Neurologic: Dyskinesia (12.2% to 16.5% )

Asthenia

1) In clinical trials, asthenia has been reported in patients who received sustained-release carbidopa/levodopa (n=748) (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009).
2) Asthenia has been reported with immediate-release carbidopa/levodopa (Prod Info PARCOPA(R) orally disintegrating tablets, 2006).

Immediate-release and controlled-release carbidopa/levodopa in PD: A 5-year randomized multicenter study

Neurology September 1, 1999 53:1012

Dyskinesia

1) Summary 
a) Dyskinesias, including choreiform movements and dystonia, are the most frequent and severe adverse effects of carbidopa/levodopa (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009; Prod Info SINEMET(R) oral tablet, 2008; Prod Info PARCOPA(R) orally disintegrating tablets, 2006). Combined use with carbidopa does not lessen dyskinesias relative to levodopa alone (Nutt, 1990). Propranolol (Carpentier et al, 1996) or fluoxetine (Durif et al, 1995) may be useful in some patients.
2) Incidence: 12.2% to 16.5% (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009)
3) In randomized, controlled clinical trials, dyskinesia has been reported in 16.5% of patients who received sustained-release carbidopa/levodopa (n=491) compared with 12.2% of patients who received immediate-release carbidopa/levodopa (n=524) (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009).
4) Dyskinesias (eg, choreiform, dystonic, and other involuntary movements and nausea) are the most frequent adverse effects of carbidopa/levodopa combination therapy (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009; Prod Info SINEMET(R) oral tablet, 2008; Prod Info PARCOPA(R) orally disintegrating tablets, 2006).
5) In a study including 100 parkinsonian patients, peak dose dyskinesias were more often present in younger patients (p less than 0.0001). However, the mean latency to dyskinesia induction after levodopa initiation was no different in younger patients versus older dyskinetic patients. Also, the overall dyskinesia-free survival of younger subjects was not worse. A delay in initiating levodopa therapy of more than 3 years after disease onset, and levodopa treatment on initiation in Hoehn-Yahr stage II compared to stage I patients, did not increase the probability of developing dyskinesias over time (Blanchet et al, 1996a).
6) Severe choreiform storm was described in a 70-year-old male treated for Parkinson disease with levodopa 250 to 1250 mg daily for 1 week. The patient experienced marked difficulty in breathing and anxiety and marked choreoathetoid movements of all voluntary muscles including the diaphragm. The patient also exhibited dystonic movements of the neck and trunk. Improvement was seen with diazepam 10 mg intramuscularly and diphenhydramine 25 mg intramuscularly. The patient was rechallenged with a single 250-mg dose of levodopa and developed an identical reaction. Dosage was adjusted at 300 to 400 mg daily after 4 months with no choreiform reactions. However, the patient gradually deteriorated and died after 1 year (Hinterbuchner & Hinterbuchner, 1974).
7) Management
a) In a randomized, single-center, double-masked, placebo-controlled, 3-week crossover study (n=24), amantadine therapy (100 mg twice daily) significantly reduced the total dyskinesia score (Goetz scale) by 24% compared with placebo (p=0.004). Furthermore, the maximal dyskinesia score was significantly decreased by 17% in the amantadine group compared with placebo (p=0.02) (Pahwa et al, 2006).
b) Propranolol in doses up to 60 mg daily for 5 to 6 weeks resulted in a mean 40% improvement in dystonic reactions in 7 patients. Four patients with ballistic or choreic dyskinesias showed the greatest improvement (up to 78%), while the one patient without benefit was characterized as pure dystonia. Daily life was dramatically improved in responding patients, with fewer falls due to motor disability; withdrawal of adjunctive apomorphine; and an increase in duration of “on” time noted. No loss of parkinsonian motor control was reported subjectively or objectively; blood pressure and heart rate were not adversely effected at the low doses of propranolol used (Carpentier et al, 1996).
c) Fluoxetine 20 mg daily for 11 days improved the dystonic response to apomorphine challenge (particularly those arising in the trunk and lower limbs) by approximately 50% in 7 chronic Parkinson patients (Durif et al, 1995).
d) At least 6 different patterns of dyskinesia in Parkinson disease have been described which are thought to be directly related to levodopa therapy.(Olanow & Koller, 1998; Jankovic, 1993). A different classification scheme suggests dyskinesias can be divided as predictable or unpredictable; predictable dyskinesias can be further subdivided into 3 types (interdose, biphasic or “off-period”). Unpredictable dyskinesias (“yo-yo”, “on-off”) are random (Giron & Koller, 1996a). These dyskinesias and their recommended management include (Olanow & Koller, 1998; Jankovic, 1993; Giron & Koller, 1996a): 
Peak-dose dyskinesia (interdose dyskinesia) and respiratory dyskinesia 
reduce each levodopa dose, add dopamine agonists, add or convert to liquid levodopa, use immediate-release formulation, decrease or eliminate selegiline, add catechol-o-methyl transferase (COMT) inhibitor
Biphasic dyskinesia
increase frequency of levodopa dosing, add/increase dopamine agonist, restrict levodopa/carbidopa to several early/midday doses
Peak-dose dystonia
reduce each levodopa dose, add dopamine agonist, botulinum toxin
Early morning foot dystonia
nocturnal levodopa/carbidopa sustained-release, nocturnal dopamine agonists, early morning levodopa/carbidopa, botulinum toxin
Myoclonus
clonazepam, valproate, methysergide
Dystonic posture (“striatal”)
increase levodopa dose, anticholinergics, botulinum toxin
Akathisia
anxiolytics, propranolol, opioids

