PHARMACOLOGY BLOCK 3 STUDY GUIDE

Prescription Writing

a.c. – before meals & p.c. – after meals

h.s. – bedtime

p.o. – by mouth

p.r.n. – when required

ad lib – at pleasure

non rep. – do not repeat

a.d. – right ear & a.s. – left ear & a.u. – each ear

o.d. – right eye & o.s. – left eye & o.u. – each eye

u.d. – as directed

inj. – injection & sup – suppository

q.d. – every day & q.h. – every hour

cc – cubic centimeter & ml – milliliter

mg – milligram & mcg – microgram

tsp – teaspoonful & tbsp – tablespoonful

Sig – write on label

stat – immediately

g/gm – gram

h/hr – hour

Drug Therapy of Anemias

Structure of hemoglobin: With 4 hemes attached to 1 globin, the molecule carries 8 atoms of oxygen.

Biosynthesis of hemoglobin: The RLS for synthesis of hemoglobin (in mitochondria) is 2-a-ketoglutaric acid+glycine –(ALA sythetase)®pyrrole, which can be enhanced by heme, barbiturates, estrogen, and sulfonamides; can lead to acute intermediate porphyria.

Areas of the body producing RBCs: Yolk sac (1^st trimester); liver, spleen, and lymph nodes (2^nd trimester); bone marrow (all bones until age 5, membranous bones such as sternum, pelvis, ribs, and vertebrae after age 20).

Aging of RBCs: Hb synthesis and glucose metabolism occur in immature and early RBCs only. Structural changes occur due to declining glycolytic activity.

RBC replacement: The formation of many new cells necessitates high mitotic activity and a high rate of DNA synthesis. Decrease in DNA synthesis will result in an insufficiency in RBC formation (anemia).

Pathophysiology: Physiologic adjustments include tachycardia, augmented CO, accelerated velocity of blood flow, increased alveolar ventilation, and increased 2,3-DPG. A normal person may tolerate as much as a 50% reduction in RBC mass without conspicuous untoward affects.

Erythropoietin – growth factor produced by kidney that controls RBC production; triggered by hypoxia (oxygen sensing cell), resulting in production of nitric oxide; NO stimulates guanylate cyclase in EPO producing cell to increase cGMP, which ultimately increases expression of EPO mRNA.

·       Targets: Early erythroid colony-forming unit (CFU-E) and late burst erythroid colony forming unit (BFU-E).

·       Indications: Anemia due to chronic renal failure, AIDS patients treated with AZT, cancer patients treated with chemotherapy, and patients undergoing elective surgery to increase RBC production.

·       Side effects: Increased clotting in dialysis patients, hypertension, seizures.

Myeloid growth factors (G-CSF, GM-CSF, M-CSF) – glycoproteins that stimulate proliferation and differentiation of hematopoietic precursors.

·       Side effects: Bone, joint, and muscle pain.

Iron: Main storage form is hemoglobin (75%) and myoglobin; other storage forms include ferritin and hemosiderin. Normal male individual needs 1 mg of iron per day; menstruating or pregnant females need more (2.0-2.5 mg). Children need 0.5-1.0 mg per day. In the U.S. an average person absorbs only 10-30% of dietary iron to balance loss (can be increased to 60% if necessary). Factors that increase iron absorption include vitamin C; factors that decrease absorption include antacids and tetracycline.

Iron Deficiency Anemia: Hypochromic microcytic anemia; only anemia resulting from iron deficiency and therefore is the only anemia that responds to iron.

Ferrous sulfate – treatment of choice for hypochromic microcytic anemia (180 mg/day).

Ferrous gluconate – tolerated better.

·       Indications: Hypochromic microcytic anemia.

·       Route: Oral AS EFFECTIVE as parenteral.

·       Toxicity: Acute iron poisoning (1 g in kids) can lead to death due to hepatic injury; treat with deferoxamine, which is a potent iron chelator but a poor calcium chelator.

·       Side effects: Constipation, diarrhea, nausea, epigastric pain.

Iron dextran

·       Indications: Hypochromic microcytic anemia who do not respond to oral therapy (idiopathic)

·       Route: Parenteral.

·       Side effects: Hypertension, headache, tachycardia, pain at injection site.

Megaloblastic Anemia: Deficiency of vitamin B12 and/or folate impairs DNA synthesis and is reflected in mitotic activity. The primary defect appears to be decreased mitotic activity consequent to lengthening of the intermitotic interval. Large, oval RBCs are characteristic. Therapy with either vitamin B12 or folate can usually reverse the symptoms. Once difference is that vitamin B12 deficiency produces neurological symptoms that can be corrected by vitamin B12 but not folates. Folate deficiency does not result in nerve damage.

Vitamin B12: Absorption takes place in distal ileum and requires intrinsic factor, which can bind 2 molecules of B12. Vitamin B12 has a cobalt requirement. B12 requirement is 2mg/day assuming 60-80% GI absorption.

Folate (pteroylglutamic acid/PGA): Occur most abundantly in fresh green vegetables, liver, kidney, eggs, yeast, dried beans, nuts, grains, and certain fruits. Minimum requirement is 50-100 mg/day. Folate is absorbed in the proximal jejunum in an energy-dependent process. Anticonvulsants (phenytoin, primidone, ethanol), trimethoprim, and methotrexate can cause a folate deficiency and thus precipitate megalobalastic anemia. A folate deficient megaloblastic anemia can also occur in association with scurvy because vitamin C is involved in conversion of folic acid to folinic acid.

Vitamin B12 – the patient with pernicious anemia should be placed on vitamin B12 for life.

1.      Indications: Megaloblastic anemia due to vitamin B12 deficiency due to vegetarianism, impaired absorption, gastric or small bowel disease, tapeworm, blind loop syndrome, or functional damage to ileum (also malnutrition, alcoholism, or pregnancy).

2.      Route: Injection appears more dependable (IM).

Folate – folic acid CANNOT correct the neurological disorders due to vitamin B12 deficiency. May also give vitamin C concurrently (antioxidant).

3.      Indications: Megaloblastic anemia due to folate deficiency due to NO vegetables in diet, impaired utilization, anticonvulsants, vitamin C deficiency, hyperthyroidism, malignant tumor, or dialysis (also malnutrition, alcoholism, or pregnancy).

Anemias Related to Marrow Defects: The bone marrow failure may be idiopathic, or it may be secondary to known toxic or inhibiting agents.

Hemolytic Anemias: Hereditary (spherocytosis corrected by splenectomy) or acquired (immune or nonimmune). Immune varieties include autoimmune hemolytic anemia, erythoblastosis fetalis, and transfusion reactions. Immune hemolytic anemias respond to corticosteroids. Hemolytic anemias are associated with a positive Coombs test. Nonimmune acquired hemolytic anemias include those caused by various chemical, bacterial, or protozoal agents. Hemolysis by ordinary doses of drugs is usually due to G6PDH deficiency.

Fundamentals of Chemotherapy

Chemotherapy began with Paul Ehrlich.

Bactericidal drugs kill organisms and more effective during logarithmic growth, since the increased metabolic activity provides maximum susceptibility. Bacteriostatic antimicrobials only prevent bacterial growth.

The use of antibiotics in fixed dosage combinations is to be avoided. However, the simultaneous administration of two or more antibiotics may be justified in certain situations.

Natural resistance depends on the absence of a metabolic process affected by the antibiotic in question. Due to three mechanisms: 1. non-susceptible metabolism; 2. ability of the organism to destroy the drug (penicillinase); 3. inability of the drug to penetrate to an appropriate location in the parasite.

Acquired resistance can arise through mutation, adaptation, or through development of infectious (multiple) drug resistance. Many gram-negative bacilli have genetic material (R factors) what is separate from the chromosomes but that mediates resistance to many different antibiotics. The R factors can be transferred from one bacterium to another (conjugation). Bacteriophages can transfer DNA via transduction to impart resistance to penicillin, erythromycin, tetracycline, and chloramphenicol. Transposition can also occur.

In general, the selection of an antibiotic should be based upon an etiologic diagnosis. Although sensitivity determinations are desirable in infections caused by E. coli, Proteus, P. aeruginosa, and Staphylococcus, they are not absolutely necessary in infections caused by some organisms that are usually sensitive to penicillin.

An antibacterial drug usually causes significant clinical improvement within 12-24 hrs. If no clinical improvement is obvious after 48-72 hrs of full therapy, it can usually be concluded that the organisms are resistant or an abscess exists.

Chemotherapeutic agents should be measured using viability.

Bacteriologic diagnosis: Disk diffusion method provides quick, basic information as to whether an organism is susceptible or resistant to a particular antibiotic. Tube dilution method provides exact concentration of antibiotic needed to kill bacteria.

In general, there is no place for prophylaxis unless it is directed against one particular organism, or a small group of organisms.

Adverse drug effects: Superinfection is the appearance of both microbiological and clinical evidence of a new infection with pathogenic microorganisms or fungi; caused by inappropriate drug use, drug resistance, inadequate dosing, or possibly catheterization. Hypersensitivity reactions can develop to most antibacterial drugs, particularly in atopic individuals.

Sulfonamides

Structure-activity relationship: Acetylation or conjugation with glucuronic acid takes place in the N4 amine group with the resulting acetylation derivatives being inactive.

Mechanism of action: Sulfonamides are bacteriostatic, enhancing phagocytosis of susceptible organisms. Sulfonamides compete with PABA for incorporation into folic acid. Only organisms that endogenously synthesize folate are susceptible.

Resistance: 1. Decreased permeability of cell wall; 2. Decreased enzyme affinity for sulfonamide; 3. Increase in PABA production.

Importance of folate: Folate coenzymes specifically catalyze the transfer and utilization of single carbon moieties that are necessary in the biosynthesis of purines, thymine, and AA (serine, glycine, methionine, histidine).

Pharmacokinetics: Peak level reached in 3-4 hrs; effect lasts for 3-4 days; absorbed from duodenum; orally administered; renal excretion rate varies; good penetration (CSF 50-80% of plasma level); acetylated derivatives are more highly bound and thus more difficult to excrete ® can lead to crystalluria in kidneys; alkalinization of the urine promotes excretion.

Toxicity and side effects: Hypersensitivity with Steven-Johnson syndrome (long acting sulfamethoxypyridazine and sulfadimethoxine); hemolytic anemia in individuals deficient in G6PDH; agranulocytosis; hepatitis; nausea, vomiting, diarrhea; crystalluria; reduction in gut bacteria can lead to vitamin K deficiency.

Drug interactions: 1. Sulfonamides given to mothers during delivery can precipitate kernicterus in neonates due to displacement of bilirubin; 2. Hypoglycemia when given with tolbutamide; 3. Cotrimoxazole increases warfarin levels; 4. Sulfa drugs displace thiopental so anesthesia lasts longer; 5. Vitamin K deficiency-associated bleeding; 6. Increased half-lives of some anticonvulsants (phenytoin).

Spectrum: Gram(+), gram (-), some filterable agents, trachoma, Nocardia.

Indications: UTIs, nocardiosis (agent of choice), chlamydial infections, shigellosis (nonabsorbable sulfas), trachoma/inclusion conjunctivitis (with tetracyclines).

Sulfadiazine – short-acting, liquid suspension available.

Sulfisoxazole – short-acting

Sulfamethylthiadazole – short-acting

Sulfamethoxazole – intermediate-acting, more likely to cause crystalluria, liquid suspension available.

Mafenide – topical, used for chronic burn lesions, a-amino-p-toluensulfonamide.

Succinylsulfathiazole & Salicylazosulfapyridine – poorly-absorbed, used to decrease gut flora, prodrugs.

Folic Acid Antagonists

Importance of folate: Biosynthesis of thymine and formylation of methionine-tRNA.

Structure-activity relationship of large molecule antifolates: Can make an isoteric replacement of an amino group for a hydroxyl group at C4. Leaving a hydrogen yields aminopterin while adding a methyl group yields methotrexate.

Structure-activity relationship of small molecule antifolates: Two amino groups for multiple substitutions (R1 and R2), which affect inhibitory properties. Relatively non-toxic compounds.

Mechanism of action: Inhibition of dihydrofolate reductase (pseudoirreversible).

Resistance: Genetic phenomenon leading to increased in dihydrofolate reductase.

Trimethoprim-sulfamethoxazole – TMP has a Vd of 100 L and its concentration in tissues exceeds that of plasma; the opposite is true of sulfamethoxazole; both agents are excreted in the urine in both free and metabolized form; SMX clearance is increased by high urine flow rate and urinary alkalization; TMP clearance is increased in acid urine; combined action is synergistic.

Indications: UTIs, prostatitis, otitis media, bronchitis, p. carinii, shigella, malaria & toxoplasmosis (given with pyrimethamine).

DNA Synthesis Inhibitors

Quinolones – Nalidixic acid, Cinoxacin

Fluoroquinolones – Norfloxacin, Ciprofloxacin, Ofloaxacin, Levofloxacin

Mechanism of action: Inhibit DNA gyrase mediated supercoiling.

Contraindications: Pregnancy and young children due to cartilage problems; NOT USEFUL IN TREATING C. DIFFICILE.

Indications: UTIs (nalidixic acid and cinoxacin), general bacterial infections (norfloxacin), bone and soft tissue infections caused by staphylococci and gram(-) organisms (ciprofloxacin, ofloxacin, levofloxacin).

Urinary Antiseptics

Nitrofurantoin – Used for treatment of UTIs; contraindicated in severe renal insufficiency; vomiting is most common side effect.

Cell Wall Synthesis Inhibitors

Penicillins

Chemistry: Penicillin contains a thiazolidine ring, a b-lactam ring, and a side chain. Amidase splits penicillin at the side chain linkage; the side chain is required for antibacterial activity. Penicillinase opens the b-lactam ring to produce penicilloic acid.

Shortcomings of penicillin G:

1. Short half life (acid labile; weak acid that is both secreted and filtered; probenecid given to decrease secretion; procaine, a PABA derivative, added to delay absorption)

2. Acid instability (penicillin V contains an oxygen atom in the side chain that decreases acid lability);

3. Penicillin-resistant staphylococci (methicillin, oxacillin, cloxacillin, and naficillin are penicillinase-resistant)

4. Narrow spectrum (ampicillin and carbenicillin are broad spectrum).

Degradation products of penicillin: Penicillamine, a cysteine derivative, is a chelating agent used in the treatment of Wilson’s disease, as well as for removing mercury and lead from the body. Penicilloic acid serves as a hapten for antigens.  

