Anticoagulants, Fibrinolytics, Antiplatelet

Anticoagulants
1. Unfractionated Heparin
-activates antithrombin III --> degrade thrombin and Xa
-nonspecific binding --> unpredictable and monitor with PTT, Xa assay, platelet count
-prevent progression of existing clots (venous thrombosis, embolism, MI)
-HIT-IgG attack AT III and factor IV complexes-->vascular damage-->thrombocytopenia
-Protamine

2. LMWH
-smaller molecule and more predictable
-degrade thrombin and Xa (more specific for Xa)
-DVT
-monitoring in larger and pregnant patients

3. Fondaparinux
-factor Xa
-DVT and pulmonary embolism

4. Direct Factor Xa Inhibitors (Rivaroxaban CYP3A4/5, Apixaban)
-reversible inhibition of free and bound Xa
-DVT and pulmonary embolism
-nonvalvular atrial fibrillation
-prothrombin complexes

5. Direct Thrombin Inhibitors (Argatroban CYP3A4/5, Dabigatran, Bivalirudin)
-bind to active site of thrombin to prevent fibrinogen --> fibrin and activation of factors V, VIII, XIII

6. Warfarin CYP2C9
-block VKORC1
-inhibit factors X, IX, VII, II, and Protein C and S
-full-thrombotic effect not achieved for several days --> need bridging therapy
-PT and INR monitoring
-bleeding, thrombosis, purple toe syndrome
-contradicted in pregnancy (nasal hypoplasia, hemorrhage, CNS abnormalities)
-Vitamin K, plasma, prothrombin complexes

Fibrinolytics
1. Streptokinase
-binds to plasminogen-->plasmin-->systemic lytic state
-systemic lytic stage-->hemostatic plugs-->concurrent use of heparin increases risk of hemorrhage
2. Alteplase
-activate plasmin in presence of fibrin
3. Tenecteplase
-activate plasmin in presence of fibrin
4. Reteplase
-activate plasmin in presence of fibrin

Antiplatelets
1. Aspirin
-block COX1-->inhibit TXA2
-MI, ischemic stroke, transient ischemic episodes (adjunctive in revascularization)

2. ADP Receptor Antagonist (Clopidogrel CYP2C19, Prasugrel, Ticagrelor)
-P2Y12 receptor inhibitor-->no fibrinogen cross-linking
-STEMI and stent placement
-bleeding, thrombocytpenia

3. Glycoprotein IIb/IIIa Inhibitors (Abciximab, Eptifibatide, Tirofiban)
-fibrinogen cannot bind
-prevention of PCI, STEMI
-used in conjunction with heparin and aspirin
-bleeding

Antimalarials

1. Chloroquine
-large volume of distribution-->need large dose so that drug can be in blood
-sequestered in tissues
-erythrocytic stage
-prevents conversion of heme to hemozoin-->oxidative stress
-K76T PfCRT mutation causes drug to accumulate in parasite's food vacuole
-G6PD deficiency and porphyria->toxic

2. Mefloquine
-widely distributed, including CNS
-neurologic side effects such as vivid dreams, anxiety, sleep disturbance
-disrupt hemozoin polymerization
-associated with amplification of pfmdr1

3. Quinine and Quinidine
-disrupt hemozoin polymerization/DNA intercalation
-short half-life
-cardiotoxic
-cinchonism, hypoglycemia, hypotension, blackwater fever, thrombocytopenia, QTc interval prolongation
-used with doxycycline-->in pregnant women and children, use clindamycin

4. Primaquine
-generation of oxidation-reduction mediators
-prophylaxis to prevent primary and latent hepatic stages
-erythrocytic, primary hepatic, latent hepatic, gametocytes
-pneumonia
-G6PD deficiency and methemoglobinemia-->toxic
-pregnancy contradicted

5. Atovaquone-Proguanil
-inhibit ETC-->collapse mitochondrial membrane
-erythrocytic and primary hepatic

6. Sulfadoxine-Pyrimethamine
-(S) inhibit dihydropteroate reductase
-(P) inhibit dihydrofolate reductase
-high resistance and slow acting

