MANAGEMENT OF DRUG-

DRUG INTERACTIONS IN
MEDICALLY ILL PATIENTS
MODERATOR: DR. ELIAS TESFAYE (ASSOCIATE PROFESSOR OF
PSYCHIATRY, CONSULTANT PSYCHIATRIST)
PRESENTER: DR. SAMUEL FEKADU (R1)
TABLE OF CONTENTS
• Introduction to general principles of pharmacokinetics and
pharmacodynamics
• Pharmacokinetics and pharmacodynamics drug ineractions
• Psychotropic side effects and drug interactions in different organ
systems and disease states
Definition of important terms
• A substrate: is an agent or a drug that is metabolized by an enzyme.
• An inducer: is an agent or a drug that increases the activity of the
metabolic enzyme, allowing for an increased rate of metabolism.
• An inhibitor: has the opposite effect, decreasing or blocking enzyme
activity needed for the metabolism of other drugs.
• Critical substrate: drug is a drug with a narrow theraputic index and
one primary p450 enzyme mediating its elimination
Introduction
• Psychopharmacological interventions are an essential part of the
management of the medically ill
• at least 35% of psychiatric consultations include recommendations for
medication
• Appropriate use of psychopharmacology in the medically ill requires
careful consideration of the underlying medical illness
potential alterations to pharmacokinetics
 drug–drug interactions
contraindications
• Drug-drug interaction can lead to hospital admissions, treatment failure
and avoidable medical complications
The principles of psychopharmacology

• Pharmacodynamics describes the effects of a drug on the body.