General toxicities: High therapeutic index; GI distress; neurological problems; hematuria; hemolytic anemia; carbenicillin is administered as a sodium salt, while penicillin G is administered as a potassium salt (caution in patients with electrolyte problems, cardiovascular, or renal disease).

Hypersensitivity reactions: 10-15%; can be immediate, accelerated, or delayed; often results from previous hidden exposure. Skin testing using the antigenic determinant, a penicilloyl derivative of lysine, is useful, but not 100% accurate.

Narrow spectrum penicillins: Penicillin G

Indications:  G(+) organisms.

Pharmacokinetics: Approximately 3-5 times more penicillin G must be administered orally than parenterally. To assure maximum and prompt absorption, oral penicillin should be prescribed one hour before or two hours after a meal. Penicillin G poorly penetrates the BBB unless the meninges are inflamed. Excretion is via the kidneys and is blocked by probenecid.

Penicillinase-resistant penicillins: Methicillin, oxacillin, nafcillin, cloxacillin

Indications: G(+) penicillinase-producing organisms (S. aureus).

Pharmacokinetics: Excreted by kidneys; does not penetrate BBB well; methicillin deteriorates rapidly in solution; methicillin has high incidence of nephrotoxicity.

Resistance: Plasmid-mediated.

Broad spectrum penicillins: Ampicillin

Indications: DOC for L. monocytogenes; additional G(+) and G(-) coverage; NOT ACTIVE AGAINST PSEUDOMONAS OR KLEBSIELLA.

Pharmacokinetics: Renal and biliary excretion; high incidence of rash; GI disturbances are common.

Broad spectrum penicillins: Amoxicillin – better absorbed from the gut than ampicillin.

Broad spectrum penicillins: Carbenicillin

Indications: P. aeruginosa, Proteus, E. coli, Enterobacter. NOT ACTIVE AGAINST KLEBSIELLA. Less active than penicillin G against G(+).

Pharmacokinetics: Extra carboxylic acid ® caution about salt content when used in large quantities.

Broad spectrum penicillins: Ticarcillin – 2-4 times more active against P. aeruginosa.

Broad spectrum penicillins: Azlocillin – 10 times more effective against P. aeruginosa.

Broad spectrum penicillins: Mezlocillin & Piperacillin – ACTIVE AGAINST KLEBSIELLA AND PSEUDOMONAS.

Murein cell wall synthesis in G(+): 1. Formation of UDP-N-acetyl muramic acid; 2. Formation of UDP-N-acetyl-muramyl pentapeptide; 3. Formation of linear peptide-polysaccharide; 4. Cross linking. Stages 1&2 occur in the cytoplasm, while stages 3&4 occur in the periplasmic space. Racemase (inhibited by cycloserine) converts L-alanine to D-alanine.

Penicillin MOA: b-lactam drug attaches to the specific penicillin binding proteins on the bacteria; cell wall synthesis is inhibited by blocking transpeptidation; autolytic enzymes are activated in the cell wall resulting in lesions and bacterial cell death.

Cephalosporins

Advantages: The greatest advantage of the cephalosporins are their relative resistance to staphylococcal penicillinase and somewhat broad antibacterial spectrum which includes P. mirabilis, E. coli, and Klebsiella (drugs of choice for Klebsiella).

MOA: Same as penicillins.

Characteristics: 1^st generation do not penetrate CSF; 2^nd-4^th generation penetrate CSF; as you advance thru the generation you gain G(-) coverage and lose G(+) coverage.

First-generation cephalosporins: Higher nephrotoxicity than subsequent generations.

1.      Cephalothin – Parenteral; agent of choice to treat staph infection (endocarditis)

2.      Cefazolin – Parenteral; effective against E. coli and Klebsiella; surgical prophylaxis.

3.      Cephalexin – Oral; acid-stable and well-absorbed.

4.      Cefadroxil – Oral; UTIs.

Second-generation cephalosporins

1.      Cefaclor – Oral; used for sinusitis and otitis media if allergic to amoxicillin.

2.      Cefamandole – Parenteral; good G(+), G(-), and anaerobic coverage; adverse effect on vitamin-K dependent clotting.

3.      Cefoxitin – Parenteral; good for anaerobes and mixed infections.

4.      Cefuroxime – Parenteral; passes thru BBB and useful in treatment of meningitis.

Third-generation cephalosporins

1.      Cefixime – Oral.

2.      Cefoperazone & Moxolactam – Adverse effect on vitamin-K dependent clotting; “don’t use this one.”

3.      Cefotaxime – Parenteral; good for multiple drug-resistant G(-) bacilli nosocomial infections.

Fourth-generation cephalosporins: Cefepime – Parenteral; excellent CSF penetration; active against G(+,-).

Adverse effects: Nephrotoxicity (1^st generation); bleeding problems (2^nd and 3^rd generation) due to methylthiotetrazole; disulfiram-like reaction. Superinfection may also be a problem with broad-spectrum (3^rd generation) cephs.

Hypersensitivity: Cephalosporins may demonstrate cross-allergenicity with the penicillins.

Summary: Cephalothin & cephaloridine (1^st generation) are good against endocarditis but nephrotoxic. Cefamandole (2^nd) and moxolactam and cefoperazone (3^rd) have bleeding problems due to methylthiotetrazole side group.

Carbapenems

Imipenem – Broad spectrum of activity that includes Pseudomonas, Actineobacter, and anaerobes (B. fragilis); given with cilastin to prevent inactivation by renal dipeptidase.

b-Lactamase Inhibitors

Clavulanic acid, Sulbactam & Tazobactam – Suicide inhibitors of b-lactamases. Clavulanic acid is used amoxicillin and is the treatment of choice for bite wound infections. Piperacillin/tazobactam sodium, Ticaricillin/clavulanate potassium.

Monobactams

Aztreonam – Resistant to b-lactamase; useful only for G(-); can lead to superinfection.

Miscellaneous

Cycloserine – MOA is inhibition of racemase; used in combination treatment of tuberculosis.

Vancomycin – MOA inhibits cell wall synthesis by binding the D-alanyl-D-alanine dipeptide in cell walls and thus inhibits peptidoglycan synthesis by interfering with transfer of the peptide. Bactericidal. Limited to treatment of S. aureus infections that are resistant to less toxic agents as well as C. difficile infections. Toxicities are like the aminoglycosides and include ototoxicity, peripheral neuropathies, and injection irritation.

Polypeptides

General: All are nephrotoxic and parenteral administration is reserved for special, difficult clinical situations.

Bacitracin – MOA is inhibition of cell wall synthesis by inhibiting pyrophosphatase reaction. Use is limited to topical application for treatment of staph infections. Intrathecal or intrapleural instillation reserved for treatment of resistant-penicillin Staphylococcal meningitis or empyema. Toxicities include nephrotoxicity and eosinophilia.

Polymixin B sulfate – MOA is disruption of cell plasma membrane. Main used is topical against G(-) bacilli. Effective against a host of organisms but toxicity is severe (curare-like effect, nephrotoxicity, phlebitis).

Colistin sulfate – Same as polymixin.

Drug interactions

Carbenicillin-Gentamicin – Antagonistic effect.

Penicillin-Chlortetracycline – Theory says no, practice says okay.

Ampicillin-Oral contraceptive – Breakthrough bleeding and loss of contraceptive power.

Cefoperazone/Moxolactam/Cefamandole-Alcohol – Disulfiram-like reaction.

Protein Synthesis Inhibitors

Gram-Positive Antibiotics – Macrolides

Erythromycin

MOA: Drug binds exclusively to the 50S subunit where it blocks the translocation step in which the peptidyl tRNA is shifted from the acceptor (A) site back to the peptide (P) site. Bacteriostatic.

Spectrum: Used primarily against G(+) infections in patients sensitive to penicillin. Also effective against G(-) N. gonorrhea, N. meningitidis, H. influenzae, B. pertussis.

Resistance: 1. Genetically altered ribosomal protein; 2. Decreased permeability to drug; 3. Induced resistance (unique to erythromycin, due to low dose). Resistance to one macrolide induces resistance to all.

Pharmacokinetics: Administered as an ester to reduce acid lability. Metabolized by liver, with high concentrations found in bile and feces. Erythromycin inhibits cytochrome p450.

Therapeutic place: Used when the patient is sensitive to penicillin. Used to treat Legionnaire’s disease, M. pneumoniae, pertussis, and as an alternate drug for Lyme’s disease and chlamydia.

Clarithromycin – Used to treat M. avium-intracellulare infections in AIDS patients as well as peptic ulcers caused by H. pylori.

Azithromycin – Used to treat M. avium-intracellulare and toxoplasmosis encephalitis in AIDS patients.

Broad-spectrum antibiotics – Lincosamides

Clindamycin & Clindamycin phosphate

MOA: Lincosamides bind exclusively to the 50S subunit and either inhibit the peptidyl transferase reaction and/or prevent translocation of tRNA from the A site to the donor site.

Spectrum: Mostly G(+), some G(-); clindamycin phosphate targets G(+,-) AND anaerobes (drug of choice).

Resistance: Erythromycin-resistant organisms are likely to be resistant to clindamycin.

Pharmacokinetics: Well absorbed in the GI tract. Metabolized by liver. Excreted by kidney and in bile.

Toxicity: Most common problem is severe and persistent diarrhea (pseudomembraneous colitis may occur).

Therapeutic place: Clindamycin and clindamycin phosphate are effective against anaerobes (specifically B. fragilis) and are alternate drugs for pneumococci, streptococci, and staphylococci.

Broad-spectrum antibiotics – Tetracyclines

MOA: Tetracyclines binds to the 30S subunit and prevent attachment of aminoacyl tRNA to the A site. They also inhibit the attachment of N-formyl methionine tRNA to the 30S subunit. Bacteriostatic.

Spectrum: First-line treatment of infection from Brucellae, Mima, and Bacteroides. G(+,-) coverage.

Resistance: Develops gradually. Mediated by R factor in G(-) bacteria.

Pharmacokinetics: Tetracyclines chelate calcium, magnesium, and aluminum. The various tetracyclines are cleared by glomerular filtration (except doxycycline).

Toxicity: Hypersensitivity; irritation of GI tract; superinfection; photosensitivity; liver damage; renal damage (due to outdated tetracyclines®Fanconi syndrome); vestibular reactions; damage to teeth, bones, and nails (don’t give to pregnant women or small children).

Therapeutic place: Broad spectrum, oddball-organisms.

Tetracycline – UTIs.

Minocycline – Lower renal clearance.

Broad-spectrum antibiotics – Chloramphenicol

MOA: Chloramphenicol prevents mRNA from binding to the 50S ribosome. Chloramphenicol also depresses the activity of peptidyltransferase. Net result is small incomplete fragments of protein. Bacteriostatic.

Selective toxicity: Inhibits protein synthesis in prokaryotes and eukaryotes.

Spectrum: Drug of choice only for S. typhii carrier state.

Resistance: R factor-mediated. May be due to acetylation of hydroxyl group.

Pharmacokinetics: Well absorbed from GI tract; hepatic metabolism is rapid; inactive conjugates are excreted in the urine (decreased renal function is no problem, decreased live function needs reduction in dose); excellent CSF diffusion as well as excellent diffusion intraocularly.

Toxicity: Dose-related bone marrow depression; dose-independent aplastic anemia; GI irritation; neurological problems; superinfection; gray baby syndrome

Drug interactions

Erythromycin-Clindamycin – Antagonism

Erythromycin-Penicillin – Synergism, antagonism, or antagonism.

Doxycycline-Carbamazepine/Phenobarbital/Phenytoin – Reduction in half-life of doxycycline due to induction of liver enzymes.

Chlortetracycline-Penicillin – Tetracycline derivatives may antagonize the bactericidal action of penicillin G under such conditions such as meningitis.

Tetracycline-Aluminum hydroxide/ferrous sulfate – Combination decreases absorption of tetracycline.

Tetracycline-oral contraceptives – Contraceptive failure.

Gram-Negative Antibiotics

Aminoglycosides

Resistance: R-factor mediated resistance resulting in 1. adenylation; 2. phosphorylation; 3. acetylation.

Pharmacokinetics: All are very poorly absorbed from GI tract (given before surgery for bowel sterilization); excreted almost entirely from the kidney via filtration; can reach very high levels in urine (alkaline environment improves effectiveness); do not pass thru BBB (although can be administered intrathecally).

Toxicity: Hypersensitivity (neomycin can produce contact dermatitis); curare-like effect on peritoneum; ototoxicity; nephrotoxicity.

Streptomycin

MOA: Streptomycin binds to the 30S subunit and blocks initiation of protein synthesis and causes misreading of the genetic code, resulting in synthesis of fraudulent proteins because of incorporation of false amino acids. Bactericidal/static depending on concentration.

Spectrum: Mainly used as an adjuvant in tuberculosis therapy. Also used for plague and in combination with penicillin against enterococci.

Resistance: Develops explosively.

Toxicity: 8^th nerve toxicity (vestibular), high frequency sounds are lost first; renal damage; curare-like effect; skin rashes.

Therapeutic place: Miliary tuberculosis, S. faecalis (with penicillin), uncommon infections (with tetracycline).

Neomycin – Bowel sterilization; nephrotoxicity and ototoxicity prohibit parenteral use; curare-like effect.

Gentamicin – spectrum similar to kanamycin and neomycin but more active against many strains of E. coli, Klebsiella, Proteus, and Pseudomonas; more active at alkaline pH; nephrotoxic and ototoxic (vestibular).

Tobramycin – Similar to gentamicin.

Amikacin – Reserved for infections resistant to gentamicin and tobramycin.

Viomycin – Second line drug in treatment of tuberculosis.

Netilmicin – New.

Spectinomycin – Not officially an aminoglycoside; indicated only in the treatment on N. gonorrhoea; takes just one dose; no renal or ototoxicity.

Drug interactions

Gentamicin-Carbenicillin – BAD combination.

Gentamicin-Cephalothin – Additive nephrotoxicity.

Gentamicin-Polymixin B – Increased nephrotoxicity.

Gentamicin/Kanamycin-Ethacrynic acid – Increased oxotoxicity.

Antituberculosis Drugs

Usual regimen: INH/rifampin/pyrazinamde and either ethambutol or streptomycin (4 drug combo)

Prophylaxis: INH for 12 mos.

Primary drugs: INH, pyrazinamide, rifampin, ethambutol, streptomycin

INH

MOA: Uncertain, but INH does inhibit synthesis of mycolic acid, a component of the cell wall.

Selectivity: INH is only effective against mycobacteria. Bactericidal.

