Lecture 13: Formulation of CNS treatments (affective and psychotic disorders) Flashcards
What is an ideal CNS drug?
- be effective against the cause of the disease
- be able to (specifically) reach the brain
- have a rapid onset and controllable duration
- be free of undesirable side-effects
What are the classes of psychiatric disorders and what are the characteristics?
Neurosis: insight is present, grasp of reality is preset, hallucinations and dilusions are absent, the symptoms resemble normal personality, non invasive treatment options are possible. Examples include anxiety, mild depression, obsession
Psychosis: insight is absent or reduced. Grasp of reality is absent. Hallucinations, delusions are present. Symproms dont resemble normal personality. Treatment options are often necexssary. Examples include schizophrenia, mania, severe depression.
What dosage form is usually used for neurosis and for psychosis?
- Oral/ transdermal for neurosis
- IV/IM for psychosis
What is the compliance for benzodiapenes?
- Dependance may occur after 4-6 weeks of treatment
- Weaning is not easy - decrease of dose by 1/8 every fortnight - withdrawal can take many months
What is the compliance for anti depressants SSRI?
- There is a suicide risk - small supply should be given at any one time
- Use of full dose for 4-6 months after symptoms have subsided is essential to prevent relapse
- Non compliance is frequent once the patients mood has improved
- Withdrawal over 2-4 weeks
What is the compliance issues for Schizophrenia?
Thought disorders, dilusions, auditive hallucinations, paranoid delusions
Acutely psychotic patient: parenteral administration to a reluctant patient
Compliance discouraged by weight gain (especially with clozapine), precipitates diabetes
75-85% patients will eventually relapse, a minumum 5 year maintainance period is recommended
Concentrated oral liquid forms help because they cannot be hidden in the mouth rather than swallowing them
Syrup-base preparations can cause tooth decay and obesity in the long term - Oral dispersible forms are preferred
Paranoid delusional states (“carers as spies or tormentors”) - Patients not swallowing tablets
What are sublingual tablets?
Drug release in the mouth followed by systemic uptake of the drug. Rapid systemic effect, without first pass liver metabolism. Sublingual tablets are placed under the tongue eg bupronorphine (can cause addiction)
What are orodispersible tablets?
Disintigration of the tablet in the mouth within one min in the presence of saliva.
Advanatges: no difficulty for swallowing. Improved compliance - no hiding tablets in the cheek pouch
Eg. risperidone (autism), aripiprazole (shhizophrenia), mirtazapine (depression)
What are extended release capsules?
Methylphendate (Equasym XL, ADHD, contains 2 types of beads; 1. IR MPH uncoated beans - 30% of the dose is rapdily released, 2. ER MPH coated beads - 70% of the dose is continuously released.
Advantages:
- Efficacy for 8 hours
- No impact of food intake
- Overcoming of the difficulties of multiple daily dosing (administered once in the day)
Ex: methylphenidate (Equasym XL®, ADHD), venlafaxine (Alventa®, depression)
What are the advantages and disadvantages of suspensions?
Advantages:
- Drug absorption faster than with tablets or capsules
- Convenient when the drug is not soluble in water and non aqueous solvent cannot be used
- The insoluble solids act as a reservoir and continuously release the drug so long term efficacy
Disadvantages:
- Risk of sedimentation
- Risk of inaccurate dosage due to spoon
Eg. Paroxetine (anxiety)
What are the advantages and disdvantages of solutions and syrups?
Advantage:
- Drug is already dissolved so absorption is faster than solid dosage forms or suspensions
- Masking of unpleasant taste of the drug (autism)
- Easy to adjust the dose for a childs weight
Disadvantage:
- Risk of deterioration faster than solid dosage forms
- Risk of inaacurate dosage ( use of spoon_
eg. risperidone (autism), amisulpride, pericyazine (schizophrenia), diazepam, fluoxetine (anxiety), methadone (addiction)
Give an example of matrix type transdermal patch. Advantages and disadvanatges
Eg methylphenidate - Daytrana®, ADHD
Application of the patch to the hip area 2 hours before an effect is needed
Removal of the patch 9 hours after application
Advantages:
- Slow release and long lasting effect
- Avoidance of hepatic first pass metabolism
- Can be removed easily and quickly in case of adverse reactions and in function of needs
- High patient compliance
- One application per day (good compliance)
- Regular drug release for 9 hours
Limitations:
- No exposure to external heat sources: the rate and extent of absorption would be significantly increased (can be higher than 2-fold)
May cause Overdose of methylphenidate
- No exposure to water: can affect patch adherence
- Contact sensitization: erythema with more intense local reaction (edema, vesicles) that does not significantly improve within 48 hours
Warnings:
- Sudden death reported in association with methylphenidate treatment at usual doses in children and adolescents with structural cardiac abnormalities or other serious heart problems
- Long-term suppression of growth: consistently medicated children (i.e. treatment for 7 days per week throughout the year)
have a temporary slowing in growth rate (about 2 cm less growth in height and 2.7 kg less growth in weight over 3 years)
What are the Principles of formulations for Parenteral administration?
Administration by injection
All parenteral products must be sterile
Preferred route when rapid absorption is essential:
- acutely psychotic patient: need of prompt drug therapy, prevent self-harm or harm to others
- when a schizophrenic patient needs long-term maintenance
What are injections?
Sterile solutions, emulsions or suspensions, in water or non-aqueous liquid
Ex: solution or emulsion of diazepam (anxiety) (Emulsion formulation preferred for IV administration), buprenorphine solution, methadone solution (addiction)
Lipophilic diazepam dispersed in a o/w emulsion:
- Higher drug payload
- Less pain on injection
- Protection of the drug by the oily environment
What is depot therapy?
Injection of a drug together with a substance that slows the release and prolongs the action of the drug
Esterification of the drug, dispersion of the drug in a oily vehicle
IM injection into skeletal muscles (gluteal, deltoid muscles, thigh) so slow release of the drug from this depot to the plasma
De-esterification of the drug by hydrolysis to be active
Effective plasma therapeutic level reached within one week, maintained for 14 to 28 days, so, Injection every 2 to 4 weeks
Ex: ariprizalole, chlorpromazine, zuclopenthixol acetate, haloperidol, zuclopenthixol (schizophrenia), flupentixol decanoate (autism)
Other delivery strategy (risperidone (schizophrenia):
Encapsulation of the drug in polylactide-co-glycolide (PLG) microspheres. Concentration: 381 mg risperidone per gram of microspheres. Unusual release: lag phase of 4 weeks, during which oral therapy must be continued
Advantages:
- Lower total dose compared to oral administration
- Facilitation of community care
- Regular contact with patients by carers
- Supervised administration
- No accumulation or abuse of unused tablets
- No issue of compliance
Disadvantages:
- Pain at the injection site
- No rapid elimination from the body if adverse effects
- Considerable patient resistance (controlling, punitive or detrimental to autonomy)
