Download DRUG INTERACTIONS AND ANESTHESIA

DRUG INTERACTIONS AND
ANESTHESIA
Rudolf Klima, M.D.
Central Arkansas Veterans Healthcare System
Associate Professor of Anesthesiology
College of Medicine, UAMS
Little Rock, Arkansas
CEEA 2012 Košice
OBJECTIVES
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Introduction
Pharmacokinetic interactions
Pharmacodynamic interactions
In Vitro Interactions
Selected groups of drugs and their
interactions
SIMPLYFIED BASIC
TERMINOLOGY
Pharmacology - study of how
chemical agents affect living processes
Pharmacokinetics - what the body does to the
drug (absorption, distribution and elimination)
Pharmacodynamics - what the drug does to the
body (dose – response relationship)
PHARMACOLOGICAL (DRUG –
DRUG) INTERACTION
A drug interaction
occurs when a drug
interferes in a negative
or positive way
with another drug
PHARMACOKINETIC
INTERACTIONS
♦ Pharmacokinetic interactions are mainly due
to alteration of absorption, distribution,
metabolism, or excretion drug which changes the
amount and duration of a drug's availability at
receptor sites
♦ Pharmacokinetic interactions are more
complicated and difficult to predict because the
interacting drugs often have unrelated actions
RATE OF ABSORPTION AND
ELIMINATION
First order kinetics - constant fraction of the drug
present will be absorbed or eliminated in a unit of time
Half-life t1/2 - time required for 50% of drug to be absorbed
or eliminated
Elimination rate constant (ke) - the fraction of drug absorbed
or eliminated per unit time
Zero order kinetics - processes in which a constant
amount of drug is absorbed or eliminated per unit time
PHARMACOKINETIC CURVE
Cmax: Maximum concentration –
may relate to some side effects
Plasma Concentration
10000
AUC: Area under the curve (filled
area) = overall drug exposure
3000
1000
Cmin: minimum or
trough concentrations:
may relate with efficacy
of drug
100
0
2
4
6
8
Time Post-dose (hr.)
http://www.thebody.com/content/art875.html
10
12
Pharmacokinetic Interactions
DRUG ABSORPTION
Absorption from gastrointestinal tract:
A/ Nonspecific interactions affecting peristalsis and
perfusion (opioids, vagolytics, vasopressors)
B/ Physicochemical interactions
■ Chelation (ciprofloxacin + 2- and 3-valent cations)
■ Adsorption (activated charcoal)
■ Cation-exchange (sodium