Resistance: Develops rapidly. Mutants decrease catalase and peroxidase, increase mycolic acid synthesis, cleave off the hydrazine group from the drug with hydrazide enzyme (most common), or survive with less mycolic acid in their cell wall.

Pharmacokinetics: Acetylation occurs in the liver and is different between fast and slow acetylators. The slow inactivator is homozygous recessive. One of the toxicities of INH is pyroxidine (B6) deficiency and slow acetylators are more likely to suffer. Also, INH inhibits the metabolism of phenytoin, which can lead to toxicity in slow acetylators. Acetyl-INH is excreted in the urine.

Toxicity: Peripheral neuropathy reversed by vitamin B6 (due to drug competing with B6 for enzyme apotrytophanase); hepatitis seen during prophylactic use in those over 35 yrs old.

Therapeutic place: Treatment is aimed at the active state of Tb. Also used for prophylaxis.

Ethambutol

MOA: Unknown, but interferes with mycolic acid and RNA synthesis.

Toxicity: Optic neuritis (color blindness), loss of visual acuity, and retrobulbar neuritis.

Therapeutic place: M. tuberculosis, M. bovis.

Contraindicated: In children under 5 yrs old.

Rifampin

MOA: Rifampin inhibits DNA-dependent RNA polymerase (b subunit).

Spectrum: M. tuberculosis and G(+) organisms.

Toxicity: Turns body fluids orange (not harmful).

Pharmacokinetics: Rifampin induces p450 enzymes, thereby decreasing the half-lives of a number of drugs.

Pyrazinamde – Can cause liver damage and uric acid retention.

Second-line drugs: Cycloserine, viomycin, kanamycin, capreomycin, PAS, ethionamide

Cycloserine – Cell wall inhibitor, CNS toxicity.

Capreomycin – Renal and oxtotoxicity.

PAS – Bad shits.

Drug interactions

INH-Rifampin – Hepatotoxicity.

Rifampin-oral contraceptives – Decreased effectiveness of contraceptive.

Antileprosy Drugs

Dapsone – Sulfa drug; adjunct therapy with corticosteroids, aminoglycosides, or antimalarials may be helpful; can cause anemia and methemoglobinemia.

Amithiazone – Greater effect on tuberculoid form than on lepromatous form; substitute for patients intolerant of sulfones.

Clofazamine – Substitute; discoloration of the skin.

Rifampin – Hepatitis and inhibits metabolism of 35 drugs.

Thalidomide – Highly effective.

Ethionamide

Tx of M. avium complex – Rifabutin, macrolides, quinolones, clofazimine, amikacin.

Antiparasitic Drugs

Malaria: P. vivax (fever spike every 24-48 hrs), falciparum (irregular fever spike pattern, blood stage only), malariae (fever spike every 4^th day), ovale.

·       Stages – primary stage in liver for all four species; secondary stage is either erythrocytic (P. falciparum) or extraerythrocytic (stay in liver, other 3 species).

·       MOA of drugs – affect DNA synthesis or folic acid metabolism

Erythrocytic drugs effective against P. falciparum: Chloroquine, mefloquine, quinine

1.      Chloroquine – Inhibits DNA synthesis; effective against P. falciparum blood form; ocular and cardiac toxicities; hemolytic anemia in G6PDH deficient individuals; cures P. falciparum but has no effect on relapsing malarias (Pp. malariae, ovale, vivax); take once a week for two weeks before trip and six weeks after leaving.

2.      Mefloquine – Like chloroquine; can also be used prophylatically; contraindicated in epilepsy, psychiatric disorders, cardiac problems, and pregnancy.

3.      Quinine – Effective against P. falciparum; inhibits DNA synthesis; cinchoism (ototoxicity, GI toxicity, visual toxicity); blackwater fever; hemolytic anemia in G6PDH deficient; used in combination with pyrimethamine or sulfadiazine.

Extraerythrocytic drugs effective against PP. vivax, ovale, malariae: Primaquine

1.      Primaquine – Affects DNA synthesis in liver tissue; also inhibits electron transport; hemolytic anemia in G6PDH deficient; methemoglobinemia; radical cure of vivax, ovale, malariae.

Drugs useful in both stages: Pyrethamine, trimethoprimm sulfones, sulfonamides – All are folic acid inhibitors that act slowly (as opposed to above listed drugs, which act quickly).

 

Amebicides

Metronidazole – Tissue and lumenal amebicide; prodrug that when activated interferes with DNA synthesis; metallic taste; disulfiram-like reaction with alcohol.

Tetracycline, erythromycin, paramomycin – Indirect-acting lumenal amebicides; work by killing bacteria that provide amoeba with nutrition.

Diiodohydroxyquin & diloxanide furoate – Direct-acting lumenal amebicides.

Emetine – Tissue amebicide; “big gun.”

Other antiprotozoals

Suramin – Trypansomes.

Pentamidine – Trypanosomes, leishmaniasis, P. carinii (in AIDS patients intolerant to cotrimoxazole); administered as aerosol or IV.

Melarsoprol – Organic arsenic.

Stibogluconate – Antimony compound.

Nifurtimox

Quinacrine – Giariasis.

Metronidazole – Trichomoniasis.

Toxoplasmosis: Organism resides in cat feces and is dangerous to the fetus during pregnancy (death, blindness, retardation); treat with pyrimethamine, trimethoprim, or a sulfa drug.

Antihelminthics – Nematodes (roundoworms)

Piperazine citrate – Broad-spectrum effective against nematodes (ascariasis and pinworms); contraindicated in epileptics.

Thiabendazole – Treatment of trichinosis (undercooked pork)

Mebendazole – Anti-nematode.

Albendazole – Anti-nematode.

Pyrantel pamoate – Anti-nematode.

Antihelminthics – Trematodes (flukes)

Praziquantel – DOC; schistosomiasis; wonder drug; DO NOT use when ocular cysticerosis exists.

Antihelminthics – Cestodes (flatworms and tapeworms)

Niclosamide – Causes worms to relax their scolexes, thereby falling off the intestinal wall; does not kill tapeworm.

Paramomycin – Useful against tapeworms.

Antifungal Agents

Nystatin – polyene antibiotic

MOA: Increase permeability of the fungal membrane by disrupting or causing a reorganization of the sterol structure. Specifically, nystating causes the formation of pores by targeting ergosterol.

Selective toxicity: Mammalian RBCs and lysosomal membranes also contain sterols (anemia).

Pharmacokinetics: Used topically and vaginally.

Therapeutic place: Nystatin is used to treat Candida infectons of the skin, mucous membranes, and intestinal tract.

Amphotericin B – polyene antibiotic

MOA, selective toxicity: Same as nystatin.

Therapeutic place: Effective for treatment of deep fungal disease (pneumonia, bone infections, meningitis, and diseemination); also effective against leishmaniasis.

Toxicity: There are number of side effects (amphoterrible); nephortoxicity is most notable; dosage should not exceed 0.5 mg/kg daily, with total administration not exceeding 5 g. The lab must determine the MIC and plasma levels should be maintained at twice that value. Anemia is also common.

Ketoconazole – imidazole

MOA: Inhibits ergosterol synthesis

Therapeutic place: DOC for chronic mucocutaneous candidiasis and may be useful for onchomycosis and other resistant fungal infections.

Toxicity: Nausea, GI problems, hepatotoxicity, gynecomastia.

Itraconazole – less toxic than ketoconazole and broader spectrum

Miconazole – used OTC for athlete’s foot and jock itch; used systemically for serious infections; toxic includes cardiac arrhythmias, decreased hematocrit; enhances warfarin’s anticoagulant effect.

Fluconazole – used in treatment of cryptococcal meningitis and oroesophageal candidiasis in AIDS patients; potential for liver toxicity and Steven-Johnson syndrome; increases phenytoin levels.

Griseofulvin

MOA: Inhibits fungal growth by binding to microtubules responsible for mitotic spindle formation.

Therapeutic place: Useful against the dermatophytes and candida. Given by mouth to patients suffering from athlete’s foot or similar fungal infections of the skin or nails.

Pharmacokinetics: Absorption is increased by a fatty meal; drug is bound to keratin; long course necessary to achieve results (up to 12 mos for toenails).

Toxicity: Most common side effect is headache; lapses in memory have also been reported.

5-Fluorocytosine, Flucytosin, 5-FC

MOA: Prodrug. Must be deaminated to 5-fluorouracil by fungal cytosine deaminase. Interferes with both DNA and protein synthesis (miscoding).

Resistance: High

Toxicity: Low but can cause severe diarrhea and fatal bone marrow depression.

Therapeutic place: mainly for C. albicans and cryptococcus.

Potentiation: Amphotericin B potentiates the antifungal effects of 5-fluorocytosine (and rifampin).

Undecylenic acid & Tolnaftate – UA is a fatty acid possessing antifungal activity and is used for treatment of athlete’s foot. Tolnaftate is used in the treatment of a wider spectrum of dermatophytic infections.

Terbafinine – Allylamine; inhibitor of squalene 2,3, epoxidase, thereby inhibiting ergosterol synthesis; toxicities (minor) include diarrhea, headache, abdominal pain, and changes in taste patterns.

Drug interactions

Ketoconazole-aluminum hydroxide – decreases peak ketoconazole concentrations.

Phenobarbital-Griseofulvin – decreased serum levels of griseofulvin.

Griseofulvin – induces d-ALA synthetase®porphyria in susceptible individuals.

Griseofulvin-Warfarin – decreased effect of warfarin

Ketoconazole-Steroids – ketoconazole inhibits steroid biosynthesis leading to endocrine disorders.

Antiviral Agents

Stages in viral replication: Attachment and penetration (stage 1); uncoating (stage 2); components of virus are synthesized (stage 3); virus particles are assembled (stage 4); virus is released (stage 5).

Gamma globulin (IgG) – Assumed to block penetration of virus (stage 1); anaphylactoid shock should always be considered.

Amantadine & Rimantadine

MOA: Prevent viral uncoating (stage 2).

Toxicity: CNS (dizziness, confusion, seizures).

Therapeutic place: Antiparkinsonian agent; prophylaxis of influenza A2 virus.

Contraindications: Epileptics, pregnancy.

Idoxuridine – antimetabolite; (thymidine analogue)

MOA: Disrupts DNA synthesis (stage 3). Only active against DNA viruses.

Pharmacokinetics: Prodrug that must be triphosphorylated by virus. Inactivated by liver.

Toxicity: Associated with IV administration – hepatotoxic, teratogenic, mutagenic, carcinogenic. Minimal toxicity when used topically.

Therapeutic place: Only approved for treatment of HSV infections of the eyelid, conjunctiva, and cornea.

Vidarabine – antimetabolite; purine analogue

MOA: Inhibits viral DNAP (stage 3). Only effective against DNA viruses.

Pharmacokinetics: Topical and IV. Prodrug that must be metabolized to a triphosphate. Reduce dose if patient is taking allopurinol for gout.

Toxicity: Topical adminstration is okay. Systemically causes GI and CNS toxicity, hepatotoxicity, carcinogenic/teratogenic/mutagenic.

Therapeutic place: Used primarily for topical ophthalmic administration (HSV keratoconjunctivitis). Used systemically for HSV encephalitis. Effective against HSV, VZV, and vaccinia.

Interferon

MOA: Cellular cytokines with antiviral activity that bind to receptors to stimulate the synthesis of proteins that interfere with all stages of viral replication.

Therapeutic place: Useful for some melanomas, chronic hepatitis B & C, Kaposi’s sarcoma.

Acyclovir – antimetabolite; guanosine analogue

MOA: Inhibits DNAP (stage 3)

Pharmacokinetics: Prodrug that must be triphosphorylated. Excreted by the kidney (probenecid inhibits secretion).

Resistance: Becoming a problem.

Toxicities: Low

Therapeutic place: EBV, VZV, HSV keratitis, HSV

Gangiclovir – Used to treat CMV in AIDS patients.

Cidofovir – Antimetabolite; cytosine analogue; disphosphate is the active drug; nephrotoxicity limited with concomitant use of probenecid and IV saline.

Sorivudine – Antimetabolite; pyrimidine analogue; used to treat VZV; will cause severe bone marrow depression when administered with 5-fluorouracil.

Ribavirin

MOA: Inhibits viral RNA synthesis (stage 3)

Pharmacokinetics: Prodrug that must be triphosphorylated.

Toxicity: Death, diminished pulmonary function, and CV problems in patients with CHF.

Therapeutic place: Aerosol used to treat severe lower respiratory tract infections due to syncytial virus. Also used in combination with interferon to treat hepatitis C.

Trifluridine – Antimetabolite; thymidine analogue

MOA: Stage 3 inhibitor of viral DNA synthesis by virtue of its incorporation into viral DNA.

Pharmacokinetics: Topical agent only. Very short half-life (20-30 min).

Toxicity: Palpebral edmea and transient burning of the eyes.

Therapeutic place: Topical treatment of epithelial keratitis of HSV.

Contraindications: Pregnancy

Foscarnet

MOA: Inhibits RNA polymerase and reverse transcriptase (stage 3)

Pharmacokinetics: Deposits into bone (binds with calcium)

Toxicity: Hypocalcemia and hypomagnesia.

Therapeutic place: IV adminstration for CMV retinitis.

Drug interactions

Vidarabine-Allopurinol – severe neurotoxicity

Acyclovir-Probenecid – decrease in acyclovir elimination

HIV Antiviral Agents

Window period – Time from point of infection to point of detectability

Latent period – Time from point of infection to point of diagnosable infection

Detection of antibodies to virus – window period of 3 mos to 1 year; ELISA, EIA, and Western blotting; blood draw (1-3 wks), rapid (SUDS) available in 5-30 min, oral mucosa (OraSure), urine (less sensitive).

Detection of the virus – days to 2 wks; detection of RNA via PCR or branched chain DNA; detection of HIV viral protein (p24 usually done).

AIDS – 10^6 virus particles, <200 CD4+ T cells/mm^3

Advanced HIV infection – 10^6 virus particles, <50 CD4+ T cells/mm3 (susceptible to CMV and M. avium complex)

HAART therapy – 2 RTIs and at least 1 PI or Efavirenz (NNRTI). Results of therapy are expected to show 1 log unit decrease at 8 weeks and no detectable virus at 4-6 months after initiation of treatment. Failed therapy should change at least 2 agents that are not likely to show cross-resistance with drugs given previously.

The goal of HIV antiviral therapy is to get the HIV viral load as low as possible and keep it there as long as possible. The majority of therapies affect the virus directly (RTIs and PIs), although some do affect the host by limiting virus activity in host.