7. Artemisinin
-cleavage of artemisinin endoperoxide bridge-->free radical-->damage to macromolecules
-short half-life
-erythrocytic and gametocytes
-first line
-anemia, hemolysis, hypersensitivity
-combination with Lumefantrine (forms heme complex/decrease synthesis?, risk of QTc prolongation)

8. Doxycycline and Clindamycin
-delayed death mechanism-->impaired apicoplast gene-->death of progeny
-GI problems and photosensitivity

Toxicology

1. Barbiturate Overdose
-alkanize urine-"ion trapping"

2. Benzodiazepine Overdose
-flumazenil-reverses toxicity

3. Alchohol
-intoxication-supportive care
-withdrawal-benzodiazepine, naltrezone, acamprostate, antabuse, clonidine

4. Phencyclidine Overdose
-benzodiazepines

5. LSD Overdose
-benzodiazepines and antipsychotics

6. Cocaine
-rhabdomyolysis-kidney cannot handle myoglobin-->sustained muscle contractions
-overdose-phentolamine and labetalol, acidify urine, supportive care (lorazepam and haloperidol)
-withdrawal-bromocriptine

7. Amphetamine
-overdose-cyproheptadine-serotonin blocker for serotonin syndrome
-withdrawal-bromocriptine

8. Methylxanthines
-toxicity-convulsions, arrhythmias, nausea, vomiting
-treat cardiac with beta-blocker

9. Nicotine
-smoking cessation-buproprion, varenicline

Opioids

1. Morphine
-treats moderate-severe pain
-less anxiety
-hypersensitivity in respiratory disease
-respiratory depression
-increase intracranial pressure

2. Codeine
-treats mild-moderate pain
-"partial activity"
-anti-tussive

3. Meperidine
-less respiratory depression in neonates
-anti-muscarinic
-metabolite can induce seizures
-serotonin syndrome
-MAOI interaction-->coma

4. Diphenoxylate
-antidiarrheal

5. Fentanyl
-more potent than morphine
-lipophilic
-transdermal or transmucosal

6. Levophanol
-treats moderate-severe pain
-D-isomer (dextromethorphan is non-addictive cough suppressant)

7. Methadone
-long duration
-NMDA antagonist
-treats opioid withdrawal

8. Heroin
-no medical use
-collapse of vessels
-HIV + hepatitis
-newborn withdrawal

9. Tramadol
-reuptake inhibitor of NE and 5-HT
-chronic neuropathic pain
-serotonin syndrome

10. Methylnaltrexone
-treats opioid-induced constipation

11. Buprenorphine
-partial agonist
-K receptor block
-precipitate withdrawal in opioid users
-treats opioid withdrawal

12. Naloxone
-treats opioid overdose

Gout Treatment

Gout is an inflammatory arthritis that is caused by the body's immune response to monosodium urate crystals in the joints. Uric acid is the product of purine metabolism and can settle out of solution. Several signs of gout include podagra and tophi. Gout should not be confused for pseudogout which is caused by calcium pyrophosphate. The difference between the two can be seen when observing the crystals. The negative birefringement urate crystals are needle-shaped.

The treatment of gout begins with treatment of symptoms. This includes NSAIDs, corticosteriods, colchicine, and ACTH. Colchicine inhibits inflammatory responses by inhibiting microtubule polymerization and inflammatory mediators.

Patients with gout who present with tophi, frequent attacks, and urolithiasis, may be started on ULT (urate lowering therapy). Allopurinol (hypersensitivity associated with HLA-B allele) is a competitive inhibitor of xanthine oxidase and febuxostat is a non-purine inhibitor of xanthine oxidase. Both will lower the production of uric acid. Uricosuric agents compete with uric acid at the transporters for reabsorption. These include probenecid (reduces excretion of penicillins) and lesinurad.

The transitioning treatment to ULT includes an anti-inflammmatory and a ULT drug.

Plasma Cell Disorders

Blood-borne Pathogens

Palpating Carotids Bilaterally

Why should you not palpate your patient's carotids arteries bilaterally?

