pharmaceutics Flashcards
Different routes of administration used in analgesia
Oral Transdermal Transmucosal Intravenous Epidural Intrathecal Nasal Rectal
Intravenous
-Rapid action from drug being presented directly to the circulation.
No lag time between administration and action.
-Physician= titrate the dose
-More predictable response compared to routes
Incomplete absorption and variability in absorption is eliminated.
-Require trained medical staff to administer so only used in acute care.
Transmucosal
-Absorption through the oral mucosa (oral cavity).
-Oral cavity rich in blood vessels.
Rapid onset of action and high blood levels.
Absorbed directly into the systemic circulation via the jugular vein (no 1st pass metabolism)
-SA limited only 100cm2.
Only small lipophilic drugs absorbed.
Transdermal
-Drug diffusion from the delivery system containing a drug reservoir.
Through the epidermis (main barrier is the stratum corneum) and dermis (rich blood supply).
-2 routes through the stratum corneum:
Hydrophilic keratinised cells and lipid channels.
Main route of absorption is lipid channels (mainly for small molecular weight lipophilic drugs).
Pharmacokinetic advantage of transderma
- Maintain sustained drug plasma profile over several days in therapeutic window.
- No dips in dose overnight/dose dumping (oral tablets).
- Good patient compliance (e.g single patch applied every few days)
-Removal of the device causes the plasma levels to fall shortly afterwards.
Some drugs can be stored in hydrophobic regions of the skin.
Transdermal patches
- Matrix or monolith systems (drug suspension)
2. Rate limiting membrane
Rectal route
- For systemic absorption of drugs and bypasses the hepatic first-pass metabolism.
- Used when oral route not appropriate (e.g presence of N/V, upper GI disease affects absorption of drug)
- Widely administer drugs that are affected by pH or enzymatic activity of the GI tract.
- For drugs that cause gastric/GI irritation when taken orally.
-Drug absorption:
Drug has to dissolve in rectal fluid (only 1-3ml)
Reduced by degradation by luminal contents, adsorption to luminal contents and defaecation.
Absorbed by passive diffusion.
Advs of rectal route
route
-Useful for infants, geriatrics and unconscious patients.
- For drugs with unacceptable taste.
- For drugs that are candidates for abuse.
Disadvs for rectal route
- Unpredictable, erratic and incomplete absorption in vivo.
- Inter and intra-subject variation
- May be difficult to self-administer by arthritic or physically compromised patients.
- Popularity of dosage form varies culturally, maybe unacceptable to certain patients.
Intrathecal
-Administration of drugs in solution by intrathecal catheter to the spinal cord.
- More invasive route
- Cerebrospinal fluid (CSF)= fluid that cushions the brain and spinal cord
- Bulk flow of CSF maybe dominant in determining distribution and pharmacokinetics.
- Used for chronic pain management, spinal anaesthesia and chemotherapy.
- Spinal anaesthetic- local anaesthetic plus opioid
`Epidural
-Injection of drug via catheter into the epidural space.
(outermost part of the spinal canal, lying outside the dura mater)
- Can result in a loss of sensation (including sensation of pain) by blocking the transmission of signals through nerve fibers in or near the spinal cord.
- To achieve epidural analgesia (opioid) or anaesthesia (local anaesthetic + opioid), a larger dose of drug is necessary than with spinal analgesia or anaesthesia.
- Onset of analgesia= slower with epidural than spinal analgesia/anaesthesia
Other different drug delivery systems available for chronic pain management
- Percutaneous catheter used with external pump
- Totally implanted catheter with a subcutaneous injection port connected to external pump
- Fully implanted fixed rate and programmable intrathecal drug delivery systems.
Nasal. route of administration
-Small drugs rapidly absorbed from the nasal cavity at rates comparable to IV drugs.
Easier= no medically trained staff required
More comfortable for than IV.
-Physiological conditions of the nose will affect the rate of absorption.
Vascularity, mucus flow, atmospheric conditions
-Formulation= influence absorption
pH, vol conc, viscosity, tonicity
-Slower clearance of the drug more time available for absorption
Multiple dosing regimens
Aim of drug therapy:
To maintain the drug within the therapeutic range.