Determine the relationship between drug concentration and response
for both therapeutic and adverse effects.
• Pharmacokinetics describes what the body does to the drug.
Characterizes the rate and extent of drug absorption, distribution,
metabolism, and excretion
• These pharmacokinetic processes determine the rate of drug delivery to and
the drug’s concentration at the sites of action.
Pharmacodynamics
• For most drugs, the pharmacological effect is the result of a complex
chain of events, beginning with the interaction of drug with receptor.
• A drug’s spectrum of therapeutic and adverse effects is due to its
interaction with multiple receptor sites.
• different responses are recruited in a stepwise manner with
increasing drug concentration
• Pharmacodynamic response is further modified—enhanced or
diminished—by disease states, aging, and other drugs
Pharmacokinetics
• Drug response, including the magnitude and duration of the drug’s
therapeutic and adverse effects, is significantly influenced by the drug’s
pharmacokinetics
• Individual differences in constitutional factors, compromised organ
function, and disease states, or the effects of other drugs and food, all
contribute to the high variability in drug response observed across
patients.
• Understanding the impact of these factors on a drug’s pharmacokinetics
will aid in drug selection and dosage adjustment in a therapeutic
environment complicated by polypharmacy and medical illness.
Absorption and Bioavailability
• The speed of onset and to a certain extent the duration of the
pharmacological effects of a drug are determined by the route of
administration.
• Drug absorption is influenced by the characteristics of the absorption
site and the physiochemical properties of a drug
• Specific site properties affecting absorption include
surface area
 ambient pH,
mucosal integrity and function,
local blood flow,
• Orally administered drugs face
several pharmacokinetic barriers
that limit drug delivery to the
systemic circulation
• Drugs absorbed through the
gastrointestinal tract may be
extensively altered by “first-
pass” metabolism before
entering the systemic circulation
• Drug formulation, drug
interactions, gastric motility, and
the characteristics of the
absorptive surface all influence
the rate of absorption, a key
factor when rapid onset is
• Drug passage from the gut lumen to the portal circulation may be
limitedby two processes:
1) a P-glycoprotein (P-gp) efflux transport pump,which serves to reduce
the absorption of many compounds by countertransporting them back
into the intestinal lumen
2) metabolism within the gut wall by cytochrome P450 (CYP) 3A4
enzymes
Distribution
• the drug is distributed throughout the body in accordance with its
physiochemical properties and the extent of protein binding
• Systemic drug distribution is influenced by serum pH,blood flow,
protein binding, lipid solubility, and the degree of ionization
• Most drugs bind to proteins, either albumin or α1 acid glycoprotein
(AAGP), to a greater or lesser extent.
• Disease may alter the concentrations of serum proteins as well as
binding affinities.
• In general, only free (unbound to plasma proteins) drug is
pharmacologically active
• Decreases in protein binding increase availability of the “free” drug to
pharmacological action, metabolism, and excretion
Drug Elimination: Metabolism and Excretion
• The general function of metabolism is to convert lipophilic molecules
into more polar water-soluble compounds that can be readily excreted.
• Although biotransformation often results in less active or inactive
