Site: Receptors, parasympathetic effector cells

Action: Competitive antagonist at muscarinic receptors, prevents activation

Applications: Causes mydriasis and cycloplegic, antidote for anticholinesterase inhibitor toxicity, retinal examination

Toxicities: All parasympatholytic effects plus sedation, delirium, hyperthermia, flushing

Anti-muscarinic

Used for anti-motion sickness via transdermal patch, reduces vertigo and post-operative nausea

Site: Receptors, parasympathetic effector cells

Action: Competitive antagonist at muscarinic receptors, prevents activation

Toxicities: Tachycardia, blurred vision, xerostomia, delirium

Muscarinic Agonist (M1 through M3), negligible at nicotonic receptors

MOA: Activates muscarinic receptors, increases IP3 and DAG

Clinical Uses: Bladder and bowel atony after surgery or spinal cord injury

Toxicities: DUMBBELSS

Muscarinic agonist, slightly susceptible to cholinesterase

Nonselective muscarinic and nicotinic agonist, negligible susceptibility to cholinesterase

Used topically for glaucoma

Muscarinic receptor agonist

Found in mushrooms

Poisioning toxicity

Nictonic agonist

MOA: Activates autonomic postganglionic neurons and skeletal muscles neuromuscular endplates

Clinical: Use in smoking cessation

Toxicity: Increased GI, nausea, vomiting, diarrhea, increased blood pressure, seizure

Like Bethanechol, partial muscarinic agonist

Clinical: Glaucoma; Sjogrens's syndrome

Oral lozenge and topical

Toxicity: DUMBBELSS

Intermediate-acting cholinesterase inhibitor

Duration of Action: .5-2 hrs.

Used for myasthenia gravis

Tertiary amine, enters CNS

Toxicity: DUMBBELSS

Intermediate-acting cholinesterase inhibitor

Duration: .5-2 hrs.

MOA: Forms covalent bond with AChE, but hydrolyzed and released

Clinical: Myasthenia gravis

Toxicity: DUMBBELSS

Short-Acting Cholinesterase Inhibitor

Duration: 5-15 minutes

MOA: Alcohol, binds briefly to active site of AChE and prevents access of ACh, amplifies all action of ACh

Clinical: Diagnosis and treatment of myasthenia gravis

Toxicity: DUMBBELSS

Long-acting Cholinesterase Inhibitor (Organophosphate)

Phosphorylates active site of AChE and forms stable bond, duration of 100 hrs.

Not as easily absorbed as other organophosphates

MOA: Very high affinity for phosphorous atom, but does not enter CNS

Effects: Regenerates active AChE, can relieve skeletal muscle end plate block

Clinical: Antidote for early stage cholinesterase inhibitor poisioning

Can cause muscle weakness in overdose

Contains muscarine and anti-muscarinic agents

May produce signs of atropine poisoning and not muscarine excess

Non-insecticidal organophosphorous compound found to have neurotoxicity, targets esterase as well which causes demyelination of longest nerves

Begins w/burning and tingling in feet, motor weakness a few days later

No treatment

Contains six insecticidal esters: pyrethrin 1 and II, cinerin I and II, jasmolin I and II

Absorbed from inhalation or ingestion, not highly toxic to mammals

Irritating to eyes, skin, and respiratory tree, may cause asthma

Inseticide that inhibits AChE by carbamoylation of esteratic site

Effects are shorter in duration than organophosphates

Spontaneous reactivation more rapid

Pralidoxime not recommended

Botanical Pesticide

Obtained from Derris elliptica, D mallaccensis, Lonchocarpus utilis, and L urucu

Produces GI irritation

Conjunctivitis, dermatitis, pharyngitis, and rhinitis can also occur

Depolarizing Neuromuscular Blocking Agent

MOA:Agonist at nicotinic ACh receptors, especially at neuromuscular junctions

Effects: Initial depolarization causes transient contractions, followed by prolonged flaccid paralysis

Clinical: Placement of tracheal tube at start of anasthetic procedure

Normal duration about 5 minutes

Toxicities: Arrhythmias, hyperkalemia, increased intraabdominal, intraocular pressure, muscle pain

Nondepolarizing Neuromuscular Blocking Agent

MOA: Competitive antagonist at nACh receptors, especially at neuromuscular junctions

Effects: Prevents depolarization by ACh, causes flaccid paralysis, histamine release