Life cycle of HIV and key points for potential therapy – 1. Binding to host cell (experimental); 2. RT; 3. Integrase (no drugs); 4. Protease; 5. Immune system stimulators (experimental); 6. Host ribonucleotide reductase.

Nucleoside analogues (NRTIs) – Prodrugs. Must be formed into triphosphate nucleotide to be incorporated into DNA. Administered orally, with bid dosing. Competitive inhibitors to reverse transcriptase at the nucleotide binding site.

·       Abacavir (ABC) – Good CSF penetration; life-threatening hypersensitivity.

·       Didanosine (ddI) – Pancreatitis, peripheral neuropathy; ddI decreases the absorption of any drug that requires gastric acidity for absorption; synergistic effects with any drug that causes pancreatitis or peripheral neuropathy.

·       Lamivudine (3TC) – Called Combuvir when combined with AZT; also used for treatment of hepatitis B; pancreatitis in pediatric patients.

·       Stavudine (d4T) – DO NOT COMBINE WITH AZT; additive effect with any drug that causes peripheral neuropathy (ddI, ddC, INH).

·       Zalcitabine (ddC) – TID dosing; peripheral neuropathy, pancreatitis, hepatitis (must monitor liver enzyme levels); additive effect with any drug that causes peripheral neuropathy.

·       Zidovudine (AZT) – Good CNS penetration; bone marrow suppression (anemia, neutropenia), myopathu, macrocytosis, hepatitis; antagonistic to d4T; marrow suppression precludes concurrent use with ganciclovir or other marrow suppressants.

Non-nucleoside analogues (NNRTIs) – These agents DO NOT require activation. Orally administered with. Cross-resistance DOES NOT develop between NNRTIs and NRTIs. Cross resistance DOES occur within class. Noncompetitive inhibitor of RT. Most metabolized in liver and excreted by kidney.

·       Delavirdine – Inhibits p450 enzymes; requires gastric acidity so caution with ddI.

·       Nevirapine – Severe but transient rash on trunk, face, and mucous membranes; induces p450 enzymes; reduces indinavir levels.

·       Efavirenz – Dizziness and “disconnected” feeling; induces p450; avoid clarithromycin.

Nucleotide analogues – Not FDA approved

·       Adefovir – Obvious CNS penetration; severe nephrotoxicity and CNS effects; induces p450; reduces indinavir levels.

·       Tenofovir

Protease inhibitors – Even in combination therapy resistance develops and it can be cross-resistance to compounds from within the same class.

·       Amprenavir – Excreted in feces; rashes, diarrhea, nausea; inhibits p450; rifampin decreases amprenavir levels dramatically; efavirenz lowers levels 40%.

·       Indinavir – Taken while fasting or with light, low-fat meal; biliary metabolism; dessication likely; kidney stones; lipodystrophy; inhibits p450; levels increased by delavirdine and nelfinavir; levels reduced by nevirapine and grapefruit juice; ddI reduces absorption

·       Lopinavir

·       Nelfinavir – Diarrhea; inhibits p450; biliary metabolism.

·       Ritonavir – Biliary metabolism; GI intolerance, paresthesias, taste perversions; potent inhibition of p450; ddI decreases absorption; increases levels of AZT and saquinivir.

·       Saquinavir – Fatal arrhythmias when used with cisapride; do not combine with indinovir; levels increased by grapefruit juice; levels increased by ritonavir.

Host’s ribonucleotide reductase

·       Hydroxyurea – Inhibits cellular ribonucleotide reductase, inhibiting formation of deoxynucleotides. This leads to induction of cellular kinases causing increased phosphorylation of NRTIs. Metabolized in liver and excreted in lungs and urine. Use only if ddI is being used. Considered salvage therapy. Bone marrow suppression, GI intolerance, and increased risk of neuropathy. Contraindicated in renal failure.

Bad combinations – d4T+AZT, ddC+ddI, ddC+d4T (peripheral neuropathy); ddC+3TC (resistance); NNRTI combinations (lack of known synergy)

Pregnancy – Only drug shown to reduce risk of perinatal HIV transmission is AZT. Initiated at 14-24 weeks of gestation and continued to onset of labor. IV AZT during labor until delivery. AZT for newborn for first 6 weeks of life beginning 8-12 hrs after birth.

Post exposure prophylaxis – Initiate therapy within 72 hrs (1-2 hrs if possible). AZT+3TC+indinavir/ nelfinavir. Check HIV RNA levels at 14 days and discontinue if undetectable.

Choosing an antibiotic

Sensitivity testing is a spectrum. Drug levels and availability should be 3-5 times the MIC.

Antibiotic failure – Wrong bug, wrong drug, wrong dose/route, wrong infectious disease, wrong diagnosis (primary, uncovered, nosicomial), hidden bugs (abcesses), protected bugs (CSF, eye, inside abcess, IV lines, prostheses), natural history (duration of therapy, slow response – Tb), host defense (bad meat), drug fever, factitious fever (bad brain), wonderful things (whole blood products, lines and catheters, prostheses).

General Anesthetics

Components of anesthesia – Amnesia, analgesia, relaxation.

Types of anesthesia

·       General – Describes a loss of sensory perception over the entire body. Requires the use of many different agents (narcotics, inhalation agents, muscle relaxants).

·       Regional – Describes a loss of sensory perception over a specific part of the body (spinal, epidural, axillary, ankle block). Local anesthetics are used.

·       Local – Describes a loss of sensory perception over a very small area of the body. Local anesthetics are used.

Phases of anesthesia – Induction (putting someone to sleep), maintenance, emergence.

Rules for differentiating amides and esters – Amides have an “i” before “-caine.”

MOA of local anesthetics – Block nerve conduction reversibly by blocking Na+ channels, which prevents depolarization and propagation of nerve impulses.

Conduction blocking factors

·       Lipid solubility – Determines anesthetic potency.

·       Degree of protein binding – Determines duration of action.

·       pKa – All anesthetics are weakly basic with pKa of about 8. Anesthetics can be manipulated by adding small amounts of bicarbonate at the time of administration. This drives the anesthetic toward the non-ionized form. The more non-ionized the anesthetic, the greater the diffusion across the membrane, which speeds the rate of onset.

Anesthetic use with epinephrine – Allows greater duration of anesthetic effect. Can lead to hypoxic necrosis in areas with reduced blood flow.

Complications

·       Traumatic injury to nerves

·       Infection

·       Bleeding

·       Tissue neurotoxic reactions

·       Hypoxic brain damage

·       Allergic reactions – To some amino esters due to release of PABA.

·       Systemic toxic reactions

New safer anesthetics – Compared with bupivicaine. Ropivicaine is structurally similar but doesn’t have the toxic effects (removed R enantiomer). Levo-bupivicaine has the bad stuff separated out.

Neuromuscular blockade – Muscle relaxants are necessary to facilitate intubation, provide muscle relaxation during surgery, and facilitate artificial ventilation. They act on two different cholinergic receptors: muscarinic and nicotinc.

Classes of muscle relaxants – Non-depolarizers and depolarizers (succinycholine)

·       Non depolarizers – Competitive inhibitors of acetylcholine at the receptor. Virtually all have “cur” in their names (cis-atricuronium & rapidcuronium). To reverse the blocking effects of these drugs, one must administer an acetylcholinesterase inhibitor such as neostigmine or edrophonium. Additionally, with the increase in acetylcholine that results from use of inhibitor, you will get increased muscarinic effects such as bradycardia and the potential for asystole, so one must give an anti-muscarinic such as atropine or glycopyrolate (preferred because it does not cross BBB).

·       Depolarizers – Bind to the receptor and cause fasciculations and then sit there for 5-10 minutes. Succinylcholine (metabolized by plasma pseudocholinesterase) is the only on used clinically but has numerous side effects:

o   Fasciculations – Prevent by giving a small dose of nondepolarizer (defasciculating dose).

o   Malignant hyperthermia – Treat with dantrolene.

Twitch monitor – Usually goes on ulnar nerve. The twitch monitor will NOT tell you how fully recovered the patient is. Train of Four – if no twitches, 95% or more of receptors are blocked; 1 of 4, 90% blockade; 2 of 4, 80%, 3 of 4, 75%; 4 of 4, 65%. The best it can tell you is that there are 2/3 of receptors still blocked. That is why the twitch monitor is used intraoperatively but not for signs of recovery.

Signs of recovery – Lift head up and hand grip (33% receptor block). Clinical signs are important.

Muscle relaxants – You don’t have to use them to intubate, but it makes things easier. Used to facilitate intubation and induction. Used to promote ideal conditions. Effects are monitored with an electric nerve stimulator and by observing clinical signs.

Stages and signs of general anesthesia – Stage I (analgesia); stage II (delirium); stage III (surgical anesthesia); stage 4 (medullary paralysis).

Bispectral index monitor – Measures the relative degree of anesthesia to prevent light anesthesia. Processed EEG (100 is wide awake). Signs of light anesthesia include body movement, increased heart rate and BP.

Inhalation anesthetics – Characteristics are controllability and non-specificity.

Factors that determine uptake of a volatile anesthetic – CO, solubility, uptake = [lambda·Q·(Pa-Pv)]/barometric pressure. Lambda is the blood:gas coefficient and is directly related to solubility

Potency – Measured by the minimum alveolar concentration (MAC). MAC of 1 is the concentration at which there is a 50% response to painful stimuli. MAC of 1.3 is the dose at which 100% of patients will not move. Supplement general anesthetic with NO unless contraindicated because NO has less effect on cardiac and pulmonary systems than inhalation agents.

Factors affecting MAC – Older age and pregnancy DECREASE MAC; alcohol abuse INCREASES MAC.

Side effects of inhalation agents – Increases respiratory rate, decreases tidal volume in a dose-dependent matter, overall a slight respiratory depression with a slight decrease in carbon dioxide.

·       Halothane – Nonflammable, as are all agents developed in the last 40 yrs; halothane hepatitis associated with repeated anesthesia, hypoxia, and female patients and due to reductive metabolism (which liberates fluoride); all can causes malignant hyperthermia (dantrolene is DOC for treatment of malignant hyperthermia); not used much anymore.

·       Isoflurane – Pungent, potent, and nonflammable; much better recovery profile than halothane (15 minutes); used for outpatient procedures; recently replaced by desflurane and sevoflurane.

·       Desflurane – Shortest recovery period so very useful in outpatient setting.

·       Sevoflurane – Now used in place of halothane in pediatric inductions (better profile).

·       Nitrous oxide – Only gas used to aid in general anesthesia.

IV anesthesia – Desirable characteristics include rapid onset, short duration, high clearance, minimal side effects, cost effectiveness, residual analgesia, and rapid recovery

Barbituates

·       Thiopental sodium – Potent, ultra short-acting, works in 5-10 sec; side effects include depression of circulation and ventilation; highly lipid soluble.

·       Methohexital

Non-barbituates

·       Etomidate – Imidazole; minimal cardiorespiratory depression; excellent for elderly patients and asthmatics (no histamine release).

·       Propofol – White milky substance; causes quicker emergence than barbs; heavily used in outpatient setting.

Note: Both barbs and non-barbs have no analgesic properties and no muscle-relaxing properties in normal doses.

Ketamine – PCP derivative; rich analgesic effects; increases heart rate and blood pressure (good for trauma patient); can produce nightmares.

Benzodiazepines – Far safer than barbs but strong potential for addiction; used as pre-anesthetic medications to reduce anxiety and produce some amnesia; no significant cardiorespiratory depression; NO analgesic properties either; work at GABA receptors in the amygdala, hippocampus, and prefrontal cortex; causes hyperpolarization thru opening of Cl- channels.

·       Diazepam (Valium) – Lasts 20-40 hrs; half-life is 1 hr per age of patient once over 60 yrs old; very addictive; very few depressive effects.

·       Lorazepam (Adavan) – Half-life of 10-20 hrs;

·       Midazolam (Verced) – Good preoperative drug.

·       Flumazenil – BENZODIAZEPINE RECEPTOR ANTAGONIST used to reverse effects of benzos; fast-acting and very selective.

Narcotics – Often given as a supplement to volatile anesthetics and contribute to the MAC. All narcotics cause a dose-dependent respiratory depression.

·       Fentanyl – 100x more potent than morphine; minimal cardiac depression; must be given IV; works for 90 min; no histamine release.

·       Sulfentanyl – 1000x more potent than morphine; no histamine release.

·       Meperidine (Demerol) – Atropine-like structure; 1/10 as potent as morphine; rarely used due to interaction with MAO inhibitors (LETHAL).

Novel agents

·       Remifentanil

·       Toradol – NSAID that is nearly as potent as morphine; no respiratory depression; affects bleeding profile.

·       Ondansetron – Potent anti-emteic used for chemo patients and in the OR with nausea-associated narcotics and general anesthetics; 5-HT subtype 3 antagonist.

Local Anesthetics

MOA: Local anesthetics bind to a receptor near the intracellular edge of the pore of the Na+ channel and block the channel in a time- and voltage-dependent fashion. Sodium permeability is reduced. Blockage of the nerve impulse propagation can occur without a significant change in the RMP. Because activated (open) and inactivated (depolarized) Na+ channels have higher affinity for local anesthetics than resting (repolarized) channels, a given concentration of local anesthetic tends to have greater effects on rapidly firing axons and those with longer AP. Slightly depolarized neurons are more susceptible to local anesthetics than hyperpolarized neurons. Increases in extracellular calcium antagonize local anesthetic action, while elevated extracellular potassium enhances efficacy. Anesthetics stabilize the inactivated state.

Effect of pH: Local anesthetics are weak bases (pKa 8-9). It is the uncharged form that penetrates the lipid membrane of the axon, but it is the charged form that binds inside the channel to produce anesthetic action. In the body, most anesthetics are charged. Thus, the rate of conversion from the charged to the uncharged form and the lipid solubility of the uncharged form are limiting factors with respect to penetration of the drug.

Structure-activity relationship: Potency is correlated with lipid solubility.

Differential sensitivity to nerve block: The smaller B and C fibers are generally affected before A fibers. Type A d fibers are blocked before type A a fibers. Pains fibers are blocked early, other sensations are affected next, and motor function is the last to disappear. Recovery occurs in the reverse order with motor function first and pain sensation last. This effect is due to the smaller diameter of pain fibers and relatively longer AP duration. With infiltration of a large nerve, sensation would be lost first over proximal areas and then distally as the drug penetrates the nerve.