Dystonia

1) Incidence: 0.8% to 1.8% (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009)
2) In randomized, controlled clinical trials, dystonia has been reported in 1.8% of patients who received sustained-release carbidopa/levodopa (n=491) compared with 0.8% of patients who received immediate-release carbidopa/levodopa (n=524) (Prod Info SINEMET(R) CR sustained-release oral tablets, 2009).

No trials of therapeutic dosing evaluated the relationship between weight and anti-Xa levels.

The large prospective trials included relatively few obese patients, with the reported mean total body weight ranging from 66 to 80.7 kg among the various trials.^[2] The highest reported body weight at baseline was 159 kg, but the actual number of patients with baseline weight above 150 kg included in these trials was not reported. The maximum dosage of dalteparin in ACS trials was 10,000 units every 12 hours, and the maximum dosage in DVT and PE trials was 18,000 units per day.^[2]

Because of the results of these trials as well as subgroup analysis finding no benefit for ACS patients treated with more than 18,000 units per day, the manufacturer of dalteparin recommends a dosage not to exceed 18,000 units per day for ACS treatment.

A prospective, open-label trial was conducted evaluating two tinzaparin doses (75 and 175 units/kg) given subcutaneously as a single dose to healthy, obese volunteers (100-160 kg); the anti-Xa activity curve was compared with that in a historical control group of nonobese patients.^[7] The ranges of area under the activity-time curve and maximum anti-Xa activity were compared between the groups and were found to overlap. The authors suggested that dosing based on body weight alone, independent of the presence of obesity, was appropriate and the dose should not be capped because of body weight.

Another prospective, open-label study investigated whether or not there were significant differences in V and CL of dalteparin in obese versus normal weight patients.^[12] Patients with thrombotic conditions requiring therapeutic doses of dalteparin were given a dose of 200 units/kg/day for venous thromboembolic disorders or 120 units/kg twice a day for unstable angina. Prescribers could choose to base the dose on lean body weight (LBW), adjusted body weight (AdjBW), or TBW. Two anti-Xa activity levels were drawn after the second or subsequent dose to determine V and CL in the 10 obese patients and 10 nonobese patients. The results showed that TBW and AdjBW (AdjBW = LBW + 0.4 [actual body weight - LBW]) correlated better with anti-Xa activity than did LBW, suggesting that either actual body weight, or some function of it, would be the most appropriate weight on which to base the dalteparin dosage.

