A comprehensive review introduction



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Dosage and Delivery

Isolated Infusion / Intravenous / Oral

Psychotropic drugs like all other medications come in a variety of forms. They can either be taken in a pill form (tablet or capsule) orally or in an injectable form (vial or ampule) intravenously. Some are inhaled and others applied directly onto the skin.

Each route of administration has its own dosage formulation and magnitude of pharmacologic action. A diazepam (Valium) tablet does not produce the same anxiolytic properties as its IV formulation. Dosages, in whatever form, present with their own unique advantages and disadvantages. The various formulations allow patients and clinicians the freedom to administer medications according to the patient’s circumstances and convenience, and clinical need.

Routes of administration/ Delivery

The route of administration plays a very important role in determining the dose of the drug to be delivered, the speed of its delivery to the target site and ultimately, the speed at which it exerts its pharmacological activity (onset of action). The route of administration affects not just the bioavailability of the drug, but its entire pharmacokinetic profile.

The different routes of administration are broadly classified into three main categories:



  • Enteral administration

  • Parenteral administration

  • Transdermal administration

Each route offers its own set of advantages and disadvantages. The table below lists the most common route from each category in comparison with each other’s advantages and disadvantages.

Effects


Oral

IV

Transdermal

Bioavailability

Unpredictable

100%

100%

Onset of action

Fast, slow and extended

Fast

Slow and extended

Risk of toxicity

Present

High

Minimal

Dose

High

Low

Low

Contamination / Infection risks

Low

High

Moderate

Table 11: Comparison of the advantages and disadvantages of the common types of routes of administration

Enteral administration

Drugs administered enterally go through the gastrointestinal tract for absorption into the circulation. Examples include tablets, syrups, solutions, capsules and suspensions. However, this isn’t always necessarily the case. Sublingual tablets are placed under the tongue to be absorbed directly into the systemic circulation. The atypical antipsychotic, asenapine, is given sublingually in doses of 5-10 mg.

Majority of the psychiatric drugs are given through the oral route. The route offers convenience and general patient acceptability. Almost all drugs mentioned in the previous sections come in a tablet form e.g. fluoxetine, quetiapine, diazepam), aripiprazole, etc.

Psychotropic drugs that require multiple dosing throughout the day are formulated as extended release capsules/tablets to reduce the burden and inconvenience of its frequent administration. An example is venlafaxine (Effexor). Its extended release capsules are sold under the brand name of “Effexor XR”.

Parenteral administration

Psychotropic drugs are also delivered parenterally. This particular route of administration allows for the direct administration into the central nervous system. One example is the injection of anesthesia directly into epidural space. Another example is the atypical antipsychotic, aripiprazole (Abilify), which is given intramuscularly. Due to the drug entering the circulation directly and bypassing the liver, most of its active and non-active metabolites are found only in trace amounts, excreted via feces and urine.

Perhaps the most common route of parenteral administration is the intravenous route. It is particularly useful in managing emergency situations and acute episodes since its onset is the fastest. Drugs such as imipramine (Tofranil), morphine (MS Contin), propranolol (Inderal), diazepam (Valium), and midazolam (Dormicum), undergo extensive first pass metabolism and have low oral bioavailability. But when delivered through the IV route, these drugs have almost 100% bioavailability.

Intravenous administration is known for its rapid effects, usually within seconds. However, another form of IV route, IV infusion, allows for the slow and steady administration of psychotropic drugs over a period of time. It does come with its own set of disadvantages such as phlebitis, extravasation, hypersensitivity, infection, embolism and fluid overload. Chlorpromazine (Thorazine) is particularly irritating to the veins and may cause swelling and redness at the site of administration.

The intramuscular route allows for depot administration in patients that need a different treatment strategy than others and this is especially true for psychotropic drugs. Examples include:


  • Those with frequent relapses

  • Those who have problems with oral medication adherence

  • Those who need a burst dosage

Haloperidol decanoate is an example. A starting dose of 50 mg is administered intramuscularly in the gluteal region. It is a long acting form of the drug that is designed to provide one-month therapy, sustained by the oral form of the drug. Other depot antipsychotic drugs that are administered as intramuscular injections are listed in the table below (105).

Drug

Route of administration

Maintenance dose

Zuclopenthixol

IM

200-400 mg bimonthly/monthly

Fluphenazine decanoate

IM

12.5-75 mg monthly

Flupenthixol decanoate

IM

20-80 mg bimonthly/monthly

Table 12: Examples of depot antipsychotics and their recommended maintenance doses

There are a few drugs that can even be administered intracerebrally in order to bypass the blood brain barrier. It is a fairly new route of administration that is still under research and development. An intracerebroventricular route also exists in which the drug is given directly into the ventricles of the brain. It is not a common route of administration and is usually reserved for terminally ill cancer patients who need analgesia for pain that is refractory to medication administered through other routes (106).

Transdermal administration

Psychotropic drugs can also be administered via the skin. The transdermal route of administration allows for the absorption of the active drug through the skin and into the systemic circulation. An example of transdermally administered psychotropic drug is selegiline (Emsam), which has been described in detail in the previous paragraphs. The transdermal route bypasses the notorious drug-drug and drug-food interactions exhibited by most of psychotropic drugs due to their oral pharmacokinetic profiles. As a result, it offers lesser side effects and decreased likelihood of overall incidence of adverse events when compared to the IV and oral routes.

