D. PARENTERAL DRUG DELIVERY

Question 1

what is the difference between the parenteral and oral route

Answer 1

• parenteral isn’t via the digestive system
• parenteral is usually applied to injectable formulations only

Question 2

what are the 4 main routes of injection

Answer 2

intravenous
intramuscular
intradermal
subcutaneous

Question 3

what are the specialised needs of parenterals

Answer 3

• sterility as they bypass infection barriers
• isotonic and pH 7.4 as this is when proteins are active
• small volumes

Question 4

where is an intradermal drug injected

Answer 4

superficial layer of skin (extremely tilted)
0.1ml

Question 5

where is an intravenous drug injected

Answer 5

the vein (in the dermis)
(very tilted)
>5mL

Question 6

where is a subcutaneous drug injected

Answer 6

loose connective tissue (SC tissue)
(slightly tilted)
1.3ml

Question 7

where is an intramuscular drug injected

Answer 7

muscle mass
(not tilted at all)
2ml

Question 8

why use parenteral delivery

Answer 8

• 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

Question 9

issues and precautions with parenterals

Answer 9

• 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)

Question 10

advantages of IV delivery

Answer 10

• rapid onset
• no issue with incomplete absorption
• good for orally inactive drugs
• suitable for unconscious, uncooperative or nauseous patients

Question 11

disadvantages of IV delivery

Answer 11

• 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

Question 12

pathway of IV injection

Answer 12

1. drug injected into vein
2. passes to heart
3. through pulmonary circulation
4. heart pumps it around tissues
5. then to gut and then liver
6. drug returns to heart through liver - metabolism begins (not first pass as goes to tissues first)

Question 13

why is absorption efficient with IV

Answer 13

blood flow in tissues is slow
(trip takes 10-30 seconds)

Question 14

IV bolus injection

Answer 14

• 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

Question 15

IV infusion

Answer 15

• 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

Question 16

how can small volumes be administered by IV

Answer 16

• directly: slowly if concentrated
• admixed into large volume parenterals (eg - glucose)

Question 17

how can large volumes be administered by IV

Answer 17

• via central venous catheter emptying into subclavian vein

Question 18

how to give a continuous infusion

Answer 18

• via a drip feed (poorly controlled)
• by a metering pump which has a set amount (eg - for analgesia or chemotherapy)

Question 19

how is continuous out of hospital treatment administered

Answer 19

• ambulatory and implantable pumps
• for patient-controlled analgesia

Question 20

what do small volume (<100ml) parenterals require for formulation

Answer 20

• 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)

Question 21

what do large volume (>100ml) parenterals require for formulation

Answer 21

• 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

Question 22

how is IM injection absorbed into muscle tissue

Answer 22

• perfusion of muscle by blood (well supplied so rapid)
• < rapid, but generally > lasting than IV

Question 23

what type of formulations can be injected intramuscularly

Answer 23

• solutions, suspensions, depot implants
• injections don’t need to be water-miscible
• small-volume route (2 mL - deltoid of arm, 5 mL - gluteal region)

Question 24

what are the common IM injection sites for adults

Answer 24

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)

Question 25

what are the common IM injection sites for infants and children

Answer 25

- 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)

Question 26

advantages of IM delivery

Answer 26

- rapid absorption - can formulate sustained depot (days/months) - implanted devices may be removable

Question 27

disadvantages of IM delivery

Answer 27

- local muscle damage - cannot be used in cardiac failure (no muscle perfusion) - must avoid blood vessels

Question 28

PKs of IM delivery

Answer 28

- 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

Question 29

what factors affect IM absorption rate

Answer 29

- 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

Question 30

intradermal delivery

Answer 30

- 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

Question 31

subcutaneous delivery

Answer 31

- 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

Question 32

what type of formulations can be injected subcutaneously

Answer 32

- injections are prepared as aqueous solutions or suspensions (no oils)

Question 33

common injection site for SC drugs

Answer 33

- 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)

Question 34

how is insulin delivered

Answer 34

- subcutaneously

Question 35

how is insulin affected by liver and kidney

Answer 35

- inactivated, 10% excreted in urine

Question 36

how are longer acting (basal) preparations made

Answer 36

- 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

Question 37

ultra short acting insulin

Answer 37

- clear solution - neutral pH with traces of Zn - Insulin Lispro (or aspart) absorbed rapidly - peaks at 1 hr and lasts < 3-4 hr

Question 38

short acting insulin

Answer 38

- regular insulin - soluble crystalline Zn insulin - effect appears in 30mins - peaks 2 hrs, lasts 5-7 hrs

Question 39

intermediate acting insulin

Answer 39

- 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)

Question 40

long acting insulin

Answer 40

- 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