This document summarizes different parenteral routes of drug administration including intravenous, intramuscular, and subcutaneous. It discusses key aspects of each route such as typical volumes administered, advantages, and disadvantages. It also covers pharmacokinetic concepts for intravenous bolus doses such as zero-order and first-order kinetics, and equations for calculating parameters like volume of distribution, half-life, loading dose, and time to steady-state.

1. Parenterals
SOM2 – Semester 2

2. The Parenteral Route
• Parenteral preparations are sterile injections, infusions or implants for use in humans or animals.
They have defined particle size limits and bacterial endotoxin units.
• Pyrogens are endotoxins shed from the coat of gram negative bacteria, which cause fever. Once
pyrogens are introduced to a preparation, the product is spoiled as their small size makes them
very difficult to detect, filter adsorb and hence remove from preparations.
• The three main parenteral routes are IV, IM and SC. Intravenous routes involve administration of
drug into a blood vessel using a higher gauge needle (same as SC) than is used in IM.

3. Intravenous Administration
• The blood vessels chosen can be peripheral (back of hand, forearm) or central (SVC or large
central vein) depending on the pH and osmolality of the product, the volume and duration of
administration.
• Central veins can also be used where there is no peripheral access, to reduce the risk of
thrombophlebitis, or where rapid uptake of a large volume is required. They are also used for long
term antibiotics, chemotherapy and TPN.
• Administration into a central vein can be via central venous access device (CVAD) or catheter
inserted into vein, with tip located in the SVC or RA.
• Non-tunneled catheters: used short term, goes straight into vein.
• Tunneled catheters: used short term, sits on the skin and then goes into vein, located in
upper chest wall and surgically inserted (i.e. Hickman lines).
• Implanted ports: used long term, surgically inserted under the skin
• Peripherally inserted central catheter (PICC): used in X-rays and positioning.
• Intravenous administration can be a single dose or continuous infusion. IV is the best way to
delivery a dose precisely and rapidly for a quick onset. Anything under 10 or 15 minutes can
be classed as a bolus injection.
• Volumes range from a few mL to a few hundred mL, i.e. in fluid replacement or nutrient
feeding. Aqueous solutions are most common, but can be o/w emulsions too.

4. Intravenous Administration
• The advantages of IV administration include; no first-pass metabolism, 100% bioavailability, rapid
dilution, rapid and predictable onset and response, useful route in emergency or if no others
available and also if product irritant via SC or IM routes.
• The disadvantages of IV administration include; it is invasive, painful, must be given by trained
nurses, has to be particle free, is difficult to reverse, carries risk of needlestick injury, is costly to
manufacture and also as issues with patient compliance and extravasation (in one side of the
vein and out the other).

5. Subcutaneous Administration
• In SC administration, the fatty tissue just beneath the surface of the skin of the anterior thigh,
outer arm or abdomen is targeted.
• The drug is absorbed through tissues and taken up by capillaries and lymphoid vessels in the
immediate vicinity of the injection site.
• Subcutaneous volumes are usually in the region of 1mL, and nearly always less than 2mL, as the
injection is painful above this volume.
• Larger volume SC injections can be given in divided doses, or via hypodermoclysis, which is a
subcutaneous infusion. It’s not common to give large volumes parenterally via the SC route, but it
can be used in emergency where there is no venous access, for palliative patients or in cases of
dehydration.
• When a larger volume SC injection is needed, the drug can be formulated to include recombinant
human hyaluronidase (rHuPH20), which temporarily breaks down connective tissues and allows
bigger volumes to be administered with less pain. These are given at a slow rate to minimise pain
and damage nonetheless. Examples include Trastuzumab (5mL) and Rituximab (11.7mL).
• SC preparations are commonly aqueous solutions or suspensions, though oily solutions and
suspensions are also used, where a delayed onset or sustained duration of action is desirable
(depot injection). The speed of diffusion and hence time to onset therefore depends on the
formulation and the lipophilicity of the drug.

6. Subcutaneous Administration
• The advantages of SC injections are that it can be used to provide a delayed onset of action, can
be used when venous access is not available, can be used to deliver suspensions and it is more
patient friendly than IV injections as patients can be trained to self administer.
• The disadvantages of SC injections are that they are still invasive and can be painful, they are
difficult to reverse, the drug can be degraded by peptidases in the subcutaneous layer, the dose is
not 100% bioavailable, the onset can be varied depending on blood flow to the area, it is
expensive to manufacture (asepsis), it is inconvenient and scarring and temperature affect
absorption.

