Psychopharmacology 1

• Patients with compromised hepatic function are better able to eliminate those drugs primarily metabolized by conjugation or renal excretion.
• In patients with renal impairment, drugs undergoing oxidative metabolism, with no active metabolites, are preferred.

• 1. Provide patient education
• Inform patient about potential adverse effects, their speed of onset, and whether tolerance will develop over time.
• Indicate the time for onset of the therapeutic effect.
• For many psychotropics, adverse effects occur immediately but therapeutic effects may be delayed by weeks.
• Generic medications may differ in appearance from the nongeneric product. Patients may avoid taking differently appearing medications unless informed of the change.
• 2. Arrange a convenient dosing schedule
• Compliance is maximized with once-daily dosing.
• Depot formulations with dosing intervals of several weeks are available for some antipsychotic agents.
• 3. Minimize adverse effects
• Select drugs with minimum pharmacokinetic interactions where possible.
• Gradually increase drug dosage over several days/weeks (“Start Low, Go Slow”).
• Use the minimum effective dose.
• Select a drug with an adverse-effect profile the patient can best tolerate.
• Reduce peak concentration-dependent adverse effects by taking the drug with food, using divided doses or extended-release formulations to reduce and delay peak drug levels.
• Schedule the dose so the side effect is less bothersome.
• If possible, prescribe activating drugs in the morning, and sedating drugs or those that cause gastrointestinal distress in the evening.
• 4. Check for patient compliance
• Schedule office or telephone visits to discuss compliance and adverse effects for newly prescribed drugs.

• Pharmacokinetic and pharmacodynamic
• A pharmacokinetic interaction occurs when an interacting substance alters a drug’s concentration due to a change in its absorption, distribution, metabolism, or excretion. 
• Pharmacodynamic interactions alter the body’s responses to a drug by altering drug binding to a receptor site, or indirectly through other mechanisms

When the drug involved has a low therapeutic index or active metabolites.

Phase I (oxidative) metabolism by one or more cytochrome P450 (CYP) enzymes.

changes in the CYP-mediated metabolism of the substrate drug by an interacting drug

• Enzyme induction is a slow process and takes five weeks
• Enzyme inhibition is a quick process and it takes five half lives until the substrate reaches a steady state

Smoking will increase risperidone metabolism through induction CYP1A2

Generally, for these interactions to be clinically relevant, a critical substrate drug must have a narrow therapeutic index and one primary CYP isozyme mediating its metabolism.

• Smoking
• Carbamazepine
• Rifampin
• Phenytoin
• Modafinil

• Amiodarone
• Fluoxetine
• Fluvoxamine
• Macrolides
• FQ
• Ketoconazole
• Citmetidine

• duloxetine
• Fluvoxamine
• Clozapine
• Olanzapine

• Carbamazepine
• Rifampin
• Phenytoin

• Amiodarone
• Fluoxetine
• Fluvoxamine
• Statins
• Citmetidine
• Protease inhibitors

• Warfarin
• Ramelteon
• Amiodarone
• Phenytoin

None

• Amiodarone
• Bupropion
• Fluoxetine
• Duloxetine
• Sertraline
• Paroxetine
• Cimetidine

• Duloxetine
• Fluoxetine
• Paroxetine
• Venlafaxine
• Beta-blockers

• Carbamazepine
• Oxcarbazepine
• Rifampin
• St. John’s wort
• Modafinil

• Amiodarone
• Fluoxetine
• Fuvoxamine
• FQ
• Macrolides
• Ketoconazole
• Cyclosporine
• Protease inhibitors
• Ethnyl estradiol
• Grapefruit juice

• Amiodarone
• Carbamazepine
• Bupropion
• Fluoxetine
• Venlafaxine
• Statins
• Macrolides
• Clozapine
• Selegiline
• lurasidone
• quetiapine 
• ziprasidone
• Aripiprazole
• benzodiazepines—except lorazepam, oxazepam, temazepam
• Buspirone
• CCB
• Cyclosporine
• Protease inhibitors
• Modafinil
• Steroids

• any of these interactions involve foods containing high levels of tyramine, a pressor amine metabolized by gut MAO-A.
• Several drugs, including some sympathomimetics and triptan antimigraine medications, are also metabolized by MAO.

drug metabolism by gut CYP3A4 and drug transport back into the gut lumen by the P-glycoprotein (P-gp) efflux transporter system form a barrier to absorption

drug toxicity due to dramatic increases in the oral bioavailability of poorly bioavailable drugs

• Buspirone
• Selegiline
• Venlafaxine
• Ramelteon
• Zaleplon
• Fentanyl
• Rivastigmine
• Quetiapine

Diltiazem, a CYP3A4 and P-gp inhibitor, increases buspirone bioavailability by 5- to 10-fold and plasma levels by 4-fold

• CYP3A4 and/or P-gp inhibitors: grapefruit juice, verapamil, diltiazem, quinidine, progestogen oral contraceptives, and proton pump inhibitors.
• CYP3A4 and P-gp inducers: St. John’s wort

rapidly acting, highly protein-bound (> 80%), low-therapeutic-index drugs with high hepatic extraction (possible candidates include propafenone, verapamil, and intravenous lidocaine)

Pharmacodynamic interactions occur when drugs with similar or opposing effects are combined

compromised physiological function such as cardiovascular disease or the elderly

Additive pharmacodynamic interactions are often employed therapeutically to enhance a drug response—this is the use of adjunctive medications

deliberately to diminish a particular adverse effect

In the treatment of chronic pain syndromes psychostimulants such as amphetamine or methylphenidate are frequently combined with morphine or other opiates to reduce opiate sedation and to enhance opiate analgesia.

• Erosion of asthma control in a patient who has successfully employed a β-agonist inhaler and is subsequently prescribed a β-blocker
• Negation of any cognitive benefit from a cholinesterase inhibitor in the presence of an anticholinergic drug like diphenhydramine.