Another transdermal patch containing a psychotropic drug is methylphenidate (Dystrana). It is usually prescribed for adolescents with ADHD.

Miscellaneous routes of administration

The intranasal route is the most favored administration technique by illicit drug users. This is because the nasal cavity is a highly vascularized port of drug entry. Legal drugs are also administered via this route as demonstrated by the intranasal nicotine (Nicotrol NS), a drug used in the management of withdrawal symptoms associated with smoking cessation.

Dosing Schemes / Guidelines

The dosage of a psychotropic drugs depend on a number of factors such as age, gender, comorbidities, liver and kidney function, extent of disease, pregnancy status, side effects experienced by the patient, response to previously administered drug or tolerability of the drug, etc.

Also, pediatric and geriatric doses for the majority of the medications differ from normal adult doses. Another very important point about dose determination pertaining to psychotropic drugs is that dose increments with these drugs need to be made carefully to avoid toxicity. As mentioned previously in the other section, age, gender and comorbidities dictate the dose requirements of individual patients. Compromised renal and liver functions, older age and gender affect the pharmacokinetic and pharmacodynamics of drugs.

The specific doses for the frequently used psychotropic drugs are discussed in detail below.

Antipsychotics

Haloperidol (Haldol) is given in tablet form with an adult dose that ranges between 0.5-5 mg depending upon the severity of the disease. Its maintenance dose for such patients is between 1 mg to 30 mg in two to three divided doses (105).

The emergency parenteral dose of haloperidol (Haldol) is 2 mg to 5 mg given intramuscularly for prompt control, which may be repeated every 4-8 hours. A dose of 8-10 mg of the drug may also be administered via this route. When patients are excessively agitated, they may require regular hourly doses.

Haloperidol (Haldol) is not recommended for pediatric patients below 2 years of age or those who weigh less than 15 kg. Children between the ages of 3-12 years and those who weigh between 15 to 40 kg can be given an initial starting dose of 0.5 mg/day in two or three divided doses. In case the dose needs to be increased, it should be done every 5-7 days by 0.25 to 0.5 mg increments.

Parenteral forms of haloperidol (Haldol) are not recommended in pediatric patients below 5 years of age. For children between 6-12 years of age, 1-3 mg IM injections can be administered every 4 to 8 hours and the therapy should be switched to oral form as soon as possible. It is recommended that patients with renal or hepatic dysfunction be given the drug with caution.

Quetiapine (Seroquel) is available in tablets 25, 50, 100, 200, 300 and 500 mg dosages. When prescribed for bipolar disorder, an initial dose of 25 mg is usually given twice daily. On the second and third day of therapy, dose increments of 25 to 50 mg to the drug regimen in 2 or 3 daily divided doses may be made. A total dose of 300 to 400 mg may be attained by the fourth day. When prescribed for schizophrenia, the dose ranges between 150 mg/day to 750 mg/day, however, doses above 300 mg/day were not proven to be more efficacious than 300mg/day. The safety of dosing regimen as high as 800 mg/day has not been proven.

The dose for adolescent patients between the ages of 13 to 17 for the first five days of therapy is 50 mg, 100 mg, 200 mg, 300 mg and 400 mg at day 1, 2, 3, 4, 5, respectively. After this, the dose may be adjusted as required between 400 mg/day to 800mg/day depending upon patient response and tolerability. An increment of more than 100 mg /day should not be made with quetiapine (Seroquel).

Clozapine (Clozaril)

Schizophrenic adults with recurrent suicidal behavior benefit from a starting dose of 12.5 mg once daily with dose increments of 25-50 mg/day, until the maintenance dose of 600-900 mg/day is reached. The safety of clozapine (Clozaril) has not been studied in pediatric patients and should not be used in such populations. In geriatric populations, a lower initial dose of 12.5-25 mg/day is appropriate which may be titrated upward slowly to reach the maintenance therapeutic levels (107).

Risperidone (Risperdal)

Adults with schizophrenia are usually started on a dose of 2 mg/day, with 1-2 mg dose increments made every 24 hours until a 4-8 mg/day maintenance dose is reached. In adolescents with schizophrenia, an initial dose of 0.5 mg is recommended with 0.5-1 mg dose increments made every 24 hours until the 3 mg maintenance dose is reached.

The table below summarizes the maximum daily doses for each population that was discussed above.


Drug

Adult

Pediatric

Geriatric




Initial

Maintenance

Initial

Maintenance

Initial

Maintenance

Haloperidol

0.5-5 mg

1-30 mg

0.5 mg

0.5 mg increase

0.5-2 mg

1-30 mg

Quetiapine

25-50 mg

400-800 mg

50 mg

400-800 mg

50-200 mg

200 mg or less

Clozapine

12.5 mg

600-900 mg

Not established


Not established

12.5-25 mg

25-150 mg

Risperidone

2 mg

4-8 mg

0.5 mg

3 mg

0.25-1 mg

1 mg




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