7. Intramuscular Administration
• Intramuscular preparations are delivered to the skeletal muscle, beneath the epidermis,
subcutaneous layer and dermis. A 20 gauge needle can be used to deliver the drug to either the
deltoid, thigh or buttocks.
• Typically, volumes will be 1 – 3mL, 5mL can be administered gluteally but will be painful for the
patient. 10mL can be given in divided doses, as is the case for a current breast cancer treatment.
• As was the case with SC injections, aqueous solutions or suspensions, as well as oily solutions or
suspensions can be administered via this route. The time to onset again depends on the
formulation of the medication and the lipophilicity of the drug.
• The choice of formulation, i.e. aqueous solution or oily suspension, will depend on the drug
properties and the desired therapeutic effect. If the drug is poorly soluble in water, then an oily
solution may be used, or alternatively an oily suspension can be used to achieve a longer duration
or time to onset of action.
• An example of this is an IM injection of Penicillin G benzathine, which provides an effective
concentration for 7 – 10 days. Haloperidol decanoate is an antipsychotic that provides a
therapeutic effect for about 3 weeks. This is particularly beneficial as it reduces issues with patient
compliance that can be associated with patients taking antipsychotics.

8. Intramuscular Administration
• The advantages of IM administration are that it can be used to deliver solutions or suspensions,
offers the potential for controlled drug release (depot), can be used to deliver larger volumes than
SC administration, is more accepted by patients than IV, offers a rapid onset (second to IV) and it
can be used to administer drugs that would irritate SC tissues.
• The disadvantages of IM administration are largely the ones shared by all injectable routes of
administration; it is invasive, painful, requires sterile preparation, requires training for
administration, is difficult to reverse, is difficult for the patient to self inject and also is costly to
produce.

9. Categories of Parenterals
• Injections and infusions are ready to administer, no reconstitution or manipulation necessary. They
are sterile, liquid solutions that are nearly always aqueous based.
• Some examples of direct injectables include insulin and low MW heparin injections (i.e.
enoxaparin – brand name Clexane), whilst some common infusion bags include 0.9% NaCl, 5%
glucose and blood related products.
• Those products that are labeled “for injection” or “for infusion” must be reconstituted or diluted
before use. Powders for injection are commonly lyophilised powders that must be mixed with a
diluent before administration (i.e. sterile water for injections). Powders for concentration or solution
are the same thing, whereas concentrates for solution are concentrated liquids that must first be
diluted before use (i.e. Trastuzumab).
• Emulsions for injection or infusion are sterile emulsions ready for injection or infusion. Examples
include the anaesthetic propofol (O/W emulsion), the calcium channel blocker Clevidipine (O/W
emulsion) and TPN lipids like intralipid or structolipid, which are also O/W emulsions for infusion.
• Suspensions for injection are ready to administer aqueous or oil-based preparations, but only for
IM or SC use, NEVER IV! IV administration would lead to thromboembolism. Drugs in these
formulations must dissolve to be absorbed, like methylprednisolone acetate suspensions

10. Categories of Parenterals
• Products labeled “for injectable suspension” require manipulation before they can be administered
as a suspension. They are usually dry solids, i.e. lyophilised powders, to which a suitable vehicle
is added to form a suspension.
• There is one exception to the rule that suspensions can never be given via the IV route, which is
Abraxane (nAb-paclitaxel). This is able to be reconstituted to be administered IV because the
particles are nanosized and so do not pose a thromboembolism risk. They are also albumin-
bound.
• Implants are a sterile parenteral preparation that is often not considered. They are usually SC or
IM administered for a systemic effect, or can be inserted into a specific location for a local effect.
• These preparations provide a long-acting continuous release of drug product, i.e. days, weeks,
months and years. They can either be pellets or reservoirs. Pellets are small, sterile solid masses
of drug with or without excipient, with or without a polymer that is permanent or biodegradable.
Reservoir implants are different in that they contain a drug encapsulated in a metal or plastic
coating, which is released gradually over time due to osmotic pressure. They are administered via
specialised insertion products and usually require surgical removal when the entire dose has been
spent.