metabolites, this is not always true.
• Biotransformation occurs throughout the body, with the greatest
activity in the liver and gut wall.
• Most psychotropic drugs are eliminated by hepatic metabolism and
renal excretion.
Metabolism
• Phase I reactions
typically convert the parent drug into a more polar metabolite by
introducing or unmasking a polar functional group in preparation
for excretion or further metabolism by Phase II pathways
Phase I reactions include oxidation, reduction, and hydrolysis
Most Phase I oxidation reactions are carried out by the hepatic
CYP system, with a lesser contribution from the monoamine
oxidases (MAOs).
• CYP450 enzymes consist of a superfamily of heme-containing
proteins localized within the endoplasmic reticulum of the liver as
well as in the brain and periphery, and are responsible for the
metabolism of endogenous substances and xenobiotics
• While approximately 40 different CYP450 enzymes have been
identified, six enzymes (CYP1A2, CYP2B6, CYP2C9, CYP2C19,
CYP2D6 and CYP3A4) are responsible for mediating ≈90% of all
CYP450 activity mediating phase I metabolism of drugs
• Phase II metabolism
it conjugates the drug or Phase I metabolite with an endogenous
acid such as glucuronate, acetate,or sulfate.
The resulting highly polar conjugates are usually inactive and are
rapidly excreted in urine and feces
conjugation reactions mainly involve enzymes belonging to the
superfamily of UGTs
Excretion
• The kidney is the primary organ of drug excretion, with fecal and
pulmonary excretion being of less importance
• Hydrophilic compounds are removed from the body through excretion
into the aqueous environment of urine and feces.
• lipophilic drugs would experience significant renal elimination were it
not for renal resorption
Drug–Drug Interactions
• a drug interaction, defined as the modification of the action of one
drug by another,can be beneficial or harmful, or it can have no
significant effect
• In medically ill patients, polypharmacy is usually the norm and
requires vigilance regarding the many potential drug–drug
interactions.
• frequently leads to clinically significant pharmacokinetic or
pharmacodynamic drug–drug interactions.
Pharmacokinetic Drug Interactions
• in these interactions one agent causes the blood level of another
agent to raised or lowered
• Pharmacokinetic interactions alter
drug absorption
distribution
metabolism
 excretion
Changes in absorption
• Are often the result of changes in the physiochemical properties of
the primary drug (i.e. changes in gastric pH) leading to decreased
absorption
• drugs can inhibit or induce the P-gp transporter.
• Common P-gp inhibitors include paroxetine, sertraline,
trifluoperazine, verapamil, and proton pump inhibitors.
• Because intestinal P-gps serve to block absorption in the gut,
inhibition of these transporters can dramatically increase the
bioavailability of poorly bioavailable drugs.
Changes in drug distribution
• The amount of drug bound to plasma proteins is dependent on the
presence of other compounds that displace the drug from its protein
binding sites (a protein-binding drug interaction) and the plasma
concentration of albumin and alpha-1 acid glycoprotein
• protein-binding drug interaction, is considered cause of drug toxicity
because therapeutic and toxic effects increase with increasing
concentrations of free drug
• These interactions are now seen as clinically significant only in very
limited cases involving rapidly acting, highly protein bound(>80%),
narrow-therapeutic-index drugs with high hepatic extraction
Changes in drug metabolism

