Topic 7

Question 1

Small Molecular Weight Drugs

Answer 1

• MW < 2000 g/mole
  • In contrast to the GI tract, systemic absorption from muscle and subcutaneous tissue sites of most drugs in solution is perfusion rate-limited
  • Increases in blood flow hasten drug absorption (and decreases in blood flow slow absorption)

Question 2

Perfusion Rate Limitation

Answer 2

• Perfusion-dependent absorption is explained by the nature of the barrier (the capillary wall {loosely knit}) between the site of injection (interstitial fluid) and blood
• Offers little impedance to the movement of drugs into blood, even for polar ionized drugs
• This low impedance by the capillary wall in muscle and subcutaneous tissue applies to drugs, independent of
- pKa
- degree of ionization, or
- molecular size up to 2000 g/mole

Question 3

Mean Input Time of SMWD via SC and IM

Answer 3

• Mean time for systemic absorption of SMW drugs given in solution by IM and SQ routes is about 5 to 40 minutes
• SC absorption is usually slower than IM, but both routes depend on the specific site of administration and the volume injected
• Practically, a larger volume can be injected IM than SQ (IM up to 5mL, SQ only 1-2mL)

Question 4

Precipitation at Injection Site

Answer 4

• Systemic input of some drugs given in solution is highly prolonged because of precipitation at the injection site
• This occurs when a salt of either a sparingly soluble acid or base is administered or when a drug is given in an oil solution or in a solvent that is rapidly diluted and systemically absorbed
- EXs: chlordiazepoxide hydrochloride and phenytoin sodium

Question 5

Macromolecules vs Small Molecules

Answer 5

• Whereas small molecules readily cross the capillary membranes in muscular and subcutaneous tissues, macromolecules (>20,000 g/mole) do not
• Consequently, by default, macro-molecules enter the lymphatic capillaries and reach blood via the lymphatic system

Question 6

Lymphatic Vessels

Answer 6

• Lymphatics (collecting lymphatics)
• Thinner walls and one-way valves that are much more frequent than in veins
• All lymph passes through at least one lymph node; some passes through several

Question 7

Mechanisms for Producing Lymph Flow

Answer 7

• One-way valves
• Pressure differential
• Muscular coat in collecting lymphatics
• Rhythmic contractions regulated by: transmural distension, Humoral mediators, Neural stimulation
• Extrinsic factors: Muscle contractions (skeletal), Breathing, Motility of GI tract

Question 8

Characteristics of Systemic Absorption: Extent

Answer 8

• Lymphatic system has proteolytic enzymes so that systemic delivery (F) after SC or IM injection is most often not complete for protein drugs
• DECREASED BIOAVALIABLITY OF LARGE OR PROTEOLYTICALLY SENSITIVE PROTEINS

Question 9

Characteristics of Systemic Absorption: Rate

Answer 9

• The systemic delivery of macromolecules is slow because

• slower rate of movement across the capillary membranes
• slow movement of lymph
• binding within lymph nodes

Question 10

Macromolecules MIT (depends on?) and Antibody MIT

Answer 10

• The mean input time is usually in the 5-48 hour range
• It depends on how much enters via the blood capillaries, how long the drug is retained in lymph nodes and at the injection site
• For ANTIBODY drugs, the mean input time is 2-8 days

Question 11

FACTORS AFFECTING ABSORPTION

Answer 11

• Molecular size (overriding factor)
• Site of injection
• Co-administration of albumin (added to slow absorption after IM/SC)
• Exercise (+rubbing can increase rate)
• Depth of injection
• Injection volume

Question 12

State why drugs given IM or SC often peak earlier than when give orally.

Answer 12

• Don’t have to go through GI tract / portal circulation

- Less barriers from site of administration to bloodstream

Question 13

Explain why we observe slow and often incomplete systemic bioavailability of protein drugs after SC or IM.

Answer 13

• Absorbed through lymphatic system, which is slower and contains proteolytic enzymes

Question 14

What are the factors that determine the extent and duration of systemic absorption through the lymphatic system?

Answer 14

• SIZE
• Location
• Volume
• Exercise
• Co-administration
• Precipitation

Question 15

Why does a larger volume have a slower input?

Answer 15

• The slower input with a larger volume has been ascribed
to
- larger volume to surface area ratio of the injected solution and
- greater distance for diffusion of drug within the injected
volume
• The mean time to input the drug can be prolonged by decreasing tissue blood flow

Question 16

Epinephrine

Answer 16

• The mean time to input the drug can be prolonged by decreasing tissue blood flow
• Adding epinephrine, a vasoconstrictor, to the injection solution with local anesthetics to increase the time the drug stays at or near the site of injection

Question 17

Chlordiazepoxide & Diazepam & Phenytoin

Answer 17

• Chlor. is sparingly soluble, salt of SA/WB
• Diazepam is sparingly soluble / slowly absorbed when injected -> solvent is rapidly absorbed
• Phenytoin is sparingly soluble weak acid

ALL CAUSE PRECIPITATION AT INJECTION SITE