BIMM118 Drugs Targeting the CNS Parkinson Epilepsy Hypnotics General Anesthetics Anxiolytics Antidepressants.

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Drugs Targeting the CNS

• Parkinson

• Epilepsy

• Hypnotics

• General Anesthetics

• Anxiolytics

• Antidepressants

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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

Antimicrobials

Unit X

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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

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classification

• Susceptible organism• Narrow spectrum, broad spectrum• Antibacterial• Antiviral• antifungal

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• 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

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• Mechanism of action• Antimetabolites• Inhibitors of viral enzymes

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Microbial drug resistance

• Organisms – staphylococcus aureus, enterococcus faecalis, enterococcus faecium, pseudomonas aeruginosa and mycobacterium tuberculosisi

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• 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

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• Antibiotic use promotes the emergence of drug-resistant microbes – especially the use of broad-spectrum antibiotics

• The more the use – the greater the chance

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Delaying the emergence of resistance

• Prescribed only when needed• Narrow-spectrum• Limit use of newer drugs• Minimize giving antibiotics to livestock

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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

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• Cultures must be obtained prior to initiation of therapy• Drug sensitivity may or may not be done

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Antibiotic combinations

Severe infection

Mixed infections

Prevention of resistance – tuberculosis

Decreased toxicity

Enhanced antibacterial action

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Appropriate prophylactic use

• Surgery• Bacterial endocarditis• Neutropenia• others

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Inappropriate uses

• Viruses• Treat FUO• Improper dosage• Inadequate information• Omission of surgical drainage

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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

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classification

• Narrow spectrum – penicillinase sensitive• Narrow spectrum – penicillinase resistant• Broad spectrum penicillins• Extended-spectrum penicillins

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Penicillin G

• Against most gram positive, gram negative cocci and nonpenicillinase-producing strains of Neisseria gonorrhoeae, anaerobic bacterial and spirochetes

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• Sodium penicillin• Potassium penicillin• Procaine penicillin • Benzathine penicillin – highly sensitive• Not given orally• IM usually• Only sodium and potassium given IV

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allergy

• Most common cause of drug allergy• Prior exposure required but may not be known• May have cross-sensitivity to cephalosporins

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Penicillinase-resistant penicillins

• Resistant to inactivation by beta-lactamases• Naficillin• Oxacillini• Cloxavillin• Dicloxacillin• Methycillin – resistant strains – respond to vancomycin and/or

rifampin

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Broad spectrum penicillins

• Ampicillin – strep, pertussis, proteus, e.coli, salmonella, shigella and h influenzae

• Diarrhea and rash – most common side effects

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• Amoxicillin – more acid resistant• Less diarrhea• Amoxicillin with clavulanate – augmentin (inhibits bacterial beta-

lactamases)

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Extended spectrum penicillins

• Ticarcillin• Carbenicillin indanyl• Mezlocillin• Pipercillin• Pseudomonas, enterbacter, proteus, klebsiella• Given with aminoglycoside for pseudomonas

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Drugs that weaken bacterial cell wall II

• Cephalosporins, imipenem, astreonam, vancomycin, teicoplanin, fosfomycin

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cephalosporins

• Most commonly used antibiotic• Similar to penicillins• Bactericidal• First generation highly susceptible – to beta-lactamases

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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

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• Most given parenterally• Some can cause bleeding tendencies• allergy

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First generation

• Prophylaxis against infection in surgical patients• Gram positive infection

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Second generation

• Some pneumonias• Otitis, sinusitis, respiratory tract infections

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Third generation

• Menigitis• Gram negative bacilli• Gonorrhea, proteus, salmonella, klebsiella

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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

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• Aztreonam – monobactams• Gram-negative aerobic bacteria• IM, IV

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Vancomycin

• Pseudomembranous colitis• MRSA• Other serious infections• Oral for GI infection• Mostly given slow IV• Ototoxicity, hypotension (with rapid IV infusion),

thrombophlebitis

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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

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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

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• Due to use – has increasing bacterial resistance• Infectious diseases, acne, PUD, periodontal disease,

rheumatoid arthritis

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Adverse effects

• GI• Bones and teeth• Suprainfection• Hepatotoxicity• Renal toxicity• Photosensitivity• Orally, IV, and IM

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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

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Therapeutic uses

• May be used as an alternative patients allergic to penicillins – respiratory tract infections

• Legionella• Pertussis• Diphtheriae• Mycoplasmic pneumoniae• strep

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• Oral, IV• Adverse effects - GI, Liver, suprainfection of the bowel,

thrombophlebitis• Clarithromycin – not as much nausea (h. pylori), respiratory tract

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• 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

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• Zithromax – respiratory tract infections, others • Not as much nausea

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clindamycin

• Cleocin – given for specific conditions• Causes pseudomembranous colitis• Inhibits protein synthesis• Anaerobic bacteria – streptococci, some pelvic and abdominal

infections• Given orally, IV, IM

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• Adverse effects – pseudomembranous colitis, diarrhea, rashes, hepatotoxicity

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aminoglycosides

• Bactericidal inhibitors of protein synthesis• Narrow-spectrum – aerobic gram-negative bacilli• Gentamycin, tobramycin, amikacin

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• 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

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• 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

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• Neomycin – often given topically, eye, ear, skin• Also given – orally prior to surgeries of the bowel, suppress

bowel flora

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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

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• 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

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• Sulfisoxazole – (Gantrisin)good for urinary tract • Trimethoprim – given for urinary tract infections• Azo-Sulfisoxazole (sulfonamide-phenzaopyridine) antibacterial

agent with an analgesia combo

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Trimethoprim-sulfamethoxazole

• Trade names – Bactrim, Cotrim and Septra• Potentiation• Urinary tract infections, pneumocystis carinii, otitis media, GI

infections, bronchitis• Oral, IV

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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

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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

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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

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Acute bacterial prostatitis

• Bacterial infection of the prostate• Usually E.coli from indwelling catheter, surgical manipulation,

instruments

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nitrofurantoin

• Macrodantin – urinary tract antiseptic – broad-spectrum antimicrobial

• Staph, strep, e.coli• Lower urinary tract only• Orally – GI, pulmonary reactions, hematologic, peripheral

neuropathy

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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

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• 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

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• 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

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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)

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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

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• 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

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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

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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

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pyrazinamide

• May be used with rifampin, isoniazid, and ethambutol initially• Hepatotoxic – GI, arthralgia,rash

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ethambutol

• Bacteriostatic – most strains are sensitive• Optic neuritis – blurred vision and lack of color discrimination• Allergic reactions, GI disturbances, elevated uric acid levels

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Fluoroquinolones

• Ciprofloxacin – bactericidal – inhibits bacterial DNA replication• Administered orally or IV• Respiratory tract infections, GI, bones, joints, etc. • Not useful against infections caused by anaerobes