• The majority of pharmacokinetic DDIs involve alterations in phase I

metabolism by inhibition or induction of a family of cytochrome P-
450 hepatic enzymes (CYP450).
• The interacting drug may be either an inducer or an inhibitor of the
specific CYP enzymes involved in the substrate drug’s metabolism
• few clinically significant drug interactions are known to involve UGTs.
• Not all combinations of substrate drug and interacting drug will result
in clinically significant drug–drug interactions
• Metabolic drug interactions are most likely to occur in three
situations:
when an interacting drug (inhibitor or inducer) is added to an
existing critical substrate drug
when an interacting drug is withdrawn from a dosing regimen
containing a substrate drug
 when a substrate drug is added to an existing regimen containing
an interacting drug.
• When prescribing in a polypharmacy environment, the clinician
should avoid medications that significantly inhibit or induce CYP
enzymes and should prefer those that are eliminated by multiple
pathways and that have a wide safety margin
potent inhibitors of P450
potent inducers of P450
Drug interactions that affect renal drug
elimination
• Are clinically significant only if the parent drug or its active metabolite
undergoes appreciable renal excretion.
• By reducing renal blood flow, some drugs, including many NSAIDs,
decrease GFR and impair renal elimination. This interaction is often
responsible for lithium toxicity
• Changes in urine pH can modify the elimination of those compounds
whose ratio of ionized to un-ionized forms is dramatically altered
across the physiological range of urine pH
Pharmacodynamic Drug Interactions
• Pharmacodynamic interactions occur when concomitantly
administered medications share similar target sites of actions (i.e.
receptor) producing either additive or antagonistic effects that can
enhance or weaken the physiologic effect of the primary drug
respectively.
• These interactions may occur directly, by altering the drug binding to
the receptor site, or indirectly through other mechanisms.
PSYCHOTROPS IN GIT
• ANTIPSYCHOTICS
• Notable side effect- constipation
• Antipsychotic induced GI hypomotility can develop and frequently
progress to paralytic ileus, IO, bowel ischemia and perforation
• Both typical and atypical antipsychotics
• Serious GI complication of clozapine is more common than
agranulocytosis
• Mortality rate 37%
• Risk factors, higher dosage, concomitant anticholinergic use,
increased age
PSYCHOTROPS IN GIT
• ANTIPSYCHOTICS
• Cimetidine inhibits oxidative metabolism of most drugs of many psychotrops
increasing their serum level
• Avoid cimetidine use with psychotrops
• Use psychotrops which are eliminated by conjugation
• Reduce psychotropic dose
• Esomeprazole and lansoprazole- increase elimination and reduce serum
olanzapine and clozapine level
• diphenhydramine, prochlorperazine, promethazine additive anticholinergic
activity when combined with antipsychotics, TCAs, and benztropine increasing
the risk of cognitive impairment and delirium
• Metoclopramide have dopamine antagonist effect increasing EPS when
combined with antipsychotics
PSYCHOTROPS IN GIT
• ANTIDEPRESSANTS
• SSRIs have increased GI bleeding
• Risk factors: concurrent use of NSAID, elderly,
individuals with the history of GI bleeding, PUD,
cirrhosis
• Weigh risk and benefit among people at risk
• PPI can counter-act the risk
PSYCHOTROPS IN GIT
• ANTIDEPRESSANTS
• Concomitant use of TCAs and drugs with anticholinergic properties may
cause an anticholinergic crisis characterized by
• Delirium, hyperthermia (especially in hot environments),tachycardia,
and paralytic ileus
• H2-receptor antagonist cimetidine is a nonspecific inhibitor of hepatic
microsomal enzymes and may impair the metabolism of TCAs leading to
elevated plasma concentrations and toxicity
• The initial dose of TCA should be reduced appreciably in elderly
patients receiving cimetidine
• TCAs has Increased risk of cardiac arrhythmias with other QT-prolonging
agents including domperidone, droperidol, dolasetron, granisetron,
PSYCHOTROPS IN GIT
• MOOD STABLIZERS
• SIDE EFFECTS: Drug induce liver toxicity
• with, sodium valproate, carbamazepine
• other drugs: duloxetine, cpz
• Despite the potential risk of liver injury, there is no justification to routinely follow liver
enzymes for most psychotrops except for valproate
• Routine liver enzyme monitoring in
• Before starting treatment as a baseline
• Presence of early signs
• Patients who are impaired to communicate
• High risk groups
• 2-3 times higher than the normal upper limit-discontinue the medication and monitor
signs of acute hepatic failure(coagulopathy and encephalopathy)
• CPZ and other phenothiazines are contraindicated in patients in primary biliary cirrhosis
Psychotropic in hepatic impairments