Clinical: Prolonged relaxation for surgical procedures

Toxicities: Histamine release, hypotension, prolonged apnea

Nondepolarizing Neuromuscular Blocking Agent

Has no effect on autonomic ganglia, cardiac muscarinic receptors, slight tendency to cause histamine release

Nondepolarizing neuromuscular blocking agent

Rapid onset, short duration, metabolized by plasma cholinsterase

Moderate tendency to cause histamine release

Nondepolarizing Neuromuscular Blocking Agent

Steroid derivative

Causes moderate increase in heart rate and smaller increase in cardiac output, with little or no change in vascular resistance

Nondepolarizing Neuromuscular Blocking Agent

Intermediate duration, metabolized in liver

Minimal side effects

Acetylsalicylic Acid

Irreversible Inhibitor of COX 1 and COX 2

Covalent modification of enzyme

Clinical: Analgesic, anti-pyretic, anti-inflammatory, CV disease, colon cancer

Low dose blocks action of probenecid, high dose uricosuric

Toxicity: Tinnitus, Uncouples oxidative phosphorylation

irreversible inhibitor of COX-1 and COX-2

  covalent modification of enzyme (acetylation of ser residue)

  toxicity:

  tinnitus

  uncouples oxidative phosphorylation

  low dose  blocks actions of probenecid, high dose uricosuric

  varied therapeutic uses

  anti-inflammatory, ant

NSAID

Nonacetylated Salicylate

Less effective than aspirin as a COX inhibitor and do not inhibit plate aggregation, preferable in pts w/asthma and bleeding tendencies

Nonselective COX Inhibitor

Salycilic acid derivative, not converted to it though

Excreted as glucoronide conjugate

More potent than aspirin, but poor penetration in CNS

Not an anti-pyretic

Potent anti-inflammatory action

Treatment of osteoarthritis and musculoskeletal sprains and strains

NSAID/Salicylate derivative

IBS/Rheumatoid arthritis

No oral bioavailability, given as suppository

IBS/Rheumatoid arthritis

Azo link of mesalamine w/sulfapyridine

NSAID/Salicylic derivative

IBS/Rheumatoid arthritis

Azo of two mesalamine molecules

Indole derivative nonselective COX inhibitor

Very potent COX inhibitor

High degree of side effects w/chronic use including pancreatitis, headaches, hematologic rxns

Clinical: Suppress uterine contractions, closure of patent ductus arteriosus, gout, ankylosing spondylitis

Indole Nonselective COX Inhibitor

Pro-drug, needs metabolic activation

Potential less GI side effects

Clinical: Suppresses familial intestinal polyopsisand development of cancers

Racemic acetic acid derivative nonselective COX inhibitor

Large difference between anti-inflammatory dose and dose which blocks GI prostaglandin biosynthesis

Less GI side effects

Fenamate NSAID

Analgesic, treatment of arthritis

Not recommended as initial therapy

May antagonize prostaglandin effects

GI side effects

Heteroaryl acetic acid NSAID

Used in osteoarthritis, rheumatoid, and juvenile rheumatoid

History of use in pediatric populations

Well-tolerated

Heteroaryl Acetic Acid NSAID

Very potent COX inhibitor

May reduce release and/or uptake of arachidonic acid

Can be formulated with misoprostol to reduce GI toxicity

Clinical: Osteoarthritis, rheumatoid arthritis, ankylosing spondylitis

Heteroaryl Acetic Acid NSAID

Potent analgesic, weak anti-inflammatory

Used to treat post-op pain as alternative to opiates

Can be given as IM injection

Nonselective COX Inhibitor

increasing popularity

low incidence of GI side effects

at lower doeses, has analgesic but not anti-inflammatory effects

Nonselective COX Inhibitor

20 times more potent than aspirin

Similar (to aspirin and other NSAIDs) in incidence of GI adverse effects

Only NSAID marketed as a single enantiomer

Nonselective COX  and Lipooxygenase Inhibitor

In addition to COX inhibition, stabilizes lysosomal membranes and may antagonize bradykinin actions

Nonselective COX Inhibitor

Unusually long life- 40-60 hrs.

uricosuric, more useful in gout

Nonselective COX Inhibitor

similar to other members of the ibuprofen class, more toxicity

Nonselective COX Inhibitor

In addition to being a COX inhibitor, inhibits neutrophil activation in the presence of PGs, may inhibit proteoglycanase and collagenase in cartilage

Long half life- 50 hrs.