Conclusion

• Probenecid inhibits excretion of weak organic acids in the proximal and distal convoluted tubules, altering the pharmacokinetics of many drugs. It also inhibits glucuronidation of some drugs. Probenecid inhibits renal tubular excretion of many β-lactam antibacterial agents (e.g., cephalosporins and penicillins), an interaction that has been exploited clinically to maintain serum levels of the antibacterial agent, thereby reducing the frequency of administration. Probenecid does not alter serum levels of ceftriaxone or ceftazidime. Probenecid does not alter the pharmacokinetics of digoxin or theophylline.

• According to the 2008 update of the Canadian guidelines on sexually transmitted infections, the combination of oral probenecid and cefoxitin, as a single dose in combination with doxycycline for 14 days, is used as an alternative to ceftriaxone for outpatient treatment regimen for pelvic inflammatory disease [www.phac-aspc.gc.ca/std-mts/sti_2006/pdf/404_Pelvic_Inflammatory_Disease.pdf].
• According to the 2005 Anti-infective guidelines for community-acquired infections, the combination of cefazolin with oral probenecid (given 30 minutes prior to cefazolin) is used as an alternative treatment regimen for severe non-facial uncomplicated cellulitis [Clin Infect Dis 2002;34(11):1440-8].
• According to the 2009 Guidelines for prevention and treatment of opportunistic infections in HIV-infected adults and adolescents, oral probenecid is administered in combination with cidofovir (administered iv) for the prevention of cidofovir-related nephrotoxicity. Cidofovir is used for the treatment of cytomegalovirus (CMV) retinitis in patients with AIDS in whom other drugs are inappropriate [www.cdc.gov/mmwr/pdf/rr/rr5804.pdf].

Bisphosphonate

steonecrosis of the jaw has been reported in patients receiving bisphosphonate therapy. Although the majority of patients affected receive either pamidronate or zoledronic acid for the management of metastatic cancer to the bone, there have been reports of osteonecrosis in patients receiving oral bisphosphonate therapy for the treatment of osteoporosis, including risedronate.[30737] Most of the reported cases have appeared after dental tooth extraction; however, some cases have appeared spontaneously. It is not possible to determine if the reported events are related to bisphosphonates, concomitant drugs or other therapies (e.g., chemotherapy, radiotherapy, corticosteroid), a patient’s underlying disease state, or other comorbid risk factors (e.g., anemia, infection, preexisting oral disease). Typical signs and symptoms of osteonecrosis of the jaw include pain, swelling, infection, or poor healing of the gums, loosening of the teeth, numbness or a feeling of heaviness in the jaw, and drainage of exposed bone. If osteonecrosis of the jaw does develop during bisphosphonate therapy, it should be noted that dental surgery may exacerbate the condition. For patients requiring dental work, no data are available to suggest whether discontinuation of bisphosphonate treatment reduces the risk of osteonecrosis of the jaw. The treating physician and dentist should use their best clinical judgment to guide the management plan of each patient based on individual benefit and risk assessments. Based on a review of the available literature, treatments that have been used include local debridement, bone resection or other surgery, antimicrobials, antiseptic mouthwash, and hyperbaric oxygen.[33138] While a consensus on the best treatment strategies does not exist, the American Academy of Oral Medicine recommends prevention. Preventive measure include evaluation by a dentist prior to intravenous bisphosphonate initiation and within 3 months of oral bisphosphonate initiation, correction of dental complications prior to drug initiation, and continued regular follow-up with a dentist. For the treatment of osteonecrosis, recommendations include superficial debridement, bone resection when indicated, systemic antimicrobial for infections with culture-directed therapy or penicillin, amoxicillin, or clindamycin empirically, or use of chlorhexidine mouthwash 3—4 times daily. Discontinuation of the bisphosphonate once osteonecrosis occurs is controversial as the half-life of bisphosphonates within the bone is estimated to be years

• cefazolin
  • better gram positive coverage
  • useful for cellulitis
• cefuroxime
  • more respiratory
  • more gram negative coverage