• The clinician prescribing psychotropic medications for a patient with

liver disease should consider
 the severity of the liver disease
 the medication being considered
the margin between therapeutic and toxic plasma levels
the presence or high risk of hepatic encephalopathy
PSYCHOTROPS IN GIT
• Antacids
• Increase gastric PH and cause delayed gastric emptying
• Can reduce drug absorption
• Take 2-3 hrs apart from other drugs
PSYCHOTROPS IN RENAL AND
UROLOGIC
• ANTIPSYCHOTICS
• Side effects
• Urinary retention- with drugs that have significant anticholinergic
activity (e.g low potency typical antipsychotics, others TCA)
• Urinary incontinence (urgency, frequency, incomplete emptying)
• 40% of patients taking clozapine
• Other atypical antipsychotics
• More common in females
PSCHOTROPS IN RENAL AND
UROLOGIC
• ANTIPSYCHOTICS
• Alfuzosin, vardenafil prolong QT interval
• With QT prolonging agents cause grater risk
• E.G including TCAs, typical antipsychotics, pimozide,
risperidone, paliperidone, iloperidone, quetiapine, ziprasidone,
and lithium.
• Hypotension risk if a1 antagonist(alfuzosin, doxazosin) and PDE5
inhibitors (sildenafil, vardenafil, tadalafil) are combined with
antipsychotics. Others TCA
• Thiazide diuretics and loop diuretics can cause electrolyte
disturbance increasing risk of arrythmia due to QT prolonging
agents
PSCHOTROPS IN RENAL AND
UROLOGIC
• MOOD STABLIZERS
• Lithium nephrotoxicity
• Lithium use may result in altered kidney morphology(10-20%)
which is interstitial fibrosis, tubular atrophy, glomerular
sclerosis
• Other contributing factors: age, episode of lithium toxicity,
combination with analgesics, presence of comorbidity
• Progress of lithium nephrotoxicity to ESRD is rare, requires
lithium use for several decades
• Lithium associated renal dysfunction during chronic use is
acceptable compared to its efficacy
• Lithium is contraindicated in acute renal failure
PSCHOTROPS IN RENAL AND
UROLOGIC
• HYPONATREMIA
• Thiazide diuretics when combined with: ox carbamazepine, carbamazepine,
SSRIs, TCAs, Antipsychotics which causes SIADH
• Psychogenic Polydipsia(PPD)
• HYPERNATREMIA
• The only psychotropic drug is lithium, via nephrogenic DI
• Most patients with lithium have polydipsia and poly urea, if severe
dehydration, renal failure and lithium toxicity
• Tx-remits days to weeks after discontinuation
• Ample fluid intake
• salt restriction, amilorides(treatment of choice)
CARDIOVASCULAR
• ANTIPSYCHOTICS
• Side effects- all antipsychotics cause hypotension(especially
orthostatic)
• Most common, 1st generation- cpz, 2nd generation-olanzapine,
clozapine(6%), quetiapine(1%)
• Antipsychotics may greatly enhance the hypotensive effects of
antihypertensive agents
• Tolerance to hypotension effect may develop overtime, starting slow
helps
• Tx; salt supplement, a adrenergic agonists,
mineralocorticoids(fludrocortisone)
CARDIOVASCULAR
• ANTIPSYCHOTICS
• QT- prolongation, all antipsychotics prolong QT interval except Aripiprazole
• Higher risk- Haloperidol, Droperidol, thioridazine, ziprasidone, sertindole
• Amiodarone, type 1antiaarrythmic drugs(e.g. Quinidine, procainamide), TCAs
increase the risk
• QT prolongation is associated with VT
• Risk factors- chronic heavy alcohol consumption, female sex, electrolyte
disturbance, presence of heart disease, other drugs
• Hierarchy of antipsychotic choice in heart disease and significant CAD is,
• 1st line Aripiprazole, others olanzapine, quetiapine
CARDIOVASCULAR
• ANTIDEPRESANTS
• TCAs- side effects
• Increased heart rate, orthostatic hypotension
• Cardiac conduction disturbances(1st, 2nd, 3rd, degree heart
block), especially in patients with prolonged PR interval
• This risk is increased when combine with amiodarone, type 1
antiarrhythmic drugs
• They increase mortality in patients with ischemic heart disease
• Overdose: lethal ventricular tachy arrythmias
• TCAs suppress central antihypertensive effect of clonidine and
their combination could lead to severe HTN
CARDIOVASCULAR
• SSRIs-
• they can reduce heart rate which occasionally can be clinically
significant, combining them with b-blockers may exacerbate
their bradycardic effect
• Fluoxetine, paroxetine, bupropion inhibit b-blockers
metabolism that can lead to significant bradycardia
CARDIOVASCULAR
• Depression management in HEART DISEASES
• On the bases of available evidence sertraline, escitalopram,
citalopram appear to be the first line pharmacotherapy treatment
