Small Molecular Weight Drugs
- 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)
Perfusion Rate Limitation
• 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
Mean Input Time of SMWD via SC and IM
- 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)
Precipitation at Injection Site
• 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
Macromolecules vs Small Molecules
- 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
Lymphatic Vessels
- 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
Mechanisms for Producing Lymph Flow
- 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
Characteristics of Systemic Absorption: Extent
- 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
Characteristics of Systemic Absorption: Rate
• The systemic delivery of macromolecules is slow because
- slower rate of movement across the capillary membranes
- slow movement of lymph
- binding within lymph nodes
Macromolecules MIT (depends on?) and Antibody MIT
- 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
FACTORS AFFECTING ABSORPTION
- 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
State why drugs given IM or SC often peak earlier than when give orally.
- Don’t have to go through GI tract / portal circulation
- Less barriers from site of administration to bloodstream
Explain why we observe slow and often incomplete systemic bioavailability of protein drugs after SC or IM.
- Absorbed through lymphatic system, which is slower and contains proteolytic enzymes
What are the factors that determine the extent and duration of systemic absorption through the lymphatic system?
- SIZE
- Location
- Volume
- Exercise
- Co-administration
- Precipitation
Why does a larger volume have a slower input?
• 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
Epinephrine
- 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
Chlordiazepoxide & Diazepam & Phenytoin
- 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
