Disease States Flashcards by Jared Gabbert

What are some of the kidney’s function besides elimination?

Maintain fluid and ion homeostasis
Maintain blood pH balance
Maintain blood osmolarity
Produce erythropoietin for RBC production
Produce Renin for BP regulation
Produce calcitriol which helps maintain calcium and phosphate

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CKD

Chronic kidney disease

GFR

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ESRD

End stage renal disease

GFR

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Creatinine is largely filtered. What is the implication for drugs removed by TS or TR?

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Describe the Intact Nephron hypothesis

A nephron simply works or does not work. As other nephrons stop working the rest of the nephrons can increase their output up to a certain point. This can maintain GFR to a certain degree.

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What are the two types of methods to calculate creatinine clearance?

Direct

Estimation (Cockroft and Gault)

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If a drug was cleared by Tubular Secretion, what will their slope be on a clearance vs. GFR graph?

Greater than 1

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If a drug was cleared by Tubular Reabsorption, what will its slope be on a clearance vs GFR graph?

Less than 1

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What is the impact of CRD on a drug’s PK parameters if that drug is renally cleared?

Half-life increases
Clearance decreases
Volume does not vary much

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Describe the general rule involving fe

If fe

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How does renal failure affect protein binding?

In severe renal failure the total drug levels can change due to fu.
This is because Albumin levels will decrease, but AAG might increase.

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How does renal failure affect hepatically cleared drugs?

Renal failure will only affect the hepatic elimination if the drug relies on transporters for removal or some metabolic processes.

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How are plasma proteins and binding to plasma proteins affected by renal disease?

There is a decrease in plasma protein synthesis and accumulated waste products can displace drugs from plasma proteins. These two effects would lead to an increase in the fraction of unbound drug (fu).

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If a drug is primarily eliminated by CYP2D6 and during renal disease the half-life is constant, but the AUC is increasing, what could be causing this?

An increase in [AAG] and the drug binds to this. This would lead to a higher bioavailability because the fraction unbound is less.

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What is the affect of CRD on volume of distribution?

It is usually increased. This is due to a decrease in clearance and fluid accumulation.

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Why are some enzymes and transporters down regulated during CRD?

High levels of PTH (parathyroid hormone), cytokines, and uremic toxins.

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What is the impact of hemodialysis on PK?

HD can cause a rapid lose of drug during the dialysis session.

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When might the impact of HD cause one to consider supplemental dosing?

When the peak and trough concentrations are too low.

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When are the true troughs of a drug after dialysis?

1 hour post

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How do you dose ESRD when someone is on HD?

Loading dose: 1.5-2mg/kg

Maintenance dose: 1mg/kg

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Are drugs with a high V or low V better removed by dialysis?

Low V because they are in contact with the dialysis membrane more often.

If a drug binds to AAG will its removal be increased by dialysis or unchanged?

Increased because AAG is normally removed by the kidney.

If a drug binds to ALB will its removal be increased, decreased, or remain unchanged by dialysis?

Decreased because ALB is not removed by dialysis.

What is the effect of intrinsic clearance during dialysis?

It is increased.

How is hepatic clearance affected by CRD?

It isn't affected.

How are basic, acidic, and neutral drugs affect by CRD?

Basic drugs are more extensively bound because of an increase in [AAG]. Acidic and neutral drugs are less bound because of the decrease in {ALB]

What are uremia's PK effects on drugs distribution/

Decreased protein binding, which lead to an increase in non-renal clearance

Describe uremia's effects on hepatic metabolism.

Uremia causes a decrease in CYP enzyme expression due to an increase in IL, TNF, PTH, and circulating inhibitors.

Describe uremia's effects on drug transporters.

Uremia causes an increase in circulating inhibitors, which leads to an increase in OAT1A4.

What are some main hepatic functions?

Synthesis of bile Synthesis of most plasma proteins Processes fats, sugars, and amino acids Stores iron, vitamins, and glucose Processes ammonia to urea and lactic acid Metabolizes drugs and dietary toxicants, bilirubin, and hormones

Describe liver cirrhosis.

Chronic damage | Affects all heptaic processes unequally

Describe biliary obstruction.

Elevates bilirubin, inhibits bilirubin excretion

What maintains liver architecture until the damage is repaired?

Collagen

What is ascites?

Build up of fluid in the abdominal cavity due to an increase in blood pressure in the liver. This could be due to shunting of the blood.

Describe the Child-Pugh classification of liver disease severity.

Measures multiple liver indicators to assess liver function.

Group A of Child-Pugh test

Mild liver disease (5-6 points)

Group B of Child-Pugh test

Moderate liver disease (7-9 points)

Group C of Child-Pugh test

Severe liver disease (10-15 points)

What are 3 problems with predicting PK in hepatic disease?

Defining the severity accurately Assessing the effects on specific metabolic pathways Elucidating the relative importance of shunting

How is fu, intrinsic clearance, oral bioavailability, and blood flow affected by hepatic disease?

Fu-increases Intrinsic clearance-decreases Oral Bioavailability-increases for high E drugs Blood flow-decreases (shunting)

Describe shunting's affect on 1st pass metabolism.

Shunting causes a decrease of 1st pass elimination because drugs will be pushed around the liver into the systemic system. Shunting causes a backup of the portal vein leading to varices.

What phase II enzyme is spared in hepatic disease?

Glucuronyl-transferase (UGT)

Which drug pathway would you select when dosing in hepatic disease?

UGT | Glucuronyl-transferase

What enymes are more affected by all liver diseases?

CYP1A2 | CYP2C19

What pharmacokinetic parameters do you anticipate to be affected by liver disease in a drug that is metabolized by CYP2C19 and Intermediate E?

Half-life, clearance due to it being intermediate E Oral bioavailability due to the enzyme that metabolizes it.

Are patients with liver disease more sensitive to Nifedipine?

No. Even though the total drug exposure is increased the EC50 of the unbound drug is about the same. Since unbound drug is driving the effect, there is no difference.

Liver disease causes an increase in these drugs' metabolite AUCs.

Bupropione | Fluoxetine

Metabolite AUC can go down in liver disease for these drugs...

Flunitrazepam Sertraline Enalapril

What do you do to the opiate or BZD dose if a patient has mod.-severe liver diease?

Cut the dose by 1/2 or 1/4

What should you replace cimetidine and ranitidine in patients with hepatic disease?

Use proton pump inhibitors

What do you expect the effects on clearance to be in a patient with heart failure?

If the drug is high E I expect clearance to drop because blood flow is decreasing. This increases AUC. It can also cause higher Hepatic bioavailability leading to increased AUC.