Chemical structures: Most local anesthetics contain three groups – lipophilc group, intermediate chai (ester or amide linkage), ionizable (hydrophilic) group. Ester-linked local anesthetics are more likely to produce hypersentivity reactions than the amide-linked compounds.

Pharmacokinetics: When blocking large nerves for regional anesthesia, the order of maximal blood levels is intercostals>caudal>epidural>brachial plexus>sciatic nerve. The presence of a vasoconstrictor retards absorption by decreasing blood flow to and away from the injection area (greatest prolongation seen with procaine and lidocaine). The toxic effects of the drug are reduced in the presence of vasoconstrictors because the blood concentration may be decreased. Cocaine produces vasoconstriction, while the others all show some vasodilation. Amide-linked anesthetics are widely distributed and taken up by most tissues. Ester-linked agents are metabolized very rapidly by plasma butyrylcholinesterase and secondarily by liver esterases. Cholinesterase inhibitors may increase the possibility of toxicity. Amides are normally cleared by hepatic microsomal metabolism. Patients with impaired liver function or reduced hepatic blood flow will be more susceptible to amide toxicity. Propanolol may prolong the half-life of lidocaine.

Esters – Short half-lives, hypersensitivity reactions, injectable, NOT SURFACE

·       Procaine – Prototype; short-acting; poorly absorbed from mucous membranes; requires injection; used for infiltration and nerve block; hydrolysis produces PABA, which may interefere with sulfonamides NOT TOPICAL.

·       Cocaine – Surface anesthesia of the respiratory tract, NOT EYE; significant CNS stimulant action; blocks catecholamine uptake; toxicity produces pyrexia.

·       Chloroprocaine – Least toxic; short-acting; contraindicated IV due to thrombosis; NOT TOPICAL; motor and sensory deficits.

·       Tetracaine – Long-acting; topical or spinal anesthesia

·       Benzocaine – Topical (creams and ointments); use on denuded areas due to poor absorption.

Amides – Longer-lasting than esters, efficiently absorbed from mucous membranes, all routes except eyes.

·       Lidocaine – Intermediate-acting; more prompt, more intense, longer-lasting than procaine; less likely to produce hypersensitivity; all routes except eyes.

·       Prilocaine – Intermediate-acting; rapid hepatic metabolism; use during labor and delivery may result in methemoglobinemia.

·       Bupivacaine – Long-acting; injectable; not effective on surface; more cardiotoxic than others.

Toxicology: Reactions due to rapid absorption of drug into the vascular system. Convulsions are best treated with IV diazepam. CNS: Global excitation due to depression of inhibitory pathways. CV: Decrease electrical excitability, conduction velocity, and force of contraction of myocardium,. Most also cause arteriolar vasodilation. Sufficienct amounts can cause severe hypotension, CV collapse and death from cardiac arrest and depression of pacemaker tissue or sudden onset of ventricular fibrillation. Allergic reactions: Reactions to esters due to liberation of PABA. Blood: Prilocaine can cause methemoglobinemia.

Therapeutic application: Infiltration anesthesia is injection of the drug into tissue without taking into consideration the course of cutaneous nerves. Epidural anesthesia requires a relatively large amount of agent. Spinal anesthesia usually results in altered CV function and headache due to loss of CSF.

Headache

Classification: Prevalence of migraine and tension headaches is 3 times higher in females than males; cluster headaches are 4-10 times more prevalent in males. Migraines and cluster headaches are referred to as vascular headaches while tension headaches are known as muscle-contraction headaches.

·       Classical migraine: Preceded by prodromal aura. Pain is throbbing or dull ache, frontotemporal, usually one-sided, and accompanied by nasusea and vomiting. Digital-lingual syndrome ipsilateral to headache. Duration is hrs to 1-2 days.

·       Common migraine: No aura.

·       Cluster headaches: Horton’s syndrome. Constant, unilateral orbital (sometimes temporal) pain with onset 2-3 hrs after falling asleep (REM sleep). Very intense and steady pain with autonomic symptoms. Most severe type of headache. Duration of 1-2 hrs recurring nightly for several weeks or mos. Episodic is 2 attacks per day for 4-12 wks with remissions of months or years. Chronic is attacks occurring for a year or longer and diminished periods of remission. Associated with heritable factors and lifestyle (smoking and drinking).

·       Tension headaches: Common everyday headache responding to NSAIDs or chronic recurrent or long-duration headache not responsive to NSAIDs. Pain is usually bilateral, often diffuse and may consist of various sensations. Chronic tension headache is often associated with depression and anxiety.

Mechanisms: Pain sensitive structures in head. Anterior pain is mediated by CN5, while posterior pain is mediated by CN9, 10, and C1-C3. Serotonin is definitely involved in migraine, tension, and cluster headaches. Noxious event causes vasoconstriction and then vasodilation.

Acute drugs – vasoconstrictors used for migraines and clusters

·       Ergotamine tartate & dihydroergotamine – Most effective treatment; oral, IV, sublingual, rectal; to avoid rebound 48 hrs should elapse between doses; DHE used IV for emergency termination.

MOA: Agonist activity at 5-HT1B and 5-HT1D; marked vasoconstrictor effects at aa. and vv.

Pharmacokinetics: Caffeine increases absorption; high first-pass effect; low oral bioavailability

Side effects: Nausea and vomiting (controlled by metaclopramide or phenothiazine); can cause severe vasoconstriction of extremeties (gangrene); dependency

Contraindications: Pregnancy, peptic ulcer disease, hepatic or renal disease, CVD.

·       Sumatriptan – 5HT1 agonist; used in treatment of acute migraine; fewer side effects than ergots; rebound headache may be more likely than with ergots.

MOA: Selective for 5HT-1 receptors (most potent at 1B and 1D). Results in vasoconstriction and inhibition of release of proinflammatory molecules.

Side effects: Coronary vasospasm when given IV; DO NOT use concurrently with ergots.

Contraindications: Angina, MI, severe hypertension.

·       Isometheptene – Sympathomimetic vasoconstrictor used in combination with acetominophen and dichloralphenazone for oral administration.

Acute drugs – analgesics used for acute migraines, clusters, and tension headaches

·       NSAIDS

·       Opioids

Prophylactic drugs

·       Methysergide – Migraines and cluster prophylaxis

MOA: Ergot alkaloid that is a mixed agonist/antagonist. Prophylactic actions presumed due to 5-HT1 antagonist activity, which causes vasodilation and prevention of noxious event.

Side effects: Fibrosis

Contraindications: Same as ergots

·       Propanolol – Preferred agent for migraine prophylaxis; agents with sympathomimetic activity (pindolol, acebutolol) are NOT effective. Inhibition of prostaglandin synthesis.

·       Ca2+ channel blockers – Migraine prophylaxis; 6-8 wks for therapeutic effect.

·       a2 Adenoreceptor agonists – Migraine prophylaxis in Europe (clonidine & gunabenz).

·       NSAIDs – Migraine and cluster prophylaxis; inhibition of prostaglandin synthesis.

·       Sedatives & antianxiety agents – Prophylaxis of tension headaches (diazepam)

·       Antidepressants – Prophylaxis of migraine and tension headaches (DOC). Mostly TCAs (amitriptyline).

·       Ciproheptadine – Migraine prophylaxis. Antihistamine, antiserotonin. Useful in children.

·       Lithium – DOC for prophylaxis of clusters.

·       Corticosteroids – Useful for cluster headaches. Short course helpful in termination and preventing chronic episodes.

·       Other treatments – Oxygen therapy, dietary and lifestyle changes, menstrual cycle (associated with migraines but not clusters).

Nonnarcotic Analgesics

COX enzymes: COX-1 constitutively expressed in all tissues; functions as a housekeeping enzyme. COX-2 enzymes expressed only in the brain; expression is induced by cytokines and prostaglandins produced by COX-2 are responsible for resetting body temp, sensitization of pain receptors, and vasodilation. Inhibition of COX-2 responsible for therapeutic effects of NSAIDs. Inhibition of COX-1 responsible for side effects of NSAIDs. IC50 is the concentration of an agent that inhibit 50% of enzyme activity.

Salicylates (aspirin) – Analgesic, anti-pyretic, anti-inflammatory, and anti-platelet properties

Chemistry: Weak acid pKa 3.5

Analgesic action: Relieves low to moderate pain from integumental structures. Hollow viscera are less responsive. Peripheral analgesic effect produced by inhibition of the synthesis of prostaglandins and thromboxanes in inflamed tissues. Potent inhibitors of COX-1 and far less potent at COX-2.

Anti-pyretic action: Lowers elevated body temperature. Does not reduce exercise-induced hyperthermia.

Anti-inflammatory effects: Inhibition of prostaglandin and thromboxane synthesis is the mechanism of anti-inflammatory action. Higher doses required. COX-2 plays a bigger role in inflammation than does COX-1. Aspirin does not inhibit the formation of leukotrienes via the lipoxygenase pathway.

Antiplatelet effect: Prolongation of bleeding time. Aspirin covalently acetylates (irreversible) a serine at the active site of platelet cyclooxygenase, thereby reducing formation of thrmoboxane A2. Aspirin should be avoided in patients with severe hepatic damage, hypoprothrmobinemia, vitamin K deficiency, or hemophilia.

Effects on organ systems

·       Respiration: Stimulate respiration directly and indirectly. High doses depress respiration and cause respiratory acidosis. Respiratory alkalosis occurs during mild poisoning. Indirect effect due to uncoupling of oxidative phosphorylation.

·       Acid-base balance and electrolytes: With severe toxicity respiratory acidosis and metabolic acidosis can occur simultaneously (low pH, low HCO3-, normal PCO2). Dehydration may occur due to sweating and vomiting. Hypokalemia can result from respiratory alkalosis.

·       GI tract: Exacerbation of peptic ulcers, GI hemorrhage, and erosive gastritis may occur in patients on high-dose therapy. Involves inhibition of prostaglandin synthesis, which protects gastric mucosa.

·       Kidney: Low doses (2 g or less) decrease urate excretion by competing with urate. Decreased renal blood flow due to inhibition of PGE synthesis

·       Blood: Antiplatelet

·       Metabolism: Uncoupling of oxidative phosphorylation. Pyrexia occurs at toxic doses.

·       CNS: In toxic doses, slaicylates produce CNS stimulation followed by depression. Dizziness, tinnitus, high tone deafness.

Pharmacokinetics: Highly bound to plasma proteins (decreased binding with increasing age). Metabolism takes place in liver. Metabolims shows mixed-order kinetics (half-life 3-6 hrs in low doses, 15-30 hrs high doses). Excreted in urine as free and conjugated metabolites. Alkalinization of urine can markedly enhance clearance.

Toxicology: Mild chronic salicylate intoxication (salicylism) causes skin eruptions, hyperthermia, and dehydration. Treatment of acute poisoning must be immediate (gastric lavage, emesis, bicarbonate to promote excretion). Hypersensitivity reactions occur. Contraindicated for long periods during pregnancy due to thrombotic effects and prostaglandin inhibition.

Drug interactions: Due to salicylate-induced displacement from plasma proteins (warfarin) and anticoagulant action (vitamin K, ethanol, anticoagulants).

Usage: Antipyretic (300-600 mg every 4 hrs); analgesic (300-600 mg every 4 hrs, can lead to loss of effectiveness and rebound headache); anti-inflammatory (4 g daily for RA, SLE sx); antiplatelet; closure of patent ductus arteriosus.

Reye’s syndrome: Do not give to children suffering from influenza and chicken pox (fatal hepatic necrosis).

Acetominophen – Analgesic and antipyretic; not anti-inflammatory.

Toxicology: Dose-dependent, potentially fatal hepatic necrosis. Renal tubular necorsis may also occur. If glutathione stores are depleted by large amounts of metabolites resulting from toxic doses, then hepatic damage ensues. N-Acetylcysteine (Mucomyst) is effective if given less than 24 hrs after ingestion.

Therapeutic use: Antipyresis and mild analgesia.Used for individuals allergic to aspirin, those with gout, hemophilia, or peptic ulcers.

NSAIDs

Technically includes aspirin, but generally refers to aspirin substitutes.

Pharmacology: Anti-inflammatory (inhibition of prostaglandin synthesis); analgesic (variable); antipyretic (variable); antiplatelet (cyclooxygenase inhibition that is reversible); inhibition of prostaglandin synthesis  (mostly COX-1, some COX-2 and/or lipoxygenase).

Pharmacokinetics: Protein-bound; hepatic metabolism; half-life 1-5 hrs (ibuprofen, indomethicin, flurbiprofen, ketoprofen); half-life >10 hrs (diflunisal, suldinac, naproxen, carprofen, piroxicam);

Adverse effects

·       GI toxicity: Dyspepsia, bleeding, ulceration, perforation (misoprostol used to prevent ulceration; H2 antagonists also helpful).

·       Fluid retention: Due to inhibition of PGE synthesis leading to decreased renal blood flow (aspirin, indomethicin, phenylbutazone).

·       Nephrotoxicity

·       Hypersensitivity: Contraindicated in patients with nasal polyps, angioedema, or bronchospastic response to aspirin.

·       Blood dyscriasis: Agranulocytosis and aplastic anemia (phenylbutazone).

·       CNS effects: Tinnitus, dizziness, anxiety, drowsiness, confusion.

·       Hepatic toxicity

·       Dermatological: Steven-Johnson syndrome.

Drug interactions: Reduced effects of antihypertensives and diuretics; increased lithium or methotrexate toxicity; potentiation of anticoagulants; displacement of protein-bound drugs; phenylbutazone mya inhibit or induce microsomal enzymes.

Ibuprofen – Inhibits COX-1/2 approximately equally. Elederly patients and patients with CAD are at risk for ibuprofen-associated renal impairment; may be used to reduce risk of Alzheimer’s disease.

Indomethacin – High incidence of dose-related toxic effects; inhibits COX-1>2; may reduce leukotriene synthesis; severe headache is a common side effect; used to treat several condition and to promote closure of patent ductus arteriosus; contraindicated in pregnancy; reserved for later use.

Ketoprofen – Inhibits both COX and lipoxygenase; used for OA and RA; does not alter warfarin or digoxin activity.

Ketorolac – IV; strong analgesic.

Naproxen – Long half-life; especially effective for termination and prevention of migraine.

Phenylbutazone – Oldest and most toxic NSAID.

Piroxicam – Longest half-life.

Sulindac – Prodrug that must be converted to sulfide in liver; long half-life (enterohepatic circulation).