• bb counteracts mechanism of catecholamine by decreasing preload (RAAS) and decreasing afterload (vasoconstriction)
• -antagonize the effects of SNS
• antiarrhythmic effect
• attenuating or reversing ventricular remodeling
• decrease myocyte death from catecholamine induced necrosis or apoptosis
• decrease hr and ventricular wall stres thereby reducing myocardial oxygen demand and inhibiting plasma renin release

Detrimental effects of NE

• tachycardia, vasoconstriction, increased contractility
• NE contributes to ventricular hypertrophy and remdoelling

Candasartan and BP

• CHARM- PRESERVE
  • candasartan 32 mg daily vs placebo
  • By 6 months, blood pressure was lowered from baseline by 6·9 mm Hg systolic and 2·9 mm Hg diastolic more in the candesartan group than in the placebo group (p<0·0001

AF Target

Lone AF with CHADS2

• CLASS IIa-For patients with nonvalvular AF who have 1 or more of the following less well-validated risk factors, antithrombotic therapy with either aspirin or a vitamin K antagonist is reasonable for prevention of thromboembolism: age 65 to 74 y, female gender, or CAD. The choice of agent should be based upon the risk of bleeding complications, ability to safely sustain adjusted chronic anticoagulation, and patient preferences. (Level of Evidence: B)
• ClassIIb- In patients with AF younger than 60 y without heart disease or risk factors for thromboembolism (lone AF), the risk of thromboembolism is low without treatment and the effectiveness of aspirin for primary prevention of stroke relative to the risk of bleeding has not been established. (Level of Evidence: C)
• The estimated prevalence of AF is 0.4% to 1% in the general population, increasing with age (18,19). Cross-sectional studies have found a lower prevalence in those below the age of 60 y, increasing to 8% in those older than 80 y
• CHADS2=0
  • 1.9% without treatment= annual stroke risk
  • 1% with ASA= annual stroke risk
  • 0.25% with ASA= major bleed (all)

STEMI Evidence

Clopidogrel

• DAP
• CLARITY- TIMI
• COMMIT
• CURE
  • 14 days clopidogrel therapy is an exptrapolation of CURE, CLARITY and commit ( 8-30 days)

ACEI

• HOPE
• EUROPA
• PEACE
• TRACE
• AIRE
• SAVE
• CCS1
• ISIS-4
• GISSI-3

ARB

• ON-TARGET
• VALIANT

CCB

• • INVEST

BB

• CCS
• TIMI2-B
• ISIS-1
• MIAMI

Statin

• MIRACLE
• PROVE IT TIMI 22
• A TO Z
• CAGE
• LIPID

COOPERATIVE-Japan study

ASTRODE

•  Serum ferritin is the storage of iron , it may be reduced in iron deficiency
• serum iron is funcational iron that is bound to transferritin. This value represents about 1/3 of total iron binding capacity (TIBC)
• TIBC measures the iron binding capcity of transferrin protein. in iron deficiency anemia, TIBC is increased due to compensatory increase in transferrin synthesis; this increase leads to a corresponding decrase in the percent saturation.

Digoxin

• inotropic effects- increase Na through NaK+ ATPase –> increase intracellular Na–> increase calcium –> increase force of contraction
• chronotropic- activate vagal parasympathetic effects and slows conduction through AV node

Cardiogenic shock vs Septic shock

• cardiogenic shock decrease CO, decrease HR–> heart is not working properly
• septic shock increase CO, increase HR, decrease resis

In the Warfarin, Aspirin, Reinfarction Study (WARIS II), warfarin without aspirin in a dose intended to achieve an INR of 2.8 to 4.2 resulted in a significant reduction in a composite end point (death, nonfatal reinfarction, or thromboembolic stroke) compared with therapy with aspirin alone (16.7% versus 20.0%) (1247). Warfarin therapy resulted in a small but significant increase in major, nonfatal bleeding compared with therapy with aspirin alone (0.62% per year versus 0.17% per year).

