SG1: PK/PD

Question 1

Discuss other routes of administration in terms of their bioavailability:

Answer 1

• Intravenous: Bioavailability is 100% (by definition).
• Intramuscular : Bioavailability 75 to  100%.
• Subcutaneous: Bioavailability 75 to  100%.
• Sublingual: Suitable for certain drugs only. Generally high bioavailability. Venous drainage from the mouth is to the superior vena cava, which protects highly soluble drugs like nitroglycerin from rapid hepatic first-pass metabolism.
• Rectal: Bioavailability 30 to < 100%. Approximately 50% of the drug that is absorbed from the rectum will bypass the liver, thus reducing the hepatic first- pass effect. Compared to the oral route it offers superior bioavailability for drugs which are subject to pronounced first pass effect and which are easily absorbed. On the other hand it offers inferior bioavailability for drugs with lower absorption rates (e.g butylscopolamine).
• Transdermal: Bioavailability 80 to  100%. Achieves systemic effects by application of drugs to the skin, usually via a transdermal patch. This route is most often used for the sustained delivery of drugs. The drug is not subject to first-pass metabolism or harsh GI environments. Bioavailability is high. Requires highly lipophilic drugs. The delivery to the site of action is slow.

Question 2

Penicillin G is effective only when given IV; penicillin V is also effective when given orally. Nitroglycerine is effective when given by the sublingual, transdermal, or injectable routes but not when given orally. Explain.

Answer 2

Penicillin G is degraded in the acidic environment of the stomach, while Penicillin V is acid-stable.

Nitroglycerine is easily absorbed but has a very high hepatic first pass metabolism, inactivating about 90% of an oral dose before systemic circulation is reached. When bypassing the portal vein, nitroglycerine will reach the systemic circulation readily.

Question 3

Consider the relevance of drug bioavailability in this situation: topical application of a corticosteroid cream to the skin

Answer 3

• Almost always significant amounts of topically applied drugs enter the systemic circulation. The skin is able to absorb a wide variety of drugs. Systemic absorption after application of a drug to the skin may be an unwanted effect:
• Absorption of drugs after topical application may also be a desired effect. Several drug patches, creams and ointments contain e.g. nitroglycerine, NSAIDs, heparin, etc.

Question 4

Definevolumeofdistribution.

Answer 4

Vd is the volume that would be required to contain all of the drug in the body at the same concentration as in the blood or plasma. It is defined operationally as:

Question 5

What is the molecular mechanism of P450 enzyme induction?

Answer 5

P450 enzyme induction typically occurs via increased transcription. Inducers enter hepatocytes and bind to xenobiotic receptors, such as the aryl hydrocarbon receptor (AhR), the pregnane X receptor (PXR), or the constitutively active receptor (CAR). Activated receptors translocate to the nucleus and bind to the promoters of the genes of various enzymes.