Disease-modifying anti-rheumatic drugs – There is currently a trend toward earlier use of the disease-modifying drugs, especially methotrexate.

Gold – Retards or prevents progression of bone and articular erosion in some patients. Gold salts are highly protein bound. Renal tubular epithelial cells have a very high affinity for gold. Gold cannot be given with penicillamine, since penicillamine will chelate and remove the gold. The most common side effects are stomatitis, rash, and proteinuria. Gold treatments must be stopped with development of nephrosis, thrombocytopenia, leukopenia, or exfoliative dermatitis.

Penicillamine – Sulfur-containing AA analog useful as a heavy metal chelator (Wilson’s disease). Penicillamine can retard progression of bone and articular destruction, but usefulness is limited by serious toxicity. Most deaths are due to aplastic anemia. Teratogenic.

Methotrexate – Approved for treatment of RA. Immunosuppressant/antimetabolite (folate antagonist).Side effects include hepatic fibrosis, pneumonitis, bone marrow depression, GI ulceration and bleeding. Aspirin and NSAIDs may increase toxicity by slowing excretion.

COX-2 Inhibitor

Celecoxib – Less effective as an analgesic; adverse effects include abdominal pain, diarrhea, dyspepsia, renal toxicity, and GI toxicity; celcoxib inhibits p450 CYP2D6, thereby increasing concentration of b-blockers, antidepressants, and antipsychotics.

Gout

Causes: Increased production or decreased excretion of uric acid.

Pathophysiology: Acid pH promotes precipitation of urate. Leukocytes are damaged by urate, bursting and emptying contents (PGIs, lysosomes, IL-1) into joint tissue. This results in inflammation and propagation of a vicious cycle.

Risk factors: Thiazide diuretics, aspirin, blood diseases, obesity, heavy alcohol intake.

Treatment of acute attack is different than treatment of hyperuricemia.

Colchicine – only effective in gouty arthritis; not analgesic; rapid relief of acute attacks; also effective for prophylaxis; reserved for those who cannot tolerate NSAIDs.

MOA: Binds to tubulin causing depolymerization and disappearance of microtubules in motile granulocytes. Breaks inflammatory cycle by inhibiting leukocyte migration.

Toxicity: Since inhibitory to mitosis, toxic in rapidly proliferating cells such as intestinal epithelium. Long-term therapy may cause marrow depression, myopathy, neuropathy.

NSAIDs (indomethacin, naproxen, sulindac, ibuprofen, fenoprofen) – Preferred treatment for acute attacks. Can also be used for prophylaxis.

Allopurinol – Used to treat hyperuricemia

MOA: Inhibits conversion of hypoxanthine and xanthine to uric acid, thereby reducing production of uric acid. Competitive inhibitor at low concentrations and non-competitive at high concentrations. Converted to alloxanthine, which also is a noncompetitive inhibitor of xanthine oxidase.

Therapeutic place: Stops formation of uric acid stones. The incidence of acute gouty attacks frequently increases during the first months of tx, probably due to mobilization of urate from stores.

Pharmacokinetics: Alkalinization of the urine and increased fluid intake can aid in excretion.

Toxicity: Hypersensitivity is most common. Caution in patients with poor kidney function.

Drug interactions: Enhances effect of probenecid and mercaptopurine toxicity. May interfere with metabolism of oral anticoagulants.

Urosuric agents: Probenecid & Sulfinpyrazone – Both inhibit reabsorption while not affecting excretion of urate. Levels must be high enough, otherwise opposite becomes true. Aspirin inhibits action of both drugs.

Other drugs: Glucocorticoids, strong analgesics

Therapeutic indications

·       Acute attack: NSAID (indomethacin/ibuprofen), colchicine for refractory episodes, steroids, analgesics.

·       Long-term treatment and prevention: Prophylaxis with low-dose colchicine or indomethacin; urosuric agent; allopurinol; adequate fluid intake; weight reduction, diet modification (no shellfish, sardines, liver), reduce alcohol.

Pharmaceutical Considerations in Treating Very Young and Geriatric Patients

Very young – The placenta is a site of metabolism for many drugs.

·       Drug absorption – The placental barrier is similar to the BBB. Warfarin is teratogenic; heparin is not. In neonates, the gut has higher pH and less bacteria, the skin is more absorbent, and IM injections are variable.

·       Drug distribution and metabolism – Theophylline levels are much higher due to less blood protein available for binding (higher amount of free drug available). Theophylline will actually be metabolized to caffeine in the neonatal liver. Chloramphenicol will have decreased conjugation, leading to longer half-life and gray baby syndrome.

·       Drug elimination and pharmacodynamics – Many antibiotics are excreted unmetabolized by the kidney so renal status affects blood levels. Digoxin is excreted in its active form in the neonate (much longer half-life – 60-70 hrs), and the neonatal heart is much less sensitive to the effects of digoxin (combats increased half-life).

·       Other issues – Accuracy of dosing, caretaker compliance, dosage is calculated by surface area rather than weight.

Geriatrics­ – Problems due to decreasing organ function (homeostenosis) and polypharmacy.

·       Pharmacokinetics – Stomach pH increased, leading to less metabolism of levodopa (good thing). Decreased blood flow to organs leads to decreased liver metabolism and decreased renal excretion. Increased body causes storage of lipophilic drugs like diazepam, lidocaine. Decreased albumin, leading to increased free levels of warfarin, phenyotin, narcotics. Increased a-glycoprotein, leading to decreased free levels of basic drugs. Decreased body water causes increased concentration of water-soluble drugs such as procainamide, acetaminophen, ethanol. Liver metabolic enzymes decrease (phase 1 mixed function oxidase reactions before phase 2), so drugs with a high first-pass effect (propanolol, diazepam) have longer half-lives (warfarin, ethanol, and digitoxin are NOT affected). Decreased kidney function (decreases 1%/yr after age 50, decreased creatinine clearance) leads to increased half-lives of drugs like digoxin, which are not metabolized in the liver.

·       Pharmacodynamics – Sensitivity can increase (opiate, benzodiazepines, antipsychotics) or decrease (b-adrenergics).

·       Other issues – Compliance, fear, comorbidities, polypharmacy.

Narcotic Analgesia

Analgesia: Placebo effect may significantly influence the overall response to pain. Other modalities are relatively unaffected. Dull pain is more effectively treated than sharp pain. Sleep is not essential for analgesic effect. Analgesia can occur without other impairment. Pain antagonizes many effects of the opioids (e.g., respiratory depression). Change perception to pain, change reaction to pain, raise pain threshold. Opioids have a greater effect on nociceptive pain than on neuropathic pain.

Opioid receptors: Mu (m) – Most important receptor; morphine; supraspinal and spinal analgesia; respiratory depression; mioisis; euphoria; reduced GI motility; physiacal dependence; Kappa (k) – Primarily spinal analgesia; dynorphin; miosis; respiraotyr depression; dysphoria; psychomimetic; Delta (d) – Spinal analgesia; enkephalin; reinforcing effects; Sigma (s) – Dysphoria & hallucinations (PCP site of action).

Mechanism of opioid receptors: G-protein coupled; reduce synthesis and action of camp; activates K+ channels and inhibits Ca2+ channels; result is hyperpolarization and inhibition of transmission. Also causes depression of neutrotransmitter release.

CNS effects: Sedation; mood changes; nausea and vomiting; respiratory depression due to decreased responsiveness of brainstem to CO2, also a depression of pontine and medullary centers associated with respiratory rhythm, histamine release and direct constriction of bronchiolar smooth muscle (don’t give to asthmatics); miosis (mu and kappa);  antitiussive effect in doses below those needed for analgesia; ADH release leading to water retention; excitatory effects especially in kids; convulsions (mu and delta).

CV effects: Orthostatic hypotension in patients with reduced blood volume.

Effects in pulmonary edema: Reduces edema by effects on CV system as well as reduced anxiety leading to decreased sympathetic tone.

CSF pressure: Increased secondary to increased pCO2. Head injury is a relative contraindication to morphine.

GI effects: Delayed stomach emptying, delayed passage of contents thru GI, antidiarrheal and constipating due to presence of mu and delta receptors on smooth muscle and/or plexus neurons; tolerance does not develop.

Biliary tract effects: Contraction of bile duct and sphincter of Oddi resulting in increased biliary and pancreatic duct pressure. Mixed agonist-antagonists do not cause this effect.

Brochial effects: Histamine release, direct constriction, depression of respiratory drive and suppression of cough reflex ® bad for asthmatics.

Renal effects: Decreased urine output.

Hypothamalic effects: Change heat-regulating mechanisms leading to decreased body temperature.

Neuroendocrine (mu): Decrease LH, FSH, ACTH, b-endorphin; increase prolaction, ADH.

Ventral tegmentum: Euphoria (mu, delta); dysphoria (kappa)

Tolerance: Does not develop to miosis, constipation, or convuliions, nor does it develop to the antagonistic effects of nalaxone.

Pharmacokinetics: Oral:parenteral potency – methadone, codeine>meperidine, pentazocine>morphine. Morphine does not readily cross the BBB and is present in only small amounts in breast milk; opposite is true for heroin. Metabolism is primarily by glucuronide conjugation with marked first-pass effect (morphine). The metabolite formed is active.

Strong agonists

·       Morphine

·       Heroin – More potent than morphine and better access to CNS (lipophilic).

·       Medperidine – Mu agonist; anti-muscarinic actions but less constipating than morphine. Is not antitussive. Used during labor because has no adverse effects on labor time. Seizure-producing (no MAOs).

·       Methadone – Longer half-life than morpine. Same side effects as morphine (lots of GI activity). Strong mu agonism. Cross-tolerance between methadone and other opioids.

·       Fentanyl – Analogs of meperidine. Short duration of action. Good for post-operative analgesia. More potent than morphine. No histamine release.

Moderate agonists

·       Codeine – Antitussive. Less potent and less efficacious than morphine. Excitatory effects in some children.

·       Propoxyphene – Has efficacy and potency somewhere between aspirin and codeine. No antitussive action.

Mild agonists (antidiarrheals) – Diphenoxylate & Loperamide

 

Partial agonist – lower addictive liability and fewer side effects; more psychomimetic activity

·       Buprenorphine – Partial mu agonist/kappa antagonist; more potent than morphine but less efficacious (maximal effect decreased); scheduled drug; may be useful in opiate detoxification.

Agonist-antagonists (mixed) – lower addictive liability and fewer side effects; more psychomimetic activity

·       Petazocine – Kappa agonist; disappointment; has similar respiratory effects to morphine; anxiety/nightmares; contraindicated in cardiac patients (increases workload).

·       Butorphanol – Kappa agonist/mu antagonist; more potent than morphine; low abuse potentital; psychmimetic effects; contraindicated in cardiac patients (increases workload).

·       Nalbuphine – Can be used in cardiac patients.

Pure antagonists – Used for narcotic poisoning, reducing side effects of opioids, reversal of neonatal respiratory distress, opioid addiction treatment, treatment of alcoholism (naltrexone reduced craving).

·       Naloxone/Naltrexone – Short duration of action; NOT good for barbituate poisoning because it is specific for opioid receptors; treatment for alcoholism; liver function must be monitored; naloxone is DOC for treatment of opioid poisoning.

Antitussive – Dextromethorphan – Not active at opioid receptors; works at central cough site.

Drug Dependence

High abuse potential: Amphetamine/cocaine, opiates, hallucinogens.

Dispositional (metabolic) tolerance – Pharmacokinetic. Less drug gets to the site of action due to metabolism or distribution change. Continuous use.

Pharmacodynamic (functional) tolerance – Decreasing effects cannot be explained by change in metabolism or distribution. Same amount of drug gets to site of action, but changes in tissues or cells result in decreased response to drug. Doing interval is important. Continuous use.

Behavioral tolerance – Individual learns to compensate for effects of drug. Occurs with occasional use.

Degree of tolerance – Depends on doing interval, dose level, type of tolerance, and duration of treatment.

Requirements for production of physical dependence – Dose interval (continuous), dose level (sufficient depression of function), duration of treatment. Shorter-acting drugs have more intense withdrawl symptoms upon termination of administration.

Opioid tolerance – High degree of cross-tolerance. No tolerance to miosis, constipation, or excitatory effects. Withdrawal symptoms include lacrimation, rhinorrhea, sneezing, yawning, other muscarinic effects, and kicking movements. Opioid withdrawl is not life-threatening, except in newborns. Methadone and clonidine (autonomic symptoms) are used to suppress withdrawl symptoms during detoxification. Ultra-rapid opiate detoxification has been attempted with naltrexone. Maintenance therapy is administered using methadone orally. Acetylmethadol is also used for maintenance therapy as it is long-acting. Buprenoprhine (partial agonist) may be able to substitute for opiates and blocks the euphoria of opiates. Treatment of neonatal withdrawl involves methadone and diazepam in some cases. Clonidine is also used.

CNS depressant tolerance – The lethal dose (death by respiratory depression) is not much greater in addicts than in non-tolerant individuals. Tolerance develops to the psychic and motor effects but not to the respiratory depressing effects. Withdrawal from these agents is much more severe and life-threatening than withdrawal from opiates. Symptoms of withdrawal include hyperexcitability that can progress to seizures and status epilepticus. Abrupt withdrawal of short-acting agents can be fatal. A common approach to treatment of withdrawal us to suppress withdrawal with pentobarbital or Phenobarbital and then gradually reduce the dose. Diazepam is given to substitute for short-acting benzodiazepines and then gradually withdrawn.

Hypnotics & Antianxiety Agents

Hypnosis is the induction of a state of drowsiness and facilitation of the onset and maintenance of sleep from which the patient can be aroused (sedation®hypnosis®anesthesia®coma®death).

General drug effects: Barbituates and alcohol strongly depress sleep latency REM sleep. Benzos strongly depress non-REM sleep (stages 3 & 4) as well as REM sleep and latency When hypnotics are discontinued, many patients experience a rebound insomnia (longer-acting benzos produce less of this, but do produce daytime sedation). Anxiolytics have little effect on the peripheral autonomic nervous system but do depress spinal reflexes and convulsions.

GABA-A receptor: At high concentrations, barbiturates may substitute for GABA (GABAmimetic). Benzodiazepine antagonsists (flumazenil) have no intrinsic activity but will block the effects of agonists and inverse agonists.