CLASS I

Warfarin alone (INR 2.5 to 3.5) or warfarin (INR 2.0 to 3.0) in combination with aspirin (75 to 162 mg) should be prescribed in post-STEMI patients who have no stent implanted and who have indications for anticoagulation. (Level of Evidence: B)

STEMI patients with or without acute ischemic stroke who have a cardiac source of embolism (AF, mural thrombus, or akinetic segment) should receive moderate- intensity (INR 2 to 3) warfarin therapy in addition to aspirin (see Figure 35). The duration of warfarin therapy should be dictated by clinical circumstances (e.g., at least 3 months for patients with an LV mural thrombus or akinetic segment and indefinitely in patients with persistent AF). The patient should receive LMWH or UFH until adequately anticoagulated with warfarin. (Level of Evidence: B)

Two trials failed to demonstrate a statistically significant reduction in the combined end points of death, reinfarction, or stroke using a regimen of low-dose aspirin in combination with low-dose warfarin (INR less than 2) (1306,1307).

In the APRICOT II trial (1249), patients less than 75 years old with STEMI received UFH, aspirin, and fibrinolytic therapy. Those who achieved TIMI 3 flow were randomized to aspirin alone (80 mg) or warfarin (INR 2 to 3) plus 80 mg of aspirin. The combined group had fewer reocclusions (15% versus 28%; p less than 0.02) and a significant reduction in the combined end points of death, MI, and revascularization (20% ARD; 23% RRR; p less than 0.01)

Magnesium

• Magnesium is principally distributed in bone (67%) and muscle (20%). Because of its predominantly intracellular distribution, measurement of magnesium in the extracellular compartment may not accurately reflect the total body magnesium content. The majority of magnesium in the extracellular fluid is in the ionized form as only 20% is bound to serum proteins. The normal range for serum magnesium is 1.4 to 1.8 mEq/L, which is equivalent to 1.7 to 2.3 mg/dL or 0.85 to 1.15 mmol/L.
• Hypermagnesemia (serum magnesium >2 mEq/L) is a rare occurrence  that is generally seen in patients with stage 4 or 5 CKD when magnesium intake exceeds the excretory capacity of the kidneys. Elderly patients are prone to hypermagnesemia because of thei rreduced glomerular filtration rate (GFR) and because of their tendencyto consume magnesium-containing antacids and vitamins
• At that point the serum magnesium concentration can be monitored every 6 to 12 hours for the next 24 hours while receiving magnesium supplementation. Once the magnesium concentration is stable in the normal range, a concentration can be obtained daily. It should be reiterated that it typically takes 3 to 5 days to fully replete total body magnesium stores
• Intravenous administration of magnesium sulfate produces an immediate effect that lasts for about 30 minutes

Digoxin

Digoxin inhibits the Na-K-ATPase membrane pump. Na-K-ATPase regulates intracellular sodium and potassium. Inhibition of this enzyme leads to an increase in intracellular sodium concentration (i.e., decreased outward transport) and ultimately to an increase in intracellular calcium as sodium-calcium exchange is stimulated by high intracellular sodium concentrations. It is believed that increased intracellular concentrations of calcium allow for greater activation of contractile proteins (e.g., actin, myosin).

Digoxin also possesses direct vasoconstrictive properties and reflex CNS-mediated peripheral vasoconstriction. Although this increases vascular resistance, in patients with failing hearts, increased myocardial contractility predominates and total peripheral resistance drops. In patients with congestive heart failure, an increased cardiac output will decrease sympathetic tone, thereby reducing the heart rate and causing diuresis in edematous patients and improving coronary blood flow.

In addition to its inotropic effects, digoxin also possesses significant actions on the electrical activity of the heart. It increases the slope of phase 4 depolarization, shortens the action potential duration, and decreases the maximal diastolic potential. The increase in vagal activity mediated by cardiac glycosides decreases conduction velocity through the atrioventricular (AV) node, prolonging its effective refractory period. In atrial flutter or fibrillation, digoxin decreases the number of atrial depolarizations that reach the ventricle, thereby slowing ventricular rate. Sympathetic stimulation, however, easily overrides the beneficial inhibitory effects of digoxin on AV nodal conduction.

When to back off high dose diuresis in CHF….monitor for:

• Goal : euvolemic
• subjective: clinical s/s–> presence of SOB, crackles, cxr
• objective: JVP, WT, Urea: SrCr ratio

ACEI Studied in HF

• rationale:
  • inflate during diastole (when aortic valve closes and EKG shows T wave)–> increase diastolic pressure–> increase tissue perfusion
  • deflate during systolie–> decrease systolic pressure–> decrease demand by decreasing afterload

• LA enlargement –> on AF for a longer period–> effect of remodelling

 GPIIb/IIIa in STEMI

• Inhibit platelet aggregation by reversibly binding to the paltelet receptor glycoprotein IIb/IIIa of human platelets, thus preventing the binding of fibrinogen, von willebrand factor and other adhesive ligands
• ClassIIa- abciximab or eptifibatide at time of primary PCI with or without stenting
• ClassIIb- combination of abciximab and half dose reteplase or tenecteplase may be considered for prevention of reinfarction an other complication sof STEMI selected pt
• not for pt greater than 75 years of age because increased risk of ICH

Rhabdomyolysis

•  rapid breakdown (lysis) of skeletal muscle (rhabdomyo) due to injury to muscle tissue.
• The destruction of the muscle leads to the release of the breakdown products of damaged muscle cells into the bloodstream; some of these, such as myoglobin (a protein), are harmful to the kidney and may lead to acute kidney failure. Treatment is with intravenous fluids, and dialysis or hemofiltration if necessary

What is the benefit of rate control in AF?

• increase ventricular filling–> improving hemodynamics and decrease s/s
• SYMPTOMATIC management
• DOES NOT prevent AF
• it only controls rate, NOT RHYTHM, so we didn’t restore the patient’s rhythm, pt can still be in afib

What is the benefit of rhythm control in AF?

• works at restore sinus rhythm and prevent AF
• if rate of spntaneous impulse generation of the abnormally automatic foci becomes less than that of SA node, normal cardiac rhythm can be restored
• alter conduction characteristics of teh pathways of reentrant loops
• if refractory period is prolonged without sig slowing conduction velocity, the tachycardia may terminate or slow in rate as consequence of a greater circuit length

Anticoagulation in pt with less than 48hr of AFIB who are cardioverted:

CHEST-For patients with AF of known duration < 48 h, we suggest cardioversion withoutanticoagulation (Grade 2C).- when only observational studies are available, or when they generalize from patients who were randomized in other population

• CHEST 2008
  • Grade 2A: benefit vs risks is unclear, based on RCTs that do not have important limitations
  • for pt with at least moderate risk for coronary event ( based on age and cardiac risk factor profile with a 10 year risk of cardiac event greater than 10%), we recommend 75-100 mg daily of AS over either no antithrombotic therApy or VKA
• ACC- 2002 Primary Prevention Guidelines
  • low dose aspirin in persons at higher CHD risk ( especially those with 10 y risk of CHD greater than 10%)
  • recommended for pt especially if moderate to high risk should be on ASA for primary prevention
• ACC UA/STEMI 2007 Guidelines
  • asa prophylaxis can uncommonly result in hemorrhagic complications and should ony be sued in primary prevention when the level of risk justifies it. Patients whose 10 y risk of CHD is 10% or more are most likely to benefit and 75-162 mg of ASA per day as primary prophylaxis should be discussed

LMWH Dosing in Renal Impairment

• Renal Drug Dosing Handbook: decrease LMWH b y50% if eGFR is less than 10%
• Enoxaparin
• CrCl less than 30 mL/min: unfractionated heparin recommended instead of LMWH; if LMWH is used, reduce usual recommended dose by 50% (guideline dosing)
• CrCl less than 30 mL/min: ST-segment elevation MI (age less than 75 yr): 30 mg IV bolus plus 1 mg/kg subcutaneously followed by 1 mg/kg subcutaneously once daily

• CrCl less than 30 mL/min: ST-segment elevation MI (age 75 yr or older): 1 mg/kg subcutaneously once daily without a bolus dose
• dalteparin
  • renal impairment: (thromboprophylaxis) 5000 units fixed dose (range 2500 units to 7500 units) SUBQ daily did not result in drug accumulation in patients with mild to severe renal impairment

LMWH vs UFH in STEMI

EXTRACT- TIMI 25 ( NEJM 2006)

N= 20506, STEMI X 6 h and fibrinolysis
UFH X 48 h vs enoxaparin x 8 days

FMI

• dc bb in coronary vasospasm
  • bb prevent smooth muscle relaxation
  • alpha is uninhibited by beta receptor–> further vasoconstriction

• Kussmaul breathing is a deep and labored breathing pattern often associated with severe metabolic acidosis, particularly diabetic ketoacidosis (DKA) but also renal failure. It is a form of hyperventilation, breathing which is increased above the normal rate
• 3amp of bicarb should be made in one litre of D5W!!! NOT NACl because (150mmol of Na+ in bicarb + 154 mmol of Na in 1litre naCl= 300mmol Na+–> hypernatremia)
• lactate (in ringer’s lactate)break down to bicarbonate
• bicarb is quickly lost as CO2
• methanol, ethylene glycol and starvation in MUDPILES leads to breakdown of ketones
• starvation lead to metabolism of fat–> breakdown to ketone
• uremia is a sign of renal dysfunction
• isosonaizid and iron in MUDPILES can lead to liver poisoning
• non AG causes:
  • gain Cl-
  • loss bicarb
    • renal lost – acutetubular necrosis
    • blood lost
    • GI- diarrhea, bicarb from pancreas, ostomy from GI resection, fistula
• resp acidosis: causes of hypoventilation( start with the brain–> spinal cord–> lung to find cause)
• liver failure–> increase progesterone–> hyperventilation
• 5.5 pH of normal saline ( acidotic)
• metabolic alklosis
  • loss of acid
    • suction of acid from stomach?
  • gain of bicarb
    • taking bicarb- cal carb from Tums or Rolades–> milk alkali
    • hold bicarb in kidney
      • drugs
        • furosemid ( blk absorption of chloride)
          • lasix= SIX hours to eliminate from body
        • steriod
          • dexamethasone because long duration of action

HF

• nitrate affect preload via venodilation
• hydralazine affect afterload via arteriodilation
• bb counteracts mechanism of catecholamine by decreasing preload (vasoconstriction of NE) and decreasing afterload (RAAS)

Connective Tissue Disorder:

• leads to increase risk of CVD secondary to
  • baseline dx is inflammatory
  • drugs used to treat connective tissue disorder uses that drugs that can worsen CV system ( i.e.prednisone)

Raynauds and BB

• Abstract: 36 patients with Raynaud’s disease (RD) were treated with a low dosage of beta-blockers, atenolol (50 mg/day) or propranolol (20 mg/day). Previous data have suggested that the pathophysiology of RD may be mediated by presynaptic beta-adrenoceptors. In this research we report that chronic beta-blocker treatment, at low dosage, can prevent the cold-induced vasospasm. The majority of patients (28) responded to atenolol, and 8 patients refractory to atenolol responded to propranolol
• beta blockers may also aggravate raynaud’s
• Abstract: A series of 102 hypertensive patients were assessed for the frequency of symptoms of Raynaud’s phenomenon and absent peripheral pulses. Out of 21 patients receiving methyldopa alone only one had cold hands and feet whereas among patients on beta-blockers the incidence was 50%. The frequency of both symptoms and absent pulses was highest in patients taking propranolol compared with those taking atenolol or oxprenolol. Patients without a foot pulse were much more likely to have cold hands. A change from propranolol to oxprenolol in some symptomatic patients resulted in improvement. In two patients the skin temperature fell after an 80-mg dose of propranolol. The mechanism by which beta-blockers induce Raynaud’s phenomenon is still not clear.