Peptic ulcer risk higher than others

Cox-2 Selective Inhibitors

somewhat selective effect on COX-2 inhibition

Popular in Europe

COX-2 Inhibitor

Pro-drug

Only nonacid NSAID in use

Somewhat selective inhibition of COX-2

Highly selective COX-2 Inhibitors

Good inflammatory action with low GI side effects

No inhibition of constitutive COX-1 in GI tract

Expensive

Because of high expression of COX-2 in kidneys, decreased biosynthesis of renal prostaglandins w/these drugs, increase hypertension, lack of anti-platelet effects and unfavorable TxA2 and PGI2 ratio, increase risk of atherosclerosis, CV disease

Acute Gout Drug

Binds to tubulin and prevents polymerization into microtubules

Interferes w/mitotic spindle formation

Inhibits migration and phagocytic actions of granulocytes

Inhibits neutrophil secretion of chemotactic factors

Side Effects: nausea, vomiting, diarrhea, abdominal pain, affects rapidly proliferating epithelial cells in GI tract

Chronic Gout Drug

Parent drug and metabolite alloxanthine inhibit xanthine oxidase, decreases uric acid synthesis

Drug interaction: inhibits metabolism of azathioprine, 6- mercaptopurine

Can be used with impaired renal function

Chronic Gout Drug

Nonpurine xanthine oxidase inhibitor

Side Effects: Liver function abnormalities, diarrhea, nausea

Chronic Gout Drug

Uricosuric agent, inhibits uric acid renal tubular absorption

Developed to inhibit renal tubular secretion of penicillin

Multiple drug interactions by blocking renal secretion

Chronic Gout Drug

Uricosuric, derivative of phenylbutazone

No anti-inflammatory or analgesic properties

DMARD/Anti-Rheumatic Drug

At doses for arthritis, effects: Inhibition of aminoimidazolecarboxamide ribonucleotide transformylase and thymidylate synthase

Enhanced adenosine release, anti-inflammatory actions inculde decrease leukocyte adhesion to endothelial cells

May inhibit transmethylation reactions of phospholipids and polyamines altering lymphocyte and neutrophil function/chemotaxis

Side effects: Nausea, mucosal ulcers, hepatotoxicity, monito liver enzymes, leucovorin can release toxicity at cost in efficacy

Anti-Rheumatic Drug

Alkylating Agent

Cross-links DNA

Toxice effects of bone marrow supporession, infertility, increased risk of infections and neoplasia

Azathioprine

Anti-Rheumatic Drug

Converted to 6-mercaptopurine, inhibits de novo purine synthesis

Primary targets T and B cells

Toxicity- any rapidly growing cell population

Anti-Rheumatic Drug

Inhibits inosine monophosphate dehydrogenase, decreases de nove purine biosynthesis

T and B cell sensitive due to lack of salvage pathway

Interferes with leukocyte adhesion by inhibition of E- and P-selectin expression

Anti-Rheumatic Drug

Azo-linkage of sulfapyridine and 5-aminosalicylic acid

Acts by scavenging free radicals as a COX inhibitor and dihydrofolate reductase inhibitor

Anti-Rheumatic Drug

Pro-Drug

Inhibits de novo ribonucleotide sythesis and triggers p53 translocation to nucleus arresting cells in G1 phase

Diarrhea as adverse side effect in about 25% patients

Some liver toxicity

Anti-Rheumatic Drug

Inhibits calineurin phosphatase activity

Decrease transcription of cytokines in T-cells

Somewhat selective effect on t-cells

Renal Toxicity

Anti-Rheumatic Drug

Unclear mechanism of action in arthritis

May decrease T-cell response to mitogens: decrease leukocyte chemotaxis, stabilize lysosomal membranes, trap free radicals, general decrease in DNA and RNA synthesis

Fairly well tolerated

Anti TNF-alpha Drug

Recombinant fusion protein consisting of two soluble TNF receptor regions linked to Fc portion of human IgG

Must be given by injection

Antibodies develop against these drugs but don't appear to alter efficacy

Increase risk of macrophage dependent infections

Screen for latent or active tuberculosis

Anti-TNF alpha drug

Chimeric monoclonal antibody w/variable murine region linked to constant human region specific against human TNF

Anti-TNF alpha drug

Recombinant human anti-TNF monoclonal antibody

Disease-Modifying Antirheumatic Drug

Inhibits T-cell activation by binding to CD 80 and 86 (on APCs) and preventing interaction w/CD28 (on T cells)