- Time between doses allows for elimination of each dose.
Drug plasma conc only maintained within the therapeutic window for short time intervals.
Long time intervals with patient undermedicated. - Equal doses at shorter time intervals. (e.g 4 hrs)
Max and min plasma conc increase with each successive dosing interval.
Time between doses less than that required for elimination.
Drug plasma conc maintained within the therapeutic window= multiple dosing for patient compliance
Extended release dosage forms
A single dose:
(A)-Prompt achievement of plasma conc of drug remains constant value within therapeutic range for a satisfactory amount of time.
(B)-Prompt achievement of plasma conc of drug and declines at a slow rate within the therapeutic range
Sublingual tablets
- Used as dosage form for transmucosal delivery.
- Small/porous fast disintegrating tablet placed under the tongue
Dispersible tablet
-Useful= patients having difficulty in swallowing (dysphagia)
-Dropped into a glass of water, CO2 liberated
Reaction of carbonate/bicarbonate with a weak acid (e.g citric acid)
Includes a flavour.
-Fast disintegration and dissolution of the drug
-Buffered water increases the pH of stomach faster emptying time/shorter residence.
Reaches small intestine quicker (main site of absorption= SA, rapid onset of action)
Gastric irritation can be avoided
Suspensions
Solid-in-liquid colloid.
-Drug in solid phase (powder)
Liquid= easy to administer to children
Widely used for oral formulations:
- Antacids (e.g Aluminium hydroxide, calcium carbonate)
- Antibiotics (e.g amoxycillin, erythromycin)
- Antifungals (e.g amphotericin, nystatin, fluconazole)
- Analgesics (e.g paracetamol, ibuprofen)
-Physical instability in suspensions
Flocculation, aggregation
Sedimentation, Ostwald ripening
Fast dissolving oral delivery systems
-Solid dosage form= dissolves rapidly in oral cavity
=results in solution/suspension without the need for water
e.g Calpol Six Plus Fast Melts
-Drug dissolves/disperses in the saliva.
Portion of drug maybe absorbed in the mouth, pharynx or oesophagus (potential for increased absorption).
Different dosage forms of Fentanyl
- Transmucosal lollipop
- Transdermal patch
colloid
disperse system in which one phase is in the form of tiny particles or droplets
emulsion system
liquid in liquid
suspension
solid in liquid
Why use disperse systems?
-Single phases may not be able to provide all the formulation requirements.
e.g Diprivan
Drug is very hydrophobic.
Cannot be dissolved in water.
Dissolve in oil and oil is dispersed in isotonic water carrier to form an emulsion.
e.g Suspension of paracetamol. Solid phase (powder)= tablet Liquid= easy to administer to children
emulsion
dispersion of a liquid in a second immiscible liquid
o/w
w/w
what do emulsions require
emulsifier
emulsion stability
to make an emulsion, a large amount of new surface must be formed
-(requires energy)
what has a higher energu, dispersed or inmixed iol/water
dispersed
emulsifier
positions at the interface between two phase for o/w emulsion
hydrophobic part-positioned in the oil droplet
hydrophilic part oritentates towards surrounding water
Emulsion applications
-Intravenous
= total parenteral nutrition (TPN), Intralipid: administration of fats (soya bean oil, medium chain triglycerides)
=Fat absorbed from GI tract circulates as chylomicrons (tiny droplets of triglycerides coated with lecithins and bile salts).
Feeding emulsions attempt to simulate these droplets.
Emulsion has a droplet diameter of 0.2-0.3 microm (large droplets harmful).
-Oral
=oral feeding of fats (enteric feeds)
=Oral delivery of hydrophobic drugs
-Intramuscular
=W/O emulsions for sustained release
=Emulsion vaccine adjuvants
Acceptable excipients for emulsions
- IV formulations
- very few oils and emulsifiers= used IV
- Oil phase: soya bean oil/ medium chain triglycerides - Emulsifiers
- Phospholipids= (purified) from egg yolk or soya beans
- some of the hydrophilic Pluronics
- small volume parenterals= polysorbate, bile salts - IM formulations
- sesame oil
- Squalane and Pluronic L121 in Syntex Adjuvant Formulation= induce immune response
Emulsions for drug delivery
-drug incorporation
- Hydrophobic oil= soluble drugs
- dissolved in oil which is then emulsified.