I remember being told it could cause less blood flow to the brain. However would that caused by the pressure you place on the vessels? Do you cut off the blood supply?

It is actually because of the carotid body located near the bifurcation of the carotid artery. The carotid body is a bundle of mechanoreceptors that reacts to changes in pressure. If you were to increase the pressure on the carotid body, it would set of the baroreceptor reflex. It signals to the brain that there is an increase in systemic pressure, and then the brain signals the body to lower blood pressure. As a result, there is less blood flow to the brain.

Thanks to Dr. Koehler and Danny!

Orthopedics of Spine

RA Treatment

NSAIDs and glucocorticoids are used to treat the symptoms of rheumatoid arthritis, while traditional and biologic DMARDs are used to treat active RA.


NSAIDs inhibit either COX-1 or COX-2, or even both. In the treatment of rheumatoid arthritis, these drugs inhibit the production of prostaglandins from arachidonic acid leading to a decrease in inflammation. One adverse effect is decrease in cytoprotection in GI via inhibition of COX-1.

Aspirin-irreversibly blocks COX-1 and COX-2, hypersensitivity (bronchospasms), Reye's syndrome, acute and chronic salicylate poisoning (ion trapping)

Acetaminophen-metabolism via sulfation/glucuronidation + CYP2E1+ glutathione detoxification, NAC for toxicity

Traditional NSAIDs
Propionic Acid Derivatives
Ibuprofen-close ductus arteriosus, inhibit aspirin
Naproxen-can be used to treat pain and fever in children>12yo
Acetic Acid Derivatives
Indomethacin-close ductus arteriosus, gout, tocolytic
Ketoroloac-non-selective, seasonal allergies, does not penetrate CSF
Diclofenac-mostly COX-2, hypersensitivity
Enolic Acid Derivative
Meloxicam-OA and RA

Coxib 
Celecoxib-COX-2 selective, no GI effects or bronchospasm but higher risk of CVD


Glucocorticoids interfere with the HPA by acting like cortisol, which then represses transcription. In turn humoral and cellular immunity are suppressed. Glucocorticoids are started and taper down in dose. The adverse effects of glucocorticoids can be summed up as Cushing Syndrome.


Methotrexate (first line traditional DMARD) inhibits DHFH, TYMS, and AICAR formyl transferase. The inhibition of DHFH and TYMS leads to decrease in DNA and RNA synthesis, and so less cell proliferation. The inhibition of AICAR formyl transferase leads to an accumulation in adenosine, which is responsible for MTX's anti-inflammatory effects. MTX can cause GI problems because it is a folate analog, so to treat these adverse effects the patient can take folate (Leucovorin). MTX can also interact with various drugs like penicillin, NSAIDs, aspirin, sulfonamides, probenecid (gout treatment) via competition with OAT. MTX can be displaced by salicylates, doxycycline, phenytoin (prevent seizures).

Other traditional DMARDs include Sulfasalazine (unknown mechanism but is capable of displacing MTX + hypersensitivity), Choloroquine (stabilizes lysosomal membranes and inhibits enzymes responsible for cartilage breakdown), and Leflunomide (inhibits DHODH-->inhibits de novo pyrimidine synthesis). Leflunomide is a teratogen (cause malformation of embryo).


The biologics can be divided into TNF-alpha antagonists and lymphocyte modulating biologics.

TNF-alpha Antagonists (need to screen for exposure to Hep B/C and tuberculosis)
Infliximab-binds to both soluble and membrane cytokine
Etanercept-binds to both soluble cytokine
Adalimumab-human mAb
Golimumab-human mAb
Certolizumab-lacks Fc fragment on antibody-->does not induce complement activation

Lymphocyte Modulating Biologics
Abatacept-inhibit T cell activation
Rituximab-inhibit B cell activation
Tocilizumab-IL-6 antagonist
Anakira-inhibits IL-1 receptor
Tofacitinib-inhibit JAK3 enzyme (cannot phosphorylate STAT-->affects transcription)

Endurance Athlete