Pharm- Gi/liver/pancreas/biliary System

Front 1

Explain the stimulation of acid production the stomach. What cells are activated and by which molecular messengers?

Back 1

The Enteric (Muscarinic) nervous system, or Gastrin hormone, stimulates ECL (Enterochromaffin-like) cells to produce Histamine. Histamine binds H2 receptors on Parietal Cells and activates Adenylate Cyclase. This results in a rise in cAMP and protein kinase stimulation of the H+/K+ ATPase. This produces the rise in gastric acid and drop in pH in the lumen of the stomach.

Front 2

What are the three major parameters that determine drug elimination by the liver?

Back 2

1) Blood flow to the liver
2) Fraction of drug in the blood that is free or not bound to plasma proteins and is capable of interacting with hepatic enzymes
3) The intrinsic ability of hepatic enzymes to metabolize the drug and/or biliary excretion.

Front 3

Define what the Extraction Ratio of a drug is. What defines a HIGH. INTERMEDIATE, and LOW extraction ratio?

Back 3

The Extraction Ratio of a drug is the ratio of hepatic clearance of a drug to the hepatic blood flow. HIGH (>0.7), INTERMEDIATE (0.7-0.3), LOW (<0.3)

Front 4

If a drug is very efficiently cleared by the liver what is the main limiting factor to its rate of clearance? What type of clearance is this called?

Back 4

In the case the main limiting factor to the rate of clearance of the drug is blood flow. This is called non-restrictive clearance.

Front 5

Name 5 drugs that we have learned about that have Flow Dependent/Non-restrictive hepatic clearance.

Back 5

Morphine, Propranolol, Verapamil, Lidocaine, Nitroglycerine

Front 6

Explain some of the pharmacokinetics that are involved with drugs that have Flow Dependent/Non-restrictive hepatic clearance. How does the "1st pass effect" affect them? Are they sensitive to changes in plasma protein binding? What sort of conditions will reduce their clearance from the body?

Back 6

These drugs experience a very significant first pass metabolism when given orally because the extraction ratio is high in the portal circulation. These drugs are far less sensitive to plasma protein binding because they are so efficiently metabolized in the liver. Conditions that reduce hepatic blood flow (i.e. CHF, Shock, and Hypotension) will reduce hepatic clearance of these drugs significantly.

Front 7

For drugs that have Flow Dependent/Non-restrictive hepatic clearance, what is one organ problem that might increase bioavailability?

Back 7

Cirrhosis of the liver can markedly increase the bioavailability of these types of drugs by reducing P-450 levels and pre-systemic (first pass) metabolism.

Front 8

For drugs with Capacity Limited/Restrictive Hepatic clearance, what is the main rate limiting factor involved in the clearance of those drugs? Why?

Back 8

The main rate limiting factor here is the propensity of plasma protein binding for that drug and is realtively independent of hepatic blood flow. If the drug is bound up and joined with plasma protein, it cannot be acted upon by the liver.

Front 9

What type of pathologic conditions will increase the clearance of drugs that normally have Capacity Limited/Restrictive Hepatic clearance?

Back 9

For this class of drugs, disease-related decreases in plasma protein levels will increase the fraction of unbound drug, which will increase hepatic clearance.

Front 10

What are some of the drugs that we know of that have Capacity Limited or Restricted hepatic clearance?

Back 10

Wafarin, Pheytoin

Front 11

Explain some of the pharmacokinetics for drugs that have Capacity Limited or Restricted hepatic clearance. What type of metabolic changes are these drugs sensitive to? Do they exhibit large 1st pass effects? Do they have longer or shorter half-lives?

Back 11

The clearances of these drugs is very sensitive to changes in binding to plasma proteins (as can occur w/ hypoalbuminemia, cirrhosis, nephrotic syndrome), as well as changes in drug metabolism and excretion. There is not a significant first pass effect associated with these drugs, and they tend to have longer half lives than other drugs (e.g. phenytoin t1/2= 43hrs

Front 12

What are some drugs that are representative of an Intermediate Hepatic Extraction ratio?

Back 12

Aspirin, Codeine, Quinidine, Nortryptyline

Front 13

Discuss the pharmacokinetics of drugs that are representative of an Intermediate Hepatic Extraction ratio?

Back 13

This class of drugs will be sensitive to changes in both hepatic blood flow and changes in binding to plasma proteins or in drug metabolism/excretion.

Front 14

How is the steady-state concentration calculated when administering a drug over long periods of time?

Back 14

This steady-state concentration is calculated by comparing the drugs infusion rate from its elimination clearance.

Front 15

What are active metabolites and why should you care about them when you are administering a drug? What is the example of active metabolites given with Lidocaine?

Back 15

Active metabolites are products that are produced from the breakdown of a particular therapeutic agent that still retain biologically active properties. These are important because they can cause effects in the patient that are very potent and unwanted. The example of active metabolites given with Lidocaine are MEGX and GX. MEGX has a similar antiarrhythmatic and convulsant potency as lidocaine, thus its levels must also be monitored when lidocaine is being administered.

Front 16

How do you calculate bioavailability?

Back 16

Bioavailability is calculated by comparing the area under the plasma[drug] vs. time curve for a drug give p.o. vs. that drug given i.v.

Front 17

Define extraction ratio for hepatic clearance.

Back 17

Extraction ratio for hepatic clearance = The Total Amount of drug coming into the liver via the Hepatic Artery and Portal Vein minus the amount leaving the liver in the hepatic vein, divided by the total amount that came in.

Front 18

What are enzyme systems does St. John's Wort interact with? Which medications can potentially be affected?

Back 18

St. John's Wort induces PGP and P-450, so that any medications that are broken down/affected by these pathways will have increased clearance. The short list of drugs that are affected include Oral Contraceptives, Protease inhibitors, Warfarin, Theophylline (asthmatics), MOA and SSRIs can interact with St. John's to produce high temps and high BP.