D. PARENTERAL DRUG DELIVERY Flashcards
what is the difference between the parenteral and oral route
- parenteral isn’t via the digestive system
- parenteral is usually applied to injectable formulations only
what are the 4 main routes of injection
intravenous
intramuscular
intradermal
subcutaneous
what are the specialised needs of parenterals
- sterility as they bypass infection barriers
- isotonic and pH 7.4 as this is when proteins are active
- small volumes
where is an intradermal drug injected
superficial layer of skin (extremely tilted)
0.1ml
where is an intravenous drug injected
the vein (in the dermis)
(very tilted)
>5mL
where is a subcutaneous drug injected
loose connective tissue (SC tissue)
(slightly tilted)
1.3ml
where is an intramuscular drug injected
muscle mass
(not tilted at all)
2ml
why use parenteral delivery
- speed of action as IV drug enters plasma immediately and rapidly disperses to tissues
- local/targeted effect ie: local anaesthetics, cytotoxics
- 100% bioavailability as drug doesn’t have to cross absorption barriers in gut. Can administer drugs that are unabsorbed/degraded by oral route
issues and precautions with parenterals
- air embolism: injection of air bubbles
- bleeding: in haemophilia so don’t use here
- cost of training and formulation
- fever from pyrogens
- infiltration/extravasation: local tissue damage so rotate injection spot
- overdosage will be serious due to rapid onset
- particulates can cause a pulmonary embolism
- sepsis so need sterile practice
- thrombosis (blood clot)
advantages of IV delivery
- rapid onset
- no issue with incomplete absorption
- good for orally inactive drugs
- suitable for unconscious, uncooperative or nauseous patients
disadvantages of IV delivery
- extensive training (locate vein)
- sterility needs to be maintained
- dosage error = serious injury/death
- complications (as stated with parenterals)
- loss of sites in long-term treatment
pathway of IV injection
- drug injected into vein
- passes to heart
- through pulmonary circulation
- heart pumps it around tissues
- then to gut and then liver
- drug returns to heart through liver - metabolism begins (not first pass as goes to tissues first)
why is absorption efficient with IV
blood flow in tissues is slow
(trip takes 10-30 seconds)
IV bolus injection
- rapid increase in drug concentration in blood plasma
- after distribution, concentration falls (reversible transfer of drug)
- drug concentration in plasma affected by dose and quantity of drug transferred into tissues
- slower decrease in drug concentration due to irreversible excretion and metabolism
IV infusion
- large volume of fluid at slow rate (antibiotics, nutrition etc)
- ensures drug enters general circulation at constant rate
- drug concentration in plasma rises and achieves steady state
- stop infusion: elimination, follows first order kinetics
how can small volumes be administered by IV
- directly: slowly if concentrated
- admixed into large volume parenterals (eg - glucose)
how can large volumes be administered by IV
- via central venous catheter emptying into subclavian vein
how to give a continuous infusion
- via a drip feed (poorly controlled)
- by a metering pump which has a set amount (eg - for analgesia or chemotherapy)
how is continuous out of hospital treatment administered
- ambulatory and implantable pumps
- for patient-controlled analgesia
what do small volume (<100ml) parenterals require for formulation
- sterile and particle free (unless delivering particles)
- pH 3-9 as long as injection is slowly/rapidly diluted
- pH > 9 = tissue necrosis
- pH < 3 = pain and phlebitis in tissue
- buffers: acetate, citrate, phosphate buffers
- co-solvents: EtOH, propylene glycol
- preservatives: benzyl alcohol, phenol
- surfactants to aid solubility (eg. deoxycholate with amphotericin B)
what do large volume (>100ml) parenterals require for formulation
- used as electrolyte balance, parenteral nutrition, plasma replacement, acid-base balance, contrast agents etc
- pH 6 to 8
- large differences of pH from physiological conditions NOT tolerated as for small volume parenterals
- usually made isotonic with glucose or NaCl
- if hypotonic solution (lower osmotic pressure than blood plasma) fluid passes into blood cells by osmosis, blood cells swell and burst