11. Pharmacokinetics of IV Bolus
• IV bolus doses (volumes less than 15mL) are used to deliver drugs directly into a venous vessel
for immediate systemic effect, with 100% bioavailability and no first pass metabolism.
• In terms of PK profiles, IV bolus doses have either zero-order or first order kinetics with linear or
exponential degradation, demonstrated via the following graphs. The one on the left is a zero-
order kinetic PK profile, the one on the right is a IV bolus showing first-order kinetics.
• Most IV bolus drugs exhibit first-order reaction kinetics, based on the one-compartment model
which assumes that introduction of drug into the plasma results in complete distribution of drug
into the plasma, which then has a constant fraction of elimination per unit time.
time time
plasmaconcentration
plasmaconcentration

12. Pharmacokinetics of IV Bolus
• The PK profile depends on three factors; the volume of distribution, the clearance and the dose
administered (and absorbed?).
• Increasing the dose increases the initial plasma concentration but does not affect the rate of
decline; this is independent of dose.
• The volume of distribution can affect the PK profile, as it is a measure of the tendency of a drug to
distribute into tissues and thus leave the plasma. Having a high volume of distribution means that
the drug distributes widely into tissues or is highly protein bound, meaning that it has a low free
concentration in the plasma after administration of a dose. This means that drugs with high
volumes of distribution will have a longer half life.
• Large volumes of distribution are associated with drugs that have a high logP/degree of
lipophilicity, as these are not preferred in the plasma for energetic reasons and either bind to
plasma proteins or are pushed out into tissues.
• Increasing the clearance of drugs results in a faster rate of drug removal from plasma and
therefore leading to a shorter half life. Total clearance is the amount of drug excreted unchanged
in the urine, plus active metabolites.

13. Pharmacokinetics - Equations
• The equation of a plasma concentration-time curve is: C = C0e-λt where C is the plasma
concentration at time = t, C0 is the plasma concentration at time = 0, λ = elimination rate constant
and t = time.
• The drug concentration at time = 0 is: D/Vd where D is dose and Vd is volume of distribution.
• The elimination rate constant = Cltotal/Vd
• The half life of a drug (t1/2) = 0.693/λ, which can be rearranged to 0.693Vd/Cltotal
• A drug has a Vd of 50L and dose of 500mg; the C0 is 500mg/50L = 10mg/L.
• The Cltotal of the drug is 2L/hr, so the t1/2 can be calculated to be: (0.693 x 50)/2 = 17.325 hours.
• The minimum effective concentration (MEC) is 2mg/L, so the time taken to reach MEC can be
calculated: 2 = 10 x e-0.04t, where λ has been calculated by 2/50. Rearranging gives 0.2 = e-0.04t,
and by taking natural logs of both sides, we can make t the subject: ln(0.2) = -0.04t, which
rearranges to ln(0.2)/-0.04 = t, so t = 40.23594781, which rounds to 40.2 hours.

14. Pharmacokinetics of Multiple
Doses
• The first-order PK profile of IV bolus doses results in frequent Cmax and Cmin values that are
outside the therapeutic windows of drugs, which is undesirable as patients will be experiencing
doses at which side effects occur, as well as doses that are sub-therapeutic.
• The PK profile can be changed by decreasing the dose and increasing the frequency, which
maximises the time spent within the therapeutic window. However, successive dosing can lead to
accumulation of drug.
• Loading doses are higher doses of drugs that are given at the onset of therapy to bring the plasma
concentration into the therapeutic window. Subsequent doses (maintenance doses) are smaller
and frequent, to keep the plasma concentration oscillating about a mean within the therapeutic
window. At this point, the dosing will have achieved a steady-state scenario.
• Intravenous infusions do not exhibit the zig-zag graph characteristics that IV bolus doses, and
instead have a linear curve appearance. Loading doses may also be used with IV infusions where
an immediate or rapid onset is required, i.e. phenytoin in status epilepticus, amiodarone for
arrhythmias, vancomycin for severe infections.

15. Pharmacokinetics - Equations
• The steady-state concentration (Css) is calculated by D/Cltotal x τ, where τ is the dosing interval.
• The loading dose (LD) is calculated by Vd x Css (peak).
• A drug has a Vd of 35L and a t1/2 of 6 hours. Toxicity is not seen at levels below 30mg/L and the
initial dose (D) is 1000mg. Repeated administration requires concentrations of 5 – 10mg/L.
• The Cltotal can be calculated by: (0.693 x 35)/6 = 4.0425
• The amount of time (in hours) after which a second dose should be given is calculated by: 5 =
C0e-λt.
• The λ can be calculated by: 4.0425/35 = 0.1155
• The C0 is calculated by: 1000/35
• Therefore t (5mg) = ln[5/(1000/35)]/0.1155 = 15.09064333 hours
• Therefore t (10mg) = ln[10/(1000/35)]/0.1155 = 9.089369043 hours
• The Css can be calculated by: 1000/(4.0425 x 12 hours) = 20.61439633mg/L
• The patient should not receive a loading dose in this case, as the C0 is 28.571428mg/L, which is
near the upper limit of 30mg/L above which toxicity occurs.