Barbituates: Weak acids (pKa 7-8). Phenobarbital is useful as an anticonvulsant as compared to others where marked CNS depression accompanies anticonvulsant effects. Long acting (Phenobarbital), intermediate- to short-acting (amobarbital, pentobarbital, secobarbital), ultra short-acting (thiopental). Alkalosis causes ionization of the drug in the plasma and a shift from tissues to plasma. Acidosis causes more drug to enter the CNS. Physical redistribution (thiopental) allows for rapid onset and recovery. Alkalinization of the urine can shorten the duration of action of barbiturates. Metabolized by hepatic microsomal enzymes. Renally excreted as glucuronide conjugates (Phenobarbital excreted 50% unchanged).

·       CNS effects: GABAmimetic. At high concentrations, barbiturates raise neuronal thresholds for excitation and decrease repetitive activity. Respiratory depression is usually the cause of death in overdose. The cough reflex is not suppressed, except at toxic doses, so laryngospasm is one of the chief complications during anesthesia.

·       Liver: Induce microsoma enzymes, thereby stimulating metabolism of many drugs (including barbiturates). Barbs stimulate d-ALA synthetase and are contraindicated in patients with acute intermittent porphyria.

·       Treatment of overdose: Alkalinize urine, maintain airway, consider lavage, NO CNS STIMULANTS.

·       Therapeutic applications: Anticonvulsant, suppression of abstinence syndromes, induction of bilirubin conjugation in congenital jaundice of the newborn.

Benzodiazepines: Have largely replaced the barbs for clinical use in producing hypnosis. Tolerance can develop more rapidly to the hypnotic effects of short-acting benzos (triazolam). The absence of rebound in the case of flurazepam is probably related to metabolites with long half-lives. Longer-acting benzos act thru metabolites. Short-acting benzos should be administered to elederly patients because of decreased ability to metabolize drugs. Choice of hypnotics represents a trade-off betweem cumulative effects leading to psychomotor impairment (long-acting) and rebound effects leading to worsening of insomnia and anxiety (short-acting). Benzos do not induce liver enzymes and do not interact significantly with other medications.

·       Clinical uses: Anxiety disorders, depression with anxiety (alprazolam has specific antidepressant activity), panic disorders (alprazolam), spastic musculoskeletal diseases, seizures (diazepam is DOC for status epilepticus), alcohol withdrawal syndrome, premedication (diazepam has amnesic action), sleep disorders, anxiety reaction to psychedelic drugs, adjunct in GI and CV disorders, adjunct in treatment of schizophrenia.

·       Advantages: Higher therapeutic index, lower tolerance, less addictive, fewer drug interactions.

·       Adverse effects: Excessive sedation and drowsiness, ataxia; more apparent in elderly; show synergism with other CNS depressants; high therapeutic index (impossible to OD on benzos).; contraindicated in 1^st trimester; alprazolam shows significant depedence problems.

Flumazenil – Benzo antagonist; no intrinsic activity; reverses the sedative and depressant effects of benzodiazepines. However, it is ineffective for most other sedatives (e.g., barbiturates).

Zolpidem – Not a BDZ; good hypnotic with less effects of stages of sleep (improves overall sleep time; synergistic effect with other CNS depressants.

Chloral hydrate – Prodrug that must be metabolized to trichlorethanol; similar to barbiturates but does not induce p450 enzymes.

Buspirone – Atypical anxiolytic; NOT A HYPNOTIC; acts at 5-HT1A and DA-2 receptors; does not produce tolerance and physical dependence.

Baclofen – Skeletal muscle relaxant; targets the presynaptic GABA-B receptor; site of therapeutic action is primarily the spinal cord; used in treatment of MS and spinal injury; few side effects.

Dantrolene – Produces muscle relaxation by interfering with calcium release in skeletal muscle; used in treatment malignant hyperthermia; occasional hepatitis that can be fatal.

Antidepressants

Introduction: Major (unipolar) depression has five or more symptoms for 2 weeks or more (10-25% females, 5-15% males). Dysthymia is a depressed mood of 2 years or longer in duration. Bipolar disease has a strong hereditary component and patients are likely to have a comorbid substance abuse disorder. Therapeutic effects of antidepressants are no observed for 3-4 weeks. In general, antidepressants that are effective in treating unipolar depression are effective in treating dysthymia. Bipolar disorder is treated with lithium, valproate, or carbamazepine, with haloperidol used to treat acute mania.

MAO inhibitors: Phenelzine and tranylcypromine non-selectively inhibit both types of MAO. Inhibition is irreversible. MAO inhibitors have serious toxicities and inhibit the metabolism of other drugs. Interaction with other agents can precipitate a hypertensive crisis.

Tricyclic antidepressants: Demethylation on the nitrogen of the side chain reduces sedative activity (desipramine & nortriptyline less sedating, norepi-specific). Tertiary amine inhibit serotonin and norepinephrine uptake, while secondary amines are norepi-specific. Tricyclics inhibit microsomal enzymes.

·       Pharmacological actions: Antidepressant action (requires presence of depression), inhibition of amine uptake pumps (develops rapidly), down-regulation of biogenic amine receptors, sedation (antagonism of H1 receptors), anticholinergic effects, quinidine-like effects on the heart (conduction defects and arrhythmias); orthostatic hypotension.

·       Adverse effects: Orthostatic hypotension (a1 blockade), ECG changes, tachycardia, conduction block, CHF, ventricular fibrillation, lowered seizure threshold, sedation, inhibition of microsomal enzymes.

·       Drug interactions: Reduced antihypertensive action of guanethidine and methyldopa. Synergists anticholinergic effects with atropine. Lowered seizure threshold requires increase in medication. Enhancement of sympathomimetics (l-dopa in Parkinson’s patients). Reduced antihypertensive action of clonidine (antagonism of a2). Additive sedative effects with alcohol.

·       Toxicity and treatment: Narrow therapeutic window. Cardiac arryhythmias, hypotension, convulsions, and coma. Treatment includes respiratory support, gastric aspiration, and lavage, activated charcoal, cooling for hyperthermia (anticholinergic effect), fluid expansion.

Third-generation drugs

Amoxapine – Non-selective reuptake inhibitor.

Maprotiline – NE reuptake inhibitor; useful in patients with low energy and persistent lethargy.

Trazodone – Atypical antidepressant relatively selective for 5-HT with no anticholinergic actions; extremely sedating and causes priapism in men.

Fluoxetine (Prozac) – SSRI that eventually causes down-regulation of presynaptic 5-HT receptors; extensively converted to metabolite with very long half-life; also useful for obsessive-compulsive disorder, panis disorder, PMS, and bulimia; side effects are headache, tremor, sexual dysfunction, and restlessness; all are transient except for headache, which may actually increase; wait 2 weeks after cessation of MAO therapy before beginning fluoxetine; fluoxetine worsens EPS when taken with antipsychotics.

Sertaline (Zoloft) & Paroxetene (Paxil) – SSRIs; sertaline does not influence metabolism of other drugs while paroxetene does; fewer side effects than fluoxetine; paroxetene only antidepressant approved for social phobia.

Bupropion – Dopamine reuptake inhibitor; can be used to wean smokers away from nicotine; high seizure incidence; used in ADHD; high seizure incidence in patients with bulimia.

Differences between tricyclics and 3^rd generation drugs: 3^rd generation drugs have little or no anticholinergic activity (amoxapine and maprotiline have low incidence); incidence of hypotension is low; adverse cardiac effect are low.

Pain Management

Analgesic ladder: Level 1 (non-opioid±adjuvant); Level 2 (weak opioid±adjuvant); Level 3 (stronger opioid±adjuvant).

Modern approach to pain: Prevent pain; dose to individual needs; use combination therapy; patient-controlled analgesia or scheduled dosing.

Extrapyramidal Dysfunction

Basic characteristics of Parkinson’s disease: Resting tremor, rigidity (maximum hypertonicty in flexors, cogwheel), akinesia (masklike facies, micrographia), autonomic dysfunction (excessive drooling), dementia, depression.

Causes: Idiopathic, iatrogenic (MPTP), encephalitis, arteriosclerosis, CO poisoning, manganese intoxication.

Pathogenesis: Degeneration of dopaminergic neurons with cell bodies in the substantia nigra pars compacta and terminals in the striatum (caudate and putamen). These neurons exert an inhibitory influence on neurons in the caudate. Release of the intact cholinergic caudate neurons from this inhibitory influence leads to rigidity and akinesia.

MPTP: Found in designer drugs. Conversion by MAO-B to MPP+, which functions as a mitochondrial poison, resulting in dopaminergic cell death. MAO-B inhibitors (deprenyl) fully protect against MPTP-induced neurotoxicity. MPTP is believed to be oxidized outside dopaminergic neurons, possibly in astrocytes or serotonergic neurons.

Levodopa – Crosses BBB via neutral AA transporter. 95-98% of L-DOPA is converted to dopamine in the periphery via dopa decarboxylase. Beneficial actions are thought to be due to influence on D2 receptors. Significant improvement in symptoms (tremor is more resistant but can be improved with anticholinergics).

·       Side effects: Orthostatic hypotension of central origin (not preventable, tolerance develops); arrhythmias and tachycardia of peripheral origin (preventable with carvidopa); nausea, vomiting, and anorexia due to stimulation of CTA (reduced with carvidopa, DO NOT USE ANTINAUSEA DRUGS SUCH AS METOCLOPRAMIDE, domperidone, diphenidol, and trimethobenzamide can be used); inhibition of prolactin secretion due to excessive dopamine; behavioral and personality changes. Bottom line: All side effects are preventable except orthostatic hypotension, adverse mental effects, and dyskinesthias.

·       Pharmacokinetics: Gastric emptying time can markedly alter absorption because drug needs to make it to small intestine.

·       Precautions and drug interactions: Contraindicated in psychotics and patients with narrow-angle glaucoma. Pyroxidine (B6) enhances peripheral conversion of L-DOPA (blocked by carvidopa). MAOIs can precipitate a hypertensive crisis. Antipsychotics and reserpine will diminish function of L-DOPA.

Carvidopa – Inhibits peripheral dopa decarboxylase but does not cross the BBB in appreciable amounts. Fixed-dose combination with L-DOPA called Sinemet. Alleviates all side effects except orthostatic hypotension, dyskinesias, and adverse mental effects (which actually may appear earlier).

Review of motor fluctuations with L-DOPA therapy

·       Wearing-off effect – Relief of symptoms last 2-3 hrs instead of 4-5. Clear relation to plasma concentration. Sustained-release formulations may benefit some, while direct agonists such as bromocriptine may help others.

·       Peak-dose dyskinesias – Correlate with dose and plasma concentration. Drug holiday may help alleviate these symptoms.

·       Freezing episodes – Not related to time or dose, and vary in time of onset.

·       On-off phenomenon – Not related to time or dose. Most disabling and very difficult to treat. Continuous administration may help, as may apomorphine (direct dopaminergic agonist) or selegiline (MAO-B inhibitor).

Anticholinergics (benztropine & trihexyphenidyl) – Much less effective than L-DOPA with more side effects.

Amantadine – Releases DA from stores inside cell. May decrease uptake and have some direct agonist activity. Does not have long-lasting effects.

Dopamine agonists (apomorphine, bromocriptine, pergolide) – Side effects can be blocked by domperidone (DA receptor blocker).

Ropinirole – D2 agonist.

Pramipexole – Selective for D3/D4. Side effect is narcolepsy.

Selegiline – MAO-B inhibitor. Potentiates effects of L-DOPA. May be neuroprotective.

Tolcapone – COMT inhibitor.

Huntington’s disease: Genetic; degeneration of cortex and basal ganglia; not curable; noncoding DNA repeats.

Tourette’s syndrome: DOC is haloperidol.

CNS Stimulants

Sympathomimetics – Amphetamine, methamphetamine, methylphediate, premoline, cocaine

·       CNS effects: Paradoxical sedation or dysphoria; increased performance on simple tasks (not necessarily fewer errors); marked euphoric flash with IV injection.

·       MOA: Indirect thru inhibition of epinephrine and dopamine uptake; release of catecholamines (newly synthesized pool, a-methyltyrosine blocks amphetamine action, but reserpine does not); inhibition of MAO (weak); direct stimulation of 5-HT receptors.

·       Therapeutic applications: ADD/ADHD (great majority show no tolerance to therapeutic effect); treatment of obesity (stimulation of lateral hypothalamic center, tolerance develops in 6-8 weeks); narcolepsy; antidepressant.

·       Side effects: Insomnia and anorexia are most common (tolerance develops); growth-suppressing effect is seen early in treatment (dose-dependent, no deficit in adult stature); may exacerbate pre-existing psychoses.

·       Contraindications: Tourette’s syndrome; glaucoma.

·       Pharmacokinetics: Weak base; excretion enhanced by urinary acidification; amphetamine is resistant to metabolism my MAO and COMT; solid form of methamphetamine (ice/crystal) can be smoked.

·       Toxicity: Tachycardia, hypertension, arrhythmias, hyperthermia, convulsions, coma; treatment is haloperidol for psychosis, a blockers for hypertension, b blockers for cardiac effects, diazepam for agitation, acidification of urine, cooling; tolerance may occur during spree; toxic psychosis occurs frequently with no tolerance development to this effect; methamphetamine is known to lesion brain 5-HT and DA receptors; psychosis marked by continuous touching of the fact and extremities (bruxism) and marked aggressiveness; withdrawal may be helped with TCAs.

·       Methylphenidate (Ritalin) – Produces same effects as amphetamine with less peripheral action; inhibits metabolism of many drugs (including TCAs)

·       Premoline – Effects similar to amphetamine; produced by enhancement of central actions of catecholamines; not a first-line therapy (liver problems).

·       Cocaine – Inhibits catecholamine uptake by the nerve terminal with no increase in release in CNS. Mixture of cocaine, amphetamine, and an opioid is known as a speedball. Crack is almost pure cocaine mixed with baking soda and ether.

o   Acute intoxication: Cardiac effects, seizures, hyperpyrexia, hallucinations, rhabdomyolosis, and paranoid psychosis occur. Death is generally from seizures and respiratory depression, but v-fib and hyperthermia are also causes. Treatment is similar to amphetamine treatment w/o use of b-blockers. IV nitroprusside used to control hypertension.

o   Abuse and dependence: Extremely addicting although degree of physical dependence is not great.

o   Perinatal toxicity: Cocaine crosses the placenta.

Methylxanthines – Caffeine, theophylline, theobromine

·       General effects: CNS stimulation (except theobromine), diuresis, stimulation of cardiac muscle and relaxation of smooth muscle (especially bronchial muscle).

·       Toxicity: Ringing in the ears is notable; theophylline can cause seizures and fatal respiratory and circulatory collapse (arrhythmias).