- if hypertonic solution (higher osmotic pressure than blood plasma) – red blood cells loose fluids and shrink
- preservatives not permitted
how is IM injection absorbed into muscle tissue
- perfusion of muscle by blood (well supplied so rapid)
- < rapid, but generally > lasting than IV
what type of formulations can be injected intramuscularly
- solutions, suspensions, depot implants
- injections don’t need to be water-miscible
- small-volume route (2 mL - deltoid of arm, 5 mL - gluteal region)
what are the common IM injection sites for adults
Point of injection – as far as possible from major nerves or blood vessel to avoid
injuries
- upper outer quadrant of gluteus maximus
- deltoid - in shoulder (more painful)
what are the common IM injection sites for infants and children
- deltoid muscles of upper arm
- mid-lateral muscles of thigh - injection at upper or lower portion of deltoid, well away from radial nerve
*gluteal area is small & composed primarily of fat - muscle poorly developed
- injection in this area too close to sciatic nerve (esp. if child is resisting injection)
advantages of IM delivery
- rapid absorption
- can formulate sustained depot (days/months)
- implanted devices may be removable
disadvantages of IM delivery
- local muscle damage
- cannot be used in cardiac failure (no muscle perfusion)
- must avoid blood vessels
PKs of IM delivery
- release of drug from formulation into intercellular fluid (ICF)
- absorption from ICF into blood and lymphatics
- transport from local blood volume to general circulation
- metabolism
what factors affect IM absorption rate
- very hydrophobic drugs don’t dissolve in ICF
- strongly ionised or water soluble drugs can’t cross capillary membrane
- strongly protein-bound drugs slowly absorbed
- some drugs in solution absorbed slowly if composition of formulation changes after injection
- muscle movement and blood flow: moving increases absorption compared to rest after IM injection
intradermal delivery
- dermis has little fluid available and is poorly perfused by blood
- drugs persist at site for long period of time
- usual site is anterior forearm
- volume for injection is small (0.1mL, up to 0.2mL)
- eg: tuberculin & allergy testing
subcutaneous delivery
- SC tissues have significant volume of interstitial fluid in which the drug can diffuse
- volume for injection is small (1.3 - 2 mL)
- less well perfused (often adipose) than IM route, so slower absorption
- cannot give irritating formulations
- used for insulin, vaccines, some vitamins
what type of formulations can be injected subcutaneously
- injections are prepared as aqueous solutions or suspensions (no oils)
common injection site for SC drugs
- anterior abdomen (belly), upper arm, thigh & buttocks
(if frequent SC injection given, alternate injection sites are used) - the injection site affects the absorption rate (e.g. insulin is more readily absorbed from the abdomen and deltoid region compared to thigh and buttocks)
how is insulin delivered
- subcutaneously
how is insulin affected by liver and kidney
- inactivated, 10% excreted in urine
how are longer acting (basal) preparations made
- precipitating insulin with protamine or zinc forms fine
amorphous solid/insoluble crystals, injected as suspension from
which insulin is slowly absorbed, e.g. isophane insulin - modifying insulin amino acid structure to create analogues (genetic engineering, rDNA tech) insulin forms a slow-dissolving precipitate once injected, e.g. insulin glargin
*analogues also created for rapid acting insulin, e.g. lispro
ultra short acting insulin
- clear solution
- neutral pH with traces of Zn
- Insulin Lispro (or aspart) absorbed rapidly
- peaks at 1 hr and lasts < 3-4 hr
short acting insulin
- regular insulin
- soluble crystalline Zn insulin
- effect appears in 30mins
- peaks 2 hrs, lasts 5-7 hrs
intermediate acting insulin
- suspension of Zn insulin crystalline, 2 µm particle size
- peaks 4 – 8 hrs, lasts 16 hours max
- onset delayed by combination of insulin and protamine
e.g. NPH (Neutral Protamine Hagedorn)
long acting insulin
- suspension mixture of 30% Semilente (amorphous
precipitate of insulin with Zn ions for rapid onset) and - 70% Ultralente (poorly soluble crystal of Zn insulin for delayed onset and prolonged duration) to give rapid absorption with sustained long action
- eg: deter, glargine
- 10 – 40 µm particle size
- peaks at 8 – 12 hr