Given by IV infusion

Increased risk of infection w/especially in combination w/anti-TNF agents

Disease Modifying Anti-Rheumatic Drug

Chimeric monoclonal antibody that targets CD20 B lymphocytes

Depletion of B lymphocytes decreases antigen presentation to T lymphocytes

Given by IV infusion

Often combined with methotrexate

Main use in treatment of rheumatoid arthritis refractory to anti-TNF agents

Rash in 30% patients w/first treatment

Gold Compound

oral administration, lipid soluble

may inhibit mononculear phagocytic and T-cell function, release of histamine, prostaglandins, or leukotrienes

Use in decline, second line drugs

Toxic, lesions of skin and mucous membranes

GI effects, renal toxicity, hematologic abnormalities

Can be beneficial in juvenile arthritis

Gold Compounts

IM, water soluble

may inhibit mononculear phagocytic and T-cell function, release of histamine, prostaglandins, or leukotrienes

Use in decline, second line drugs

Toxic, lesions of skin and mucous membranes

GI effects, renal toxicity, hematologic abnormalities

Can be beneficial in juvenile arthritis

Increase intake of eicospentanoic acid (EPA)- fish oil

Increase phospholipid content of EPA as substitute for eicosatetraneoic acid

Cyclooxygenase-derived metabolites of EPA are muh less potent manipulators of inflammation than the corresponding metabolites of AA (prostaglandins)

Vitamind D Synthetic Derivative

No 1-OH needed for activation

Does need liver 25-OH

1alpha-Hydroxycholecalciferol

Doxychalciferol

Vitamin D Synthetic Derivative

Already has 1-OH group

Does need liver 25-OH

Calcitriol Analog

Suppressor of PTH gene expession, limited action on intestine and bone

Used in chronic renal failure, primary hyperthyroidism

Low affinity for serum-binding protein leads to longer half-life than calcitriol

Salmon and human forms, salmon more potent

Direct effect on osteoclast to reduce bone resorption

Decrease calcium and phosphate resabsorption in kidney

Act on osteoblasts to decrease osteoclast recruitment and activation

Decrease IL-6, IL-1, TNF-alpha

Increase IGF-1, BMP-6, TGF-B

Antagonize Vitamin D stimulated intestinal calcium absorption

Stimulate renal calcium excretion

Block bone collagen synthesis

Increase PTH stimulated bone resorption

Retard formation and dissolution of hydroxyapatite

Inhibited by osteoclasts, leads to decreased osteoclast function

In structure, close to pyrophosphate

Bisphosphanates

Metabolized into ATP analog, accumulates in osteoclasts

Impairs cell function and viability, induces apoptosis

Bisphosphanate

Inhibition of protein prenylation important for osteoclast function

Less side effect of decrease bone mineralization

Bisphosphanate

Some renal toxicity

Inhibits bone resorption

Renal toxicity

Binds free ionized calcium

High risk procedure

Calcium chelator

High risk procedure

IV- calcium chloride, gluconate, gluceptate

Oral- Calcium carbonate, citrate, lactate

Calcimimetic

Inhibits PTH secretion by lowering the the concentration of Ca at which PTH secretion is suppressed

Used for treatment of primary and secondary hyperparathyroidism and hypercalcemia associated with parathyroid carcinoma

Reduce renal calcium excretion

Useful to inhibit renal calcium stone formation

Accumulates in bone and teeth

May stabilize hydroxyapatite

Increases bone volume, may increase osteoblast activity

Both acute and chronic toxicities limit use

Primary agent used in the treatment of soft tissue and bone sarcomas

MOA: 1. Inhibits topoisomerase II to block the resealing of DNA breaks during DNA synthesis, 2. Reacts w/cytochrome P450 reductase and iron to form superoxide anion radicals which cause DNA strand breakage, 3. Intercalates w/DNA to inhibit DNA replication

Toxicity: 1. Myelosuppression, 2. cardiac toxicity

Used in combination therapy w/doxorubicin to treat osteosarcoma

MOA: Displacement of chloride by water activates cisplatin to form crosslinks w/DNA to inhibit DNA replication

Toxicity: Nephrotoxicity, ototoxicity, marked nausea and vomiting

Alkylating Agents

Used to treat soft tissue and osteosarcoma

Used to treat both soft tissue and bone sarcomas

MOA: Intercalates w/DNA forming a stable complex that specifically blocks the transcription of DNA by RNA polymerases

Toxicity: Hematopoietic suppression

Alkylating Agent

Adds significantly to doxorubicin in prolonging remission duration, survival, and response rate in soft tissue sarcomas