·       Chronic toxicity: Symptoms resemble anxiety neurosis.

·       MOA: Antagonism of adenosine receptors; inhibition of phosphodiesterase; alteration of calcium-mediated membrane mechanisms.

·       Therapeutic uses: Migraine headache (with ergotamine); adjunct to analgesics; recurrent apnea in preterm infants; maintain wakefulness; theophylline for asthma.

Nonopioid Drugs of Abuse

Hallucinogens (psychomimetics) – LSD, psilocybin, psilocin, dimethyltriptamine (serotonin-related)

·       Common effects: Mydriasis, tachycardia, increased BP, hyperreflexia, tachypnea, increased muscle tone. Predominance of sympathomimetic effects. Perceptual distortions from simple to complex hallucinations. Magical and paranoid thinking.

·       LSD – Tolerance develops. No withdrawal symptoms. Cross-tolerance with other psychokinetic. Flashbacks and bad trips treated with reassurance or diazepam. Proposed MOA is that LSD activates auto receptors on raphe neurons, resulting in depression of firing of the raphe cells, and decreased release of 5-HT from terminals (raphe acts as mental filter).

PCP – Dissociative anesthetic that has hallucinogenic effects. Related to ketamine,

·       Acute intoxication: Confusional state including unpredictable and violent behavior. Blank-stare appearance. Behavior may change to combativeness. Gross ataxia, rigidity, nystagmus, repetitive movements, and seizures. Strong analgesic effect (could be shot and wouldn’t know it).

·       Toxic psychosis: Much like schizophrenia. More common than with other hallucinogens. Psychosis may persist for weeks or months and is difficult to treat (PCP and metabolites persist in body fat).

·       Treatment: Reassurance and isolation to reduce external stimuli. Haloperidol for seizures. Diazepam for anxiety.

Marijuana

·       Signs and symptoms of acute use: Tachycardia, conjunctival reddening.

·       Chronic use: Chronic users show less psychomotor impairment and less anxiety with same dose. Reverse tolerance has not been substantiated.

·       Dependence: Withdrawal is mild. Tissue stores decrease slowly. Strong psychological dependence in some people.

·       Approved use: Dronabinol is approved for prevention of nausea and vomiting associated with cancer chemotherapy and as an appetite-stimulant in AIDS-related anorexia. Not effective in cisplastin therapy.

·       Adverse effects: Chronic heavy use may lead to possible endocrine and immunologic disturbances, chronic bronchitis and asthma (squamous cell metaplasia), reduced exercise tolerance in patients with CAD.

Deliriants – Antimuscarinics. Bad trip man.

Inhalants – Solvents (liver, heart, and kidney problems; aplastic anemia with benzene), propellants (fluoroalkanes may precipitate arrhythmias and v-fib), nitrites (occasional methemoglobinemia).

Antipsychotics

Therapeutic benefits: Antipsychotics also relieve the manic phase of bipolar affective disorder. There is no proven difference in antipsychotics efficacy among conventional antipsychotics. Atypical antipsychotics may relieve symptoms in schizophrenic patients resistant to other agents and may produce a better quality of response.

Conventional antipsychotics – Still used for parenteral administration for acute agitation, when there is a lack of benefit or intolerance to atypical antipsychotics, in special populations (pregnant patients), and in noncompliant patients, for whom depot medication is indicated (haloperidol & fluphenazine).

Phenothiazines

• Structure-activity relationship: Substitution at position 2 imparts antipsychotics activity. Substitutions on the nitrogen at position 10 alters potency and adverse effects. Aliphatic and piperdine substituted compounds are low potency and more likely to cause sedation, orthostatic hypotension, and hypersensitivity than piperazine substituted compounds. Piperazine compounds (fluphenazine & trifluopenazine) are high potency, more likely to cause EPS and have antiemetic activity, but they cause less hypotension or sedation.
• MOA: Phenothiazines are antagonists at D1, D2, adrenergics, serotonin, and muscarinic receptors. The degree of binding at D2 receptors correlates with clinical potency in alleviating schizophrenia. Dopamine receptor blockade in mesolimbic-mesocortical dopaminergic system. Inhibition of adenylyl cyclase.
• Behavioral effects: Antipsychotic, sedation (tolerance develops), decreased spontaneous activity.
• Lowered seizure threshold: Aliphatic and piperidine compounds.
• Toxic Confusional state: Due to central anticholinergic effects.
• Extrapyramidal effects: Found in patients with D2 receptor occupancy>80%. Parkinsonism (reduce dose or change drugs); acute dystonia (diazepam); akathsia (reduce dose); tardive dyskinesia (gradual reduction of dose, switch to clozapine, results from supersensitivity of DA receptors); perioral tremor.
• Antiemetic effect: Blockade of CTZ. Piperazine-substituted compounds are more potent. Promethazine (Phenergan) is an effective antiemetic.
• Autonomic nervous system effects: a-Adrenergic receptor block leads to orthostatic hypotension. Muscarinic receptor block leads to dry mouth, urinary retention, aggravation of glaucoma. Also antihistamine and antiserotonergix activity.
• Cardiac effects: Quinidine-like.
• Endocrine effects: Increased prolactin secretion®gynecomastia.
• Temperature regulation: Poikilothermic (assume temperature of the environment).
• Adverse effects: Large therapeutic index. Toxic retinopathy and weight gain in addition to above-mentioned problems.
• Neuroleptic malignant syndrome (NMS): Fever, diaphoresis, marked muscular rigidity, leukocytosis. Death from respiratory or renal failure, CV collapse, arrhythmias. MUST STOP DRUG. Mechanism relates to sudden decrease in DA activity. Must cool patient. Treat with bromocriptine, Sinemet, etc.
• Drug interactions: Potentiation of CNS depressants and opioids; synergistic depression with alcohol (decreased metabolism); reduced effectiveness of L-DOPA; additive anticholinergic and a-blocking effects; interference with antihypertensive guanethidine; inhibition of phenytoin metabolism; cardiotoxicity with quinidine-like meds (thioridazine).

Haloperidol – High-potency conventional antipsychotics. First-line drug for treatment of schizophrenia. EPS are common, and more frequent than with phenothiazines. Has precipitated NMS; potent D2 antagonist; fewer side effects but orthostatic hypotension persists; lacks anticholinergic effects; effective for acute mania.

Others – Thiothixene (high potency, similar to piperazine-substitutes), Loxapine (hypertension rather than hypotension; oculogyric crisis); Molindone (no weight gain, low potency).

Atypical antipsychotics – Bind less avidly to D2 receptors and thus produce less EPS and endocrine disturbances. They reduce both positive and negative symptoms of schizophrenia, they are more effective than conventional antipsychotics, and appear to improve cognitive function as compared to conventional drugs.

Clozapine – 5HT2=a1>D1>D2. Minimal EPS with apparent lack of tardive dyskinesia. Ability to bind to 5-HT2 receptors thought to mediate antipsychotics effects. Also binds to D4 receptors in limbic areas. Powerful anticholinergic effects in the caudate (no EPS).

• Adverse effects: Agranulocytosis (WBC<3000, granulocytes<1500®interrupt treatment; WBC<2000, gran<1000®permanent discontinuation); seizures; withdrawl (do not remove drug without valid reason); sedation, siaolorrhea, tachycardia.

Risperidone – 5HT2=D2=a1. Most widely used antipsychotics in 1996. First-line therapy. Only significant side effect is NMS.

Olanzapine – 5HT2>D2=D1=a1. Blocks a whole lot of receptors. Exhibits selectivity for limbic/frontal cortex DA activity, Weight gain does occur. Once daily administration.

Quetiapine – Low-affinity binding to all receptors. Less beneficial effect on negative symptoms.

Sertindole – 5HT2>a1>D2. Potent antianxiety effects. Required EKG monitoring due to cardiac SE. Once daily administration.

Summary of therapeutic uses of antipsychotics

• Therapy of psychosis
• Treatment of acute manic phase of biopolar disorder (Haloperidol)
• Relief of panic attacks and psychosis associated with drug use (Haloperidol)
• Relief of delusional symptoms
• Potentiation of opioids
• Antiemetics (phenothiazines)
• Treatment of Tourette’s disorder (Haloperidol)
• Huntington’s chorea

Mood-stabilizing drug – Lithium

Therapeutic effects: DOC for management of mild to moderate mania and for the prevention of both depressive and manic episodes in bipolar disorder (prophylactic use). Also used for cluster headaches.

MOA: Effect on inositol phosphates.

Pharmacokinetics: Acute mania (0.75-1.2 mEq/L); maintenance (0.6-1.2); TOXIC (>2.0). Distributed in TBW. Excreted by kidneys. Low sodium in diet leads to increased lithium reabsorption (toxicity). Thiazides and NSAIDs can increase plasma concentration.

Adverse effects: Nausea, fatigue, thirst, polyuria, fine tremor (responsive to propanolol), GI irritation, mild diarrhea, weight gain, edema, acne, leukocytosis. Occasional effects include nephrogenic diabetes insipidus, renal tubular necrosis, interstitial fibrosis, and metallic taste. Contraindicated in pregnancy.

Overdose toxicity: No specific antidote. Treat with fluids and electrolytes, osmotic diuretics, peritoneal dialysis, and anticonvulsants.

Alternatives to lithium: Valproate and carbamazepine.

Anticonvulsants

Epilepsy is a periodic disturbance of excessive neuronal discharge for which the behavioral consequence is seizure.

Partial seizures – Simple or complex. Complex partial seizures are associated with bizarre generalized EEG activity during seizure and evidence of temporal lobe abnormalities. 60% of all seizures. Typically due to some type of trauma to the brain (lesion, infarct, etc.).

Generalized seizures – Generalized tonic-clonic (grand mal) seizures involve a sequence of maximal tonic spasm of all musculature followed by clonic jerking and prolonged depression of all central functions. Absence (petit mal) seizures are brief (10-45 sec) and abrupt losses of consciousness with high-voltage, bilaterally synchronous, 3Hz wave pattern in EEG; usually some symmetrical clonic activity. 40% of all seizures. Usually genetic (mutation of genes encoding voltage- and ligand-gated channels).

Seizure mechanisms: Either a reduction in inhibitory synaptic activity or enhancement of excitatory synaptic activity may trigger a seizure.

Status epilepticus: Continuing or recurring seizures without restoration of consciousness between seizures. Can be caused by withdrawal of antiepileptic medication and barbituate abstinence.

General MOA of anticonvulsants: Elevtaion of the threshold for discharge of epileptic neurons in the seizure focus and prevention of the spread of seizure activity to normal neurons.

Phenytoin – Grand mal, simple & complex partial, status epilepticus. May exacerbate petit mal seizures. Significant anticonvulsant action without generalized CNS depression.

·       MOA: Slows the rate of recoevery of voltage-activated NA channels from inactivation. Because the action of phenytoin on Na channels is use-dependent, it does NOT leads to generalized CNS depression and sedation.

·       Pharmacokinetics: Wide variations among patients and dosing. Protein binding is important (toxic when albumin is low). Mixed-order kinetics.

·       Side effects: Cerebellar damage (chronic use); peripheral neuropathy; skin rashes (Steven-Johnson); gingival hyperplasia.; hirsutism; megaloblastic anemia correct by folic acid.

·       Drug interactions: INH inhibits metabolism; Phenobarbital/carbamazepine stimulate metabolism; displacement of phenytoin from albumin; phenytoin stimulates metabolism of other drugs.

Carbamazepine – Grand mal, simple & complex partial. DOC in partial seizures and treatment of trigeminal neuralgia.Chemically related to TCAs, which can cause seizures. Useful in treatment of bipolar disorder. Induces microsomal enzymes and increases metabolism of many drugs. Adverse effects in 50% of patients. Usually mild but can include agranulocytosis, aplastic anemia, fatal hepatitis, CHF, Steven-Johnson. Clearance reduced by propoxyphene and valproate.

Phenobarbital – Used for little kids, complex partial, and status epilepticus. MOA is similar to other barbs in relation to GABA-A receptor. More sedative than phenytoin. Not effective in petit mal and may exacerbate them (like phenytoin). Excretion dependent on pH. Induces microsomal enzymes. Drowsiness in adults with paradoxical excitement in children. Contraindicated in acute intermittent porphyria.

Primodine – Same spectrum as Phenobarbital. Not a first-choice drug. Active metabolites are Phenobarbital and phenylethylmalonamide. Drowsiness is common.

Ethosuximide – DOC for petit mal (absence seizures).Action may be in thalamus, where it blocks spiking patterns thru reduction in low-threshold calcium- or T-currents responsible for 3Hz pattern. Low incidence of side effects.

Valproate – A whole bunch of seizures. Broad-spectrum antiepileptic. MOA combines actions of phenytoin and ethosuximide, as well as unique action in inhibiting enzymes responsible for degrading GABA (allows GABA-R currents to remain high). 90% binding to albumin displaces phenytoin. Most common side effects are nausea and vomiting, with most serious side effects being hepatic toxicity and pancreatitis. Clonazepam addition results in absence status (MOA unknown). Valproate inhibits metabolism of other drugs. Metabolism of valproate is stimulated by carbamazepine.

Clonazepam – Absence, myoclonic and atonic seizures, SE. Similar in action to diazepam. Tolerance may develop to anticonvulsant action. Abrupt withdrawal can lead to status epilepticus. Addition to valproate therapy may precipiate absence status.

Diazepam – IV used to terminate status epilepticus. MOA previously mentioned. Drowsiness and lethargy are common side effects.

Other drugs – ACTH & corticosteroids, acetazolamide, 5-hydroxytrytophan

Gabapentin – Used in addition to other antiseizure medications. Increases the release of GABA by an unknown mechanism. Resembles valproate in experimental models.

Lamotrigine – Used in addition to other medications. Seems to function like phenytoin and carbamazepine by blocking sodium channels.

t-vinyl GABA – Irreversible inhibitor of degradative enzyme GABA transaminase and has been demonstrated to increase GABA levels in experimental animals.

Felbamate – Partial seizures. Seizures caused drug to be withdrawn. Inhibits NMDA responses and potentiate GABA responses. Used in partial seizures and Lennox-Gastaut syndrome.

Drugs of choice:

·       Tonic-clonic – Carbamazepine, phenytoin, valproate

·       Partial seizures – Carbamazepine, phenytoin

·       Absence – Ethosuximide, valproate

·       Atypical absence, myloclonic, tonic – Valproate

·       Status epilepticus – IV diazepam, IV phenytoin, IV Phenobarbital.