E. Coli
• Hypersensitivity, Stevens-Johnson syndrome, hemolytic anemia, kernicterus, renal damage
BIM
M11
8
• Sulfisoxazole – (Gantrisin)good for urinary tract • Trimethoprim – given for urinary tract infections• Azo-Sulfisoxazole (sulfonamide-phenzaopyridine) antibacterial
agent with an analgesia combo
BIM
M11
8
Trimethoprim-sulfamethoxazole
• Trade names – Bactrim, Cotrim and Septra• Potentiation• Urinary tract infections, pneumocystis carinii, otitis media, GI
infections, bronchitis• Oral, IV
BIM
M11
8
Urinary tract infections
• Community acquired – usually E. coli• Hospital acquired – Klebsiella, proteus, pseudomonas, staph,
enterobacter• Acute cystitis – single dose, short course, conventional therapy• Acute urethral syndrome – dysuria, frequency, urgency, pyuria –
chlamydia, gonorrhea, gardnerella
BIM
M11
8
Recurrent UTIs
• Reinfection – often with females – 1-2 per year will be treated as separate infection
• More frequently – long term prophylaxis with lower doses of certain drugs
• Relapse – recolonization – may also require long term therapy, may need surgical procedure – depending on cause
BIM
M11
8
Acute pyelonephritis
• Infection of the kidney – patient will be “sicker”• Mild – moderate infection will be treated on outpatient with oral
agents• Severe infection – hospital and IV antibiotics
BIM
M11
8
Acute bacterial prostatitis
• Bacterial infection of the prostate• Usually E.coli from indwelling catheter, surgical manipulation,
instruments
BIM
M11
8
nitrofurantoin
• Macrodantin – urinary tract antiseptic – broad-spectrum antimicrobial
• Staph, strep, e.coli• Lower urinary tract only• Orally – GI, pulmonary reactions, hematologic, peripheral
neuropathy
BIM
M11
8
Antimycobacterial agents
• Slow growing microbes, therapy needs to be prolonged• Tuberculosis – epidemic proportions due to resistant strains,
AIDS• People may harbor the organism but may have no symptoms
(inactive)• May be in lungs only – may be disseminated throughout body
BIM
M11
8
• Transmitted by inhalation of sputum particles (coughing, sneezing)
• Rapid response by immune system (phagocytes) keeps most individuals from developing obvious signs and symptoms
• Necrosis of lung tissue can be result – if patient develops clinical disease
BIM
M11
8
• Screening very important especially in high-risk populations• PPD, CXR, sputum evaluations – cultures best but take longer• Drug resistance is becoming more concerning – highest multi-
drug resistance in New York City
BIM
M11
8
treatment
• Must always consist of two or more drugs to which the organism is sensitive
• Decrease the incidence of resistance• Decrease the incidence of relapse• Usually starts with daily therapy – four drugs – isoniazid,
rifampin, pyrazinamide, ethambutol (2 months)
BIM
M11
8
treatment
• Then after, four months of isoniazid and rifampin• Multidrug-resistant tubercle bacilli – treatment may start with as
many as seven drugs – treatment will last longer• Special considerations in those with HIV infection
BIM
M11
8
• Directly observed therapy – to promote compliance• Continuing evaluation of treatment – cultures, CXR, symptoms• Prophylaxis therapy – patients who have had recent known
exposure, HIV, patients with known exposure and immunosuppression
BIM
M11
8
isoniazid
• First – line primary agent• Suppresses bacterial growth by inhibiting synthesis of mycolic
acid (component of cell wall)• Oral and IM• Peripheral neuropathy, hepatoxicity, anemia, GI distress
BIM
M11
8
rifampin
• Broad-spectrum antibiotic• Inhibits protein synthesis• Always given in conjunction with other antituberculosis drug• Can cause hepatoxicity• Discoloration of body fluids, GI, rash, flu-like syndrome
BIM
M11
8
pyrazinamide
• May be used with rifampin, isoniazid, and ethambutol initially• Hepatotoxic – GI, arthralgia,rash
BIM
M11
8
ethambutol
• Bacteriostatic – most strains are sensitive• Optic neuritis – blurred vision and lack of color discrimination• Allergic reactions, GI disturbances, elevated uric acid levels