• Sertraline efficacy is limited to patients with recurrent depression
and depression onset before index cardiac event
• TCA remain gold standard in terms of efficacy, but they have a
substantial Side effect burden and carry increased mortality rate
• Nortriptyline might be a reasonable option
• Limited data suggest data suggest a preferential role of paroxetine
in CHF
 CARDIOVASCULAR
• MOOD STABLIZERS
• Lithium can cause sinus node dysfunction(sinus brady cardia, sinus arrest)
• Lithium is sensitive to diuretics
• Thiazide diuretics, CCBs, ACE inhibitors, ARBs increase serum Li concentration
• Acetazolamide and osmotic diuretics increase Li clearance
• In patients who are elderly, medically ill, or on salt-restricted diets, may increase
lithium toxicity
• Lithium toxicity may occur even when serum levels are not elevated in patients
also taking diltiazem or verapamil.
• Valproate and lamotrigine have no significant cardiac side effects
• Valproate can cause thrombocytopenia which may be important in patients
taking anticoagulants
CARDIOVASCULAR
• Carbamazepine appears to be relatively free of cardiac effects in healthy
patients, but some electrocardiographic abnormalities have occurred in patients
with heart disease and is relatively contraindicated in patients with heart block.
• Hyponatremia, a common side effect of carbamazepine, can be significantly
exacerbated by interaction with the added hyponatraemic effect of diuretics
• Carbamazepine and phenytoin are Pan-inducer of CYP 450 metabolic enzymes
Increased metabolism and lower levels of most cardiac medications,
• including warfarin, beta-blockers, antiarrhythmics, statins, calcium channel
blockers, etc.
• Avoid carbamazepine if possible. Monitor cardiovascular function. Increase
cardiac agent dosage as necessary.
RESPIRATORY SYSTEM
• ANTIPSYCHOTICS
• Asthma- patients who had recently discontinued antipsychotics use are at
high risk, abrupt discontinuation of drug with high anticholinergic activity,
such as clozapine, may cause cholinergic rebound, impairing the effectiveness
of anticholinergic asthma medications
• OSA- weight gain associated with olanzapine, quetiapine and other atypical
antipsychotics is problematic in patients with OSA
 RESPIRATORY SYSTEM
• cigarette smoke can increase the clearance of several drugs such as
• antipsychotic including chlorpromazine, fluphenazine and
haloperidol (except, aripiprazole, quetiapine, risperidone,
ziprasidone)
• Benzodiazepines
• SSRIs, TCAs
• Smoking cessation in patients taking FGAs has been associated with
emergence of EPS-related symptoms due to a decreased clearance of
the drug.
RESPIRATORY SYSTEM
• In smokers receiving antipsychotics, the prevalence of antipsychotic-
associated EPS is significantly less than non-smokers.
• polycyclic aromatic hydrocarbons from smoking significantly increase
olanzapine clearance by 98 %, reducing serum concentrations.
Olanzapine-related parkinsonian symptoms have also been reported in
a patient after smoking cessation
• the dose of antipsychotic may need to be increased in smokers,
Reduction or cessation of smoking necessitate reduction in dosage of
psychotropic medication
RESPIRATORY SYSTEM
• Anxiolytics and sedative hypnotics
• Respiratory depression resulting from sedative hypnotics is the
most common adverse respiratory effect associated with
psychotropic medications
• May precipitate respiratory failure in patients with marginal
respiratory reserve and contraindicated in patients with CO2
retention(e.g COPD) and OSA
• 20% increment in mortality rate in patients on long term
oxygen
• Only short term use
CNS
• CNS(Dementia)-ANTIPSCHOTICS
• Psychosis, aggression, and agitation are common in patients with moderate to
severe dementia
• The adverse effect of antipsychotics outweigh the benefits when used for this
indication
• But they are effective in controlling anger, aggression and paranoia (e.g
olanzapine, risperidone)
• Antipsychotics should be used sparingly at lowest effective dose and should
be considered short term adjunctive medication
• Other medications benzodiazepines, mood stabilizers
• SSRIs have modest evidence to be effective(sertraline, citalopram),
Porsteinsson et al. 2014
CNS
• CNS(Dementia)
• Algorithm of treatment of Psychosis and Agitation in dementia as
suggested by researchers (2005)
cholinesterase inhibitors, augmented with an SSRI in depressed patients