- drug must be very hydrophobic (log>5) or drug will transfer through aq phase and crystallize out. (e.g Diprivan) - Surface-active drugs
-adsorbed at the interface
-increasing number of complex drugs are insoluble in both oil and water.
-more difficult to formulate due to solubility problems
(can solubilise drug in emulsifier solution, then use this to emulsify the oil phase)
e.g Amphotericin B, Taxol
Emulsion examples:
Diprivan injection
-Propofol= most widely used drug for IV anaesthesia
-Drug is very hydrophobic.
Dissolved in soya bean oil
-Oil is dispersed in isotonic water carrier to form an emulsion.
Oil droplet sizes ~150nm (small).
Importance of emulsion stability
If oil droplet size increase, life-threatening to the patient.
Emulsion examples:
Intralipid
Intralipid consists of lecithin emulsifier, soya oil and water.
Lethicin= natural emulsifier from eggs (mixture of a group of compounds= phospholipids)
Charge on emulsion= enough to make the emulsion stable for several years
Consequences of disperse system instability
- Flocculation
- Coagulation/ aggregation
- Coalescence
Physical instability of disperse systems:
Flocculation
Particles/droplets cluster together in an open structure.
Particles/droplets maintain their individual identity.
Can be redispersed to single particles/droplets by shaking.
Sometimes flocculation is desirable in a formulation.
Physical instability of disperse systems:
Coagulation/Aggregation
Small aggregates form.
SA is decreased so surface tension is experienced by fewer molecules.
Attractive forces between particles very strong.
Cannot be redispersed to single particles by shaking.
Permanent failure of the medicine.
Physical instability of disperse systems:
Coalescence
Droplet structure lost entirely.
Impossible for patient or clinician/nurse to reform the emulsion.
Total failure of the medicine.
Also known as ‘cracking’ in emulsions.
Forces acting on particles in disperse systems
Particles of <2 microns diameter= constantly moving due to Brownian motion
[
-As particles approach they experience:
1. Forces of repulsion due to electrostatic interactions.
Energy of electrostatic repulsive interaction= Vr
- Forces of attraction due to VDWs forces
Energy of attractive interaction due to VDWs forces= Va - Steric forces if they have a non-ionic surfactant on their surfaces.
Energy of steric interactions (hinderance)= Vs
Overall potential energy= Vt
Vt= Va + Vr + Vs
Vt= Va + Vr
All of the forces vary with particle separation distance.
When the particles are widely separated the forces are weak, but get stronger as the particles get closer.
Diagram= Force (V) against particle separation (H)
Steric forces are important for non-ionic surfactants (e.g polysorbate 80)
Va= attractive force
Va= -Aa/12H
Va changes as a function of 1/H.
A= constant of proportionality
A depends on the particle material and the suspending fluid.
Small separations= very sharp increase in attraction
Big separations= small attractive force
Vr= repulsive forces
source of charge in colloidal particles
-ion distribution
=ionic substances acquire charge by uneven dissolution of oppositely charged ions, if more cations dissolve then the surface becomes negatively charged
-ion adsorption
:
Primary Minimum
permanent aggregation of particles
primary maximum
repulsive barrier to aggregation
secondaru minimum
weak attraction cause flocculation
Kinetic energy:
Coagulation
High Kinetic energy
Primary max= insufficient to stop particle
Kinetic energy:
Flocculation
Low kinetic energy
Primary max= Too great a barrier.
-Particle has insufficient energy to continue its path towards neighbouring particle.
-Insufficient energy to escape the secondary minimum.
Kinetic energy:
Stable colloidal formulation
Intermediate kinetic energy.
Primary max too great a barrier.
Particle has insufficient energy to continue its path towards neighbouring particle.
Particle also escapes the secondary minimum (Brownian motion).
k
debye-huckel constant
1/k
debye-huckle length
the diffusuion layer of the electrical double layer