MOA: Alkylating agent that is activated by a liver CYP enzyme through N-demethylation to form MTIC, in target cell spontaneous cleavage yields the active alkylater, methyl diazonium ion

Toxicity: Moderate myelosuppression

Used in combination w/ifosfamide in treatment of osteosarcoma due to their different MOAs and lack of cross-resistance

MOA: Forms a ternary complex w/topoisomerase II and DNA to form a complex that cannot dissociate and DNA replication is blocked, cell cycle specific for the S or G2 phases

Toxicity: Myelosuppression, nausea, vomiting

Used to treat osteosarcoma

MOA: Methotrexate inhibits dihydrofolate reductase which indirectly inhibits thymidylate synthase and hence, DNA synthesis

Leucovorin is converted to the N5,N10-methylene-tetrahydrofolate, which provides the carbon donor for the methylation of dUMP to form TMP by thymidylate synthase

Combats myelosuppression

Increases absolute neutrophil count during high-dose chemotherapy

Combat myelosuppression

Cause little suppression of bone marrow function and are used in combination therapies w/dactinomycin and cyclophosphamide

Bleomycin MOA: Intercalates w/DNA and then reacts w/oxygen and iron to form oxygen radicals, causes fragmentation of the deoxyribose DNA chain

Bleomycin Toxicity: Bleomycin-inactivating enzyme, hydrolase, present in many tissues to protect them from bleomysinc toxicity, enzyme is low in lung and pulmonary toxicity is primary side effect

MOA: Binds to tubulin molecules so that they fail to polymerize to form a spindle, this blocks mitosis and leads to tumor cell death

Toxicity: Causes little myelosuppression, causes predictable neurotoxicity characterized by numbness of extremities leading to loss of motor function

1. Antimicrobial agent is given just before and during the surgery

2. Use beyond 24 hrs. after surgery is potentially harmful due to risk of inducing resistant organisms of superinfection

3. Cephalosporins or vancomycin are drugs of choice because of their broad spectrum

1. Evidence of a new infection during chemotherapy of the primary infection indicates a superinfection.

2. Intestinal flora keep each other in check.

3. Extended use of a broad spectrum antibiotic alters the natural flora so that one species becomes dominant and invades the host.

4. Expanded-spectrum third-generation cephalosporins and tetracyclines sometimes cause a superinfection.

1. Extensive debridement and resection of infected bone, dead-space and soft-tissue management, rigid fixation of fractures (pins)

2. Local antimicrobial therapy w/antibiotic-impregnated polymethylmethacrylate beads (overcomes compromised blood supply to the region)

3. Prolonged systemic antimicrobial therapy specific for the causative organisms

1st Generation- Cephalothin (used historically but no more), Cefazolin

2nd Generation- Cefuroxime (Ceftin)

3rd Generation- Ceftriaxone (Rocephin)

Drug of choice for methicillin-resistant staphylococci (MRSA)

Serum levels have to be carefully monitored to prevent ototoxicity and nephrotoxicity

Active against a variety of vancomycin-resistant, penicillin-resistant, and methicillin-resistant organisms

MOA: Prevents formation of 70 S ribosome complex by binding to the 23 S subunit of the 50 S ribosome to block initation of protein synthesis in gram-positive bacteria, like S. aureus

Resistance: Mutations in 2 or more copies of the 23S rRNA gene involved in protein synthesis

Effective against vancomycin-resistant strains of Enterococcus faecium and skin infections caused by S. Aureus

MOA: Acts synergistically by binding to and changing the conformation of the 50 S ribosomal subunit in gram-positive bacteria to interfere with polypeptide-chain formatoin

Drug combination inhibits cytochrome P450 enzyme, CYP3A4, to slow the metabolism of a many other drugs

Antibacterial agent of class Cyclic Lipopeptides

Effective against antibiotic resistant gram-positive bacteria, including isolates resistant to methicillin, vancomycin, and linezolid when administed IV

MOA: Binds to bacterial membranes and causes a rapid depolarization of membrane potential, loss of membrane leads to inhibition of protein, DNA, and RNA synthesis, which results in bacterial cell death

IV metronidazole for 7-10 days

MOA: Chemically activated to form a highly reactive hydroxylamine on the nitro group which degrades DNA in anaerobic organisms

Drug against microfilarial forms of susceptible filarial species, rapid disappearance of developmental forms of W.bancrofti, B. malayi, L.loa

MOA: Direct effect on W. bancrofti by causing organelle damage and apoptosis

Toxicity: Anorexia, nausea, headache, vomiting, rxns due to host response to destruction of parasites