SSRIs

antipsychotics

Mood stabilizers
CNS
• ANTIDEPRESSANTS
• Sertraline, citalopram, escitalopram have fewer drug-drug
interactions and indicated for this use
• Avoid TCA because of the danger of substantial anticholinergic
activity

• ANXIETY-SSRIs first line

• BZDs in patients with prominent anxiety and infrequent
episodes of agitation
CNS
• CNS(Parkinson's Disease)-ANTIPSYCHOTICS
• Approximately 60% of Parkinson's disease patients will experience
psychosis at some point in their illness
• Antipsychotics worsen motor symptoms via dopamine antagonism
• Psychotogenic effects of dopamine agonists may erode the
therapeutic effects of antipsychotics in patients with schizophrenia
• TX-1ST decrease dopaminergic drugs to the lowest effective dose
• 2nd line CLOZAPINE(drug of choice)

• Risperidone, olanzapine, aripiprazole have been found to be

ineffective and worsen motor function
CNS
• CNS(Epilepsy)
• In psychosis associated with epilepsy antipsychotics with a high
risk of lowering seizure threshold, such as clozapine and low
potency typical should be avoided

• For depression SSRIs are first line of treatment because they have
little effect on seizure threshold
CNS
• Pharmacokinetic interaction of greatest clinical significance is the
induction of CYP1A2, CYP2C9, CYP2C19 and CYP3A4 mediated by
phenytoin, phenobarbital, carbamazepine and ethosuximide
resulting in decreased levels of many psychotrops, some
exceptions: lorazepam, oxazepam, trazodone
• Fosphenytoin and amantadine increase the risk of QT prolongation
of TCAs and antipsychotics
• Clozapine with carbamazepine increase the risk of bone marrow
suppression and agranulocytosis
• SSRIs inhibit metabolism of anticonvulsants
ENDOCRINE SYSTEM
• psychotropic induced metabolic syndrome
• 30-50% of patients on antipsychotics
• Antipsychotics cause wight gain and insulin resistance and also reduce
effectiveness of diabetes medications
• Follow weight gain, HTN, glucose tolerance and lipid derangements
• Dosage adjustments/change(aripiprazole, ziprasidone are weight neutral)
• Dietary education/exercise
• Metformin (750mg/day) shown to be effective
• May need to increase dosage of oral hypoglycemic agents in diabetic patients
ENDOCRINE SYSTEM
• MOOD STABIZERS
• Lithium causes goiter formation
• Lithium hypothyroidism
• Up to 38% of patients treated with lithium
• Decreased T3 and T4, exaggerated elevation of TSH, early transient
hyperthyroidism can happen
• If >4 month/clinical hypothyroidism T4 replacement and switch to other
mood stabilizers
• Lithium hyperparathyroidism
• 10% of patients
• Follow serum calcium with TFT
• Withdrawal of lithium doesn’t help needs parathyroidectomy
ENDOCRINE SYSTEM
• Valproate and carbamazepine can cause Hypothyroidism, decreased
FSH and LH, hypogonadism
• Corticosteroid can increase blood level of lithium
• Carbamazepine, phenobarbital, phenytoin due to its CYP 2C9 and CYP
3A4 induction Possibly reduced levels and effectiveness of oral
hypoglycemics
• Carbamazepine due to its induction of Phase 2 metabolism (UGT-
sulfation) Increased hepatic T4 metabolism and decreased effect
GYNEACOLOGICAL
• ANTIPSYCHOTICS
• Side effect-hyperprolactinemia
• Causes impotence, menstrual dysregulation, infertility, sexual dysfunction,
galactorrhea, gynecomastia
• Risk for osteoporosis, breast CA AND CVD
• follow prolactin levels in symptomatic patients only
• in patients who have increase prolactin level follow ca level
• TX- decrease dosage
• Change medication
• Metoclopramide( Peripheral and central dopamine receptor antagonism
Increased hyperprolactinemia and galactorrhea with antipsychotics
GYNEACOLOGICAL
• MOOD STABLIZERS
• Carbamazepine, phenytoin, phenobarbital, oxycarbamazepine
induce CYP3A4
• Causes decreased level of OCP and vaginal ring
• Reported failure of contraceptives in setting of anticonvulsants
• Estrogen increase glucuronidation of may drugs decreasing their
activity
• Such as lamotrigine, oxazepam, lorazepam, olanzapine
• Estrogen containing contraceptives decrease lamotrigine levels by
50%
• Dose adjustments needed during/after discontinuation of
hormonal contraceptives
ANTIBIOTICS

• Macrolides, fluoroquinoles, azole antifungals &

antiretroviral drugs are potent inhibitors of CYP
isoenzymes
• Affected drugs: BDZs, carbamazepine, haloperidol,
aripiprazole, quetiapine, clozapine, olanzapine
• Rifampin a potent inducer of liver enzymes
• Isoniazid is a potent inhibitor
Antimicrobial Effect on psychiatric drugs

Clarithromycin, Increase alprazolam, midazolam level

erythromycin
(Inhibition of CYP 3A4) Increase carbamazepine level
Increase buspirone level
Increase clozapine level
cause QT interval prolongation and ventricular arrhythmias(TCA and antipsychotic)
Ciprofloxacin, Benzodiazepine serum levels increased
Norfloxacin
(Inhibition of CYP 1A2
and 3A4) Clozapine And olanzapine levels increased

Anti fungals Increase alprazolam and midazolam

(ketoconazole and
itraconazole) Increase busprion level
(Inhibition of CYP 3A4)
QT interval prolongation and ventricular arrhythmias

Antimalarias Increase phenothiazine levels

References
• The American Psychiatric Association Publishing Textbook of
Psychosomatic Medicine and Consultation-Liaison Psychiatry 3rd
ed CONV. PD , 2019
• Clinical Manual of Psychopharmacology in the Medically ill 2 nd
edition
THANK YOU