Spironolactone

• Spironolactone is a renal competitive aldosterone antagonist. It inhibits the effect of aldosterone by competing for the aldosterone-dependent sodium-potassium exchange site in the distal tubule cells. This increases the secretion of water and sodium, while decreasing the excretion of potassium .
  • decrease preload
• Feedback decreases vasopressin and decrease afterload from vasoconstriction
• Block aldosterone receptor to attenuation of  cardiac fibrosis and ventricular remodeling

• amiodarone is known to inhibit CYP3A4 and 2D6
• 200mg amiodarone for 6 wk and simva 80mgx 4 wk has been associated with weakenss and muscle pain
• simvastatin dose should not exceed 20mg daily
• alternative: selective statin that is not a CYP 3A4, such as pravstatin and rosuvastatin
• atorva: 2.24
• simva: 0.21-0.65
• amiodarone: terminal elimination half-life ranges from 26—107 days with a mean of around 53 days

Heparin Recommendation in STEMI:

Amiodarone

• Amiodarone is both an antiarrhythmic and a potent vasodilator.
• amiodarone acts directly on the myocardium to delay repolarization and increase the duration of the action potential. Delayed repolarization is a result of inhibition of potassium ion fluxes that normally occur during phase 2 and 3 of the action potential.[24497] This results in prolongation of the effective refractory period in all cardiac tissue (e.g., atria, ventricles, AV node, and His-Purkinje system).
• By definition, class III agents act only on the repolarization phase of the action potential and therefore should leave conduction unchanged. However, amiodarone possesses actions similar to both class II and class IV antiarrhythmics: Amiodarone is a weak sodium channel blocker (class I effect). The result of this cellular action is a slowing of the upstroke velocity of phase 0 which reduces the rate of membrane depolarization and impulse conduction. Amiodarone also depresses automaticity of both the SA and AV nodes directly (class II effect),[24497] and slows conduction in the His-Purkinje system, and in the accessory pathway of patients with Wolff-Parkinson-White syndrome.
  Amiodarone also noncompetitively inhibits alpha- and beta-receptors, and possesses both vagolytic and calcium-channel blocking properties. The drug relaxes both smooth and cardiac muscle, causing decreases in coronary and peripheral vascular resistance, left ventricular end-diastolic pressure (LVEDP) and systolic blood pressure, thereby decreasing afterload.
• The 2006 ACC/AHA/ESC practice guidelines for inpatient pharmacological cardioversion of atrial fibrillation recommend a dose of 1.2—1.8 g/day PO, divided, until a total of 10 g has been administered, followed by a maintenance dose of 200—400 mg/day (Class IIa recommendation). For outpatient therapy, 600—800 mg/day PO in divided doses is recommended until a total of 10 g has been administered, followed by a maintenance dose of 200—400 mg/day (Class IIa recommendation).

Digoxin:
(How does it affect HR? MOA?)

• • : Digoxin inhibits the Na-K-ATPase membrane pump. Na-K-ATPase regulates intracellular sodium and potassium. Inhibition of this enzyme leads to an increase in intracellular sodium concentration (i.e., decreased outward transport) and ultimately to an increase in intracellular calcium as sodium-calcium exchange is stimulated by high intracellular sodium concentrations. It is believed that increased intracellular concentrations of calcium allow for greater activation of contractile proteins (e.g., actin, myosin).
  • Digoxin directly increases the force and velocity of myocardial contraction in both healthy and failing hearts.
  • Digoxin also possesses direct vasoconstrictive properties and reflex CNS-mediated peripheral vasoconstriction. Although this increases vascular resistance, in patients with failing hearts, increased myocardial contractility predominates and total peripheral resistance drops. In patients with congestive heart failure, an increased cardiac output will decrease sympathetic tone, thereby reducing the heart rate and causing diuresis in edematous patients and improving coronary blood flow
  • shortens the action potential duration, and decreases the maximal diastolic potential. The increase in vagal activity mediated by cardiac glycosides decreases conduction velocity through the atrioventricular (AV) node, prolonging its effective refractory period. In atrial flutter or fibrillation, digoxin decreases the number of atrial depolarizations that reach the ventricle, thereby slowing ventricular rate