For a drug to be excreted it needs to be:

1. Hydrophillic and charged

2. Hydrophobic and uncharged

3. Lipophillic and unchanrged

4. Lipophobic and uncharged

The goal of metabolism is to convert a drug from being hydrophobic to hydrophillic and uncharged to charged in roder to be excreted by the kidneys. The kidneys will reabsorb lipophillic uncharged drugs easily.

GFR would be reduced by 50%. Normal GFR is 125 cc. It would be reduced to around 62 cc. At 50 years old, there is a 10% decline in GFR. Every decade thereafter, you lose 10% kidney function.

What percentage of CO is filtered by the kidneys?

Normal CO is 5 L. The kidneys filter 20% of that which is 1250 ml. Half of that is plasma, 600 ml. 25% of that is filtered by the gomeruli. 125 ml is the average GFR.

Lasix works at the loop of Henle and inhibits the Na/K/Cl co-transporter. It inhibits the reabsorption of 30% of Na back into the body. The urine will have more sodium, potassium, and water.

(140-age)x weight (kg)/72x Scr

(140-80)x 80/72x2

GFR=33.3

At a GFR of 20 a patient would exhibit

1. Hypophosphatemia

2. Hyperphosphatemia

3. Hypokalemia

4. Hyperkalemia

At a GFR of 20, a patient would be unable to maintain phosphate homeostasis. The patient would but unable to excrete phosphate and would have hyperphosphatemia. At a GFR of 10, a patient is unable to excrete potassium.

It takes 3-5 half lives for a drug to reach steady state. It would take 50 hours for a drug to achieve steady state with a half life of 10. 10x5=50. 

Before giving Lipitor, which lab value would you be sure to check?

Check LFTs! Lipitor has very high first pass effect (80%) so you should always check LFTs before prescribing it.

Day 1: 50 mg

Day 2: 25 mg

Day 3: 12.5 mg

Day 4: 6.25 mg

Day 5: 3.12 mg

A neonate would best absorb drugs that are:

1. hydrophobic 

2. hydrophillic

3. lipphillic

Which mechanisms might be in play in the patient with HTN and cardiac disease?  

Chronically elevated BP leads to adverse changes in cardiac structure and function. Sustained pressure on vessels causes damage to endothelium resulting in hypertrophy, narrowing the blood vessels. It decreases the amount of circulating NO and prostacycline (vasodilators). Results in decreased perfusion to all the organs.

JNC8 recommends BP goal <140/90 for patients with heart disease.

Medications include ACEIs, ARBs, diuretics, CCBs, and beta blockers.

Which mechanisms might be in play in the patient with HTN and renal disease?  What are the goals of treatment for the patient with renal disease? Which medications might be beneficial and why?  Which medications would be contraindicated and why?

JNC8 recommends to initiate therapy in patients with CKD with BP of >140/90 and lower it to a BP goal <140/90.

Treatment: JNC 8 Recommends an ACE or an ARB without regard to race in patients with CKD or Diabetes.

CKD without proteinuria can use ACEI, ARB, Beta blocker or thiazide.

Thiazides are not effective with renal insufficiency with SCr >2.5.

Lasix is more effective

ACEIs reduce the progression of nephropathy, decreased pressure in glomerulus.

Decreasing GFR too much in patients who already have renal disease can send them into renal failure.

GFR of 10- kidneys can’t excrete potassium.

Diabetes and hypertension frequently occur together. There is substantial overlap between diabetes and hypertension in etiology and disease mechanisms. Obesity, inflammation, oxidative stress, and insulin resistance are thought to be the common pathways.

Diabetes and hypertension share common pathways such as SNS, RAAS, oxidative stress, adipokines, insulin resistance, and PPARs. These pathways interact and influence each other and may even cause a vicious cycle. Hypertension and diabetes are both end results of the metabolic syndrome.

Metabolic syndrome is the name for a group of risk factors that raises your risk for heart disease and other health problems, such as diabetes and stroke.

1. Abdominal obesity: a waist circumference of 102 cm (40 in) or more in men and 88 cm (35 inches) or more in women. For Asian Americans, the cutoff values are ≥90 cm (35 in) in men or ≥80 cm (32 in) in women
2. Serum triglycerides 150 mg/dl or above.
3. HDL cholesterol 40mg/dl or lower in men and 50mg/dl or lower in women.
4. Blood pressure of 130/85 or more.
5. Fasting blood glucose of 100 mg/dl or above.

• Aging- reduced elasticity of large conduit arteries. Kidney decline.

• Sodium sensitivity, defined as the extent of the rise in arterial blood pressure with an increase in sodium chloride intake, is heightened with age.

• The prime objective of this therapy is to prevent stroke

Thiazides inhibit the Na Cl transporter in the distal convoluted tubule inhibiting 10% of sodium reabsorption. Causes increased sodium and water in the filtrate. There will be more K in urine because of effect of Aldosterone.

Reduced excretion of calcium in urine. Good for older adults with osteoperosis or osteopenia.

Loop diuretic such as Lasix. I would prescribe 20 mg PO once daily.

I would elect to use a loop diuretic with a patient with severe CKD (stage III, IV, V). I would choose a thiazide for a patient with mild CKD (stage I, II). I would choose a thiazide for an elderly patient with osteoporosis. I would not use a diuretic in patients with gout or hyperuricemia.

It inhibit the cotransport of the Na+/K+/2Cl- in the luminal membrane of the ascending limb of the Loop of Henle.

Hyperglycemia

Hyperuricemia

blocks effects of Aldosterone. Blocking vasoconstriction and sodium and water retention. Results in Increased potassium.

What is the MOA of an ACEI?

1. dry cough mediated by the accumulation in the lungs of bradykinin, substance P, and/or prostaglandin.

2. ANGIOEDEMA

3. Acute renal failure- AngII, by constricting the efferent arteriole, helps to maintain adequate glomerular filtration when renal perfusion pressure is low. Inhibition of ACE can induce acute renal insufficiency in patients with bilateral renal artery stenosis, stenosis of the artery to a single remaining kidney, heart failure, or volume depletion owing to diarrhea or diuretics.

4. Skin rash: ACE inhibitors occasionally cause a maculopapular rash that may itch, but that may resolve spontaneously or with antihistamines. Although initially attributed to the presence of the sulfhydryl in some ACE inhibitors.

5. Hyperkalemia- Significant K+ retention is rarely encountered in patients with normal renal function. However, ACE inhibitors may cause hyperkalemia in patients with renal insufficiency or diabetes or in patients taking K+-sparing diuretics, K+ supplements, β receptor blockers, or NSAIDs.

Valsartan- Direct antagonism of angiotensin II (ATII) receptors; displacing AT II from AT I receptors and preventing AT II mediated aldosterone secretion.

Start at 80 mg PO once daily. 

1. bradycardia,

2. decreased myocardial contractility

3. decreased lipolysis

1. vascoconstriction
2. bronchoconstriction,
3. increased peripheral resistance
4. uterine smooth muscle contraction
5. decreased muscle and liver glycogenolysis

They can cause more peripheral vasoconstruction, esp with beta 2 blockage. A cardio selective beta 1 blocker may be ok to prescribe.

Amlodipine is a dihydropyridine calcium channel blocker that reduces the influx of extracellular calcium into cardiac and vascular smooth muscle cells via L-type calcium channels.

highly protein bound, very long half life (30-50 hours)- better control and better compliance. How long to reach steady state- 5X 50. 10 days. Slowly metabolized by liver. 60% is excreted in urine.

Initial dosing started at 5mg once daily with a maximum dose of 10mg once daily.

Which drug is considered a Benzothiazipine?

1. Cardizem
2. Verapamil
3. Amlodipine

Which drug is considered a Phenylalkaline?

1. Verapamil
2. Cardizem
3. Norvasc

Constipation, syncope, venous pooling-edema, hypotension, reflex tachycardia (dihydropyridines)- because baroreceptors try to increase HR to provide adequate CO. Increasse in HR can increase 02 demands.

• According to JNC8 Guidelines, a patient >18 with diabetes BP goal should be < 140/90.

• In nonblack population including those with diabetes, initial pharmacological therapy should include a thiazide, CCB, ACEI, or ARB.

• If the patient is black, treatment should include a thiazide or a CCB (NOT AN ACEI or ARB). This is because in the ALLHAT trial, there was a 51% higher rate of stroke in black persons taking ACEIs compared with use of CCB. Also, ACEIs were less effective in reducing BP in black people.

• HOWEVER, If patient has CKD and Diabetes, regardless of race, initial or add on therapy should include an ACEI or an ARB to improve kidney outcomes.

• I could prescribe a nonblack patient with diabetes a thiazide, ACEI, ARB or a CCB according to JNC8 guidelines. I would probably choose an ACEI instead of a thiazide, because thiazides can potentially increase serum glucose by activating the RAS system.  Lisinopril would be my drug of choice.  I would start at 10 mg once daily (not maintained on a diuretic) ( 5 mg once daily if pt is maintained on a diuretic).

  
  Lisinopril acts as a competitive inhibitor of ACE, preventing the conversion of ATI to ATII (a potent vasoconstrictor) and reduces the secretion of aldosterone.

There is no evidence to support initiating therapy with any one antihypertensive drug class over another for the primary prevention of IHD. Therefore, an ACEI, ARB, CCB, or thiazide diuretic can be prescribed.  

• The <140/90-mm Hg BP target is reasonable for the secondary prevention of cardiovascular events in patients with hypertension and CAD (Class IIa; Level of Evidence: B).

• Although CCBs are useful in the management of hypertension in patients with stable angina, there is no consensus about their role in preventing cardiovascular events in patients with established CAD.
• ACE inhibitors should be prescribed to all CAD patients with stable angina who also have hypertension, diabetes mellitus, an LV ejection fraction ≤40%, or CKD unless contraindicated (Class I; Level of Evidence: A)

• Again, I would probably prescribe an ACEI to this patient who has established CAD. Lisinopril 10 mg PO once daily or 5 mg if patient is already on a diuretic. However, thiazide diuretics are considered equally as effective for patients with established CAD. I could give hydrochlorthiazide 25 mg PO once daily. Most patients will need to be on several different drugs.

  ***If the patient also has stable angina, beta blockers would be first choice and then CCBs.

The patient has renal disease?  GFR of 64?  Which antihypertensive would you prescribe?

If an ACEI was given to a patient with GFR 64 (stage 2 CKD), the GFR would reduce by 25-30% to become 44.8. This is still ok to give to a patient.

ACEIs can actually reduce the progression of nephropathy because of decreased pressure in the afferent and efferent arterioles and decreased pressure in the glomerulus (reduces intraglomerular pressure), an antifibrotic effect, which could contribute to the slowing of renal disease progression, Protein excretion progressively declines over weeks to several months. ACE inhibitors and ARBs can cause a decline in renal function and a rise in serum potassium

An ACEI will decrease GFR by 25-30%. Therefore, a patient with a GFR of 30 could potentially reduce GFR to 21, which is dangerous territory. A patient with a GFR of 20 (stage 4 CKD) cannot maintain phosphorus excretion (contributing to hypocalcemia). GFR <15 is stage 5 CKD, or kidney failure.

The patient is an 80 or 15-year old female.  Discuss the treatment approach for hypertension.

According to JNC guidelines, in population >60, initiate pharmacologic treatment to lower BP  to a goal of <150/90.

In a population <60, initiate pharmacologic treatment to lower BP <140/90.

For both the 85 year old female, I would prescribe a thiazide diuretic. Protects calcium in patients. Can also prescribe CCB or an ACEI (check GFR- depressed renal function).

For the 85 year old I would start at 12.5 mg.

LPL

(Lipoprotein lipase)

IN the syhesis of VLDL. There is a lot of TG. As the VLDL traverses the caps, a ot of the TG is uptaken by the LPL and stores TG and fatty acids as fat in the adipose tissue. Fibrates do almost the same thing. They works on PPAR receptor. Activates LPL and  takes up triglyceride and fatty acids out of VLDL into the adipose tissue for storage. Removed from the VLDL and hence becomes an IDL with much less triglycerides. Work very well on triglyceride lowering. They decrease some of the covering, APO c, 1 and 3 coverings. Protein coverings. By decreasing the covering, they increase the circulating HDL in the body. Increase HDL. Make it easier for HDL to go back to the liver. Increase HDL reverse transport. Can increase levels of lithiasis. Always increase myopathy or rhabdo risk when combining meds. COMPETES with COUMADIN. An increase circulating level of coumadin, knocking coumadin back into circulation. Increased potential bleeding. Avoid with liver or renal disease. Only lowers LDL by 5-20%. Increases HDL 10-20%. Major effect is TG levels, reduce 20-50%. 

What is the MOA of statins?

(Lipitor)

Inhibits HMG CO A Reductase, which inhibits cholesterol synthesis. 

What are the 4 statin benefit groups?

1. Clinical ASCVD (Stroke, PAD, 

2. Primary elevation of LDL >190

3. 40-75 with Diabetes with LDL >70-189

4. Without clinical ASCVD or diabetes who are 40-75 years with LDL 70-189 mg/dL and have estimated ASCVD risk of >7.5% or higher.

1. Rhabdomylosis- muscle breakdown

2. myocitis

Statins are thought to interfere with CoQ10 enzymes levels, which helps prevent muscle breakdown.

Check for elevated CPK

Aways check LFTs before administering statins.

The liver forms bile acids. Eating triggers the release of bile acids from the common bile duct into the small intestine, emulsifying the fats to be absorbed. 90% is reabsorbed at the ileum and resyntheisized and packaged to form more bile acids. Bile acid resins are negatively charged ions that bind with bile acids preventing them from being reabsorbed back into the body. Insetad the remain in the GI tract and are excreted in the feces. Not as effective as statins and cause a lot of GI side effects. Onaly half as effective as statins.

CHOLESTYRAMINE

 Initial: 4g 1-2 times/day

may decrease Warfarin absorption

constipation, puritis

B3 vitamin that inhibits the breakdown of fat.

It prevents very low density lipid (VLDL) synthesis in the liver by inhibiting VLDL secretion, which decreases LDL production. Clearing VLDL through lipoprotein lipase removes triglycerides from the plasma, as does the prevention of free fatty acid release from adipose tissue.

Major side effect is flushing, because of release of prostaglandins. Asperin inhibits this.

Starting dose is: 1.5-2g PO daily in divided doses.

symptoms plus casual plasma glucose >200 mg/dL, fasting plasma glucose >126,  or plasma glucose >200 post 2-h ingestion of 75 g glucose.

The body produces a basal amount of insulin and in produces insulin in response to glucose (aka meal). The pancreas has a small amount of insulin and then it starts to synthesize insulin to cover the glucose ingested by the meal. We use a basal regimen to mimic the body’s production and we correct at meal times.

Pancreas has stored insulin, has a small amount that is ready to go. Pancreas starts to release pre packaged insulin. Pancreas starts synthesizing more insulin. To cover glucose ingested. Addtionally, the body and pancreas supplies a steady stream of insulin throughout the day. Glargine or Lantus is a peakless basal insulin, covers a 24 hour period. Given in combo with fast acting insulin. Lispro or Aspart, given a few minutes before somebody eats. Works the way the body works.

Inhibits thromboxane A2, which inhibits platelet aggregation. 

Inhibits remainder of the life of the platelet (no nucleus)

Side effects:

-tinnitus

-microscopic bleeding of the stomach- non-steroidal class of medications- inhibits prostaglandins, which is good for pt at risk for CV or acute MI. In stomach they contribute to a healthy stomach lining. Help make mucosa think and increase blood supply to mucosa. Contributes to increased risk of ucler disease and bleeding. All patients will have microscopic bleeding of mucosa. Iron trapping- gets caught in the mucosal lining. All NSAIDS, but especially aspirin. 

-It is well absorbed and has a high bioavailability.

Pro drug- it must be metabolized to its active form. P450 enzyme 2C19. 

Clopidrogel (Plavix)- P2Y12 ADP receptor inhibitor. Inhibits the activation of GPIIb/IIIa receptors required for platelets to bind to fibrinogen and to each other. It is a pro-drug, which relies entirely on its active metabolite CYP2C19.

Dose- 300 mg loading dose, followed by 75 mg once daily for up to 12 months

TTP

very long half life

1. Anti thrombin

2. Protein C

helps balance out the coagulation properties.

The USPSTF recommends the use of aspirin for men age 45 to 79 years when the potential benefit due to a reduction in myocardial infarctions outweighs the potential harm due to an increase in gastrointestinal hemorrhage. See the Clinical Considerations section for discussion of benefits and harms. 

MEN 45-79

MI

The USPSTF recommends the use of aspirin for women age 55 to 79 years when the potential benefit of a reduction in ischemic strokes outweighs the potential harm of an increase in gastrointestinal hemorrhage. See the Clinical Considerations section for discussion of benefits and harms.

WOMEN 55-79

ISCHEMIC STROKE

Unfractioned Heparin

LMMW Heparin

UFH- 30,000 daltons. 5,000 u. Because of lenght, they interact with Factor 10a and factor 2. UFH is very erratic in its action. Erratic bioavailability. It attaches to a lot of cellular elements- macrophages, RBCs, platelets and is inactivated. No sustained effect. Always check platelet count (attaches to platelets)- will be decreased and then rebound after 3-4 days- if not, be concered for Hepartin induced thrombocytopenia. half life is 1.5 hours.

LMWH (Lovenox)- very short pentasaccaride sequence. 4500 daltons. Only able to attach to Factor 10a (inhibits development of prothrombin). Has a sustained bioavailability. They are excreted more slowly and have a longer half life (3-4 hours).

Heparins work by potentiating the effect of antithrombin, specifically affect factors 2, 7 , 9 , and 10- and in the presence of antithrombin they inactivate those factors.

Anything <6,000 is considered LMW

Biguinide

Short half life of 6 hours.

Dose is 500 mg PO BID.

Most concerning side effect- GI.

Contraindicated with Cr >1.5 and elevated LFTs.

Reduces fatty acid syhthesis. Attaches to OTC receptors in liver, which decreases its production of glucose, it helps to decrease gluconeogenesis. Also and insulin sensitizer, helping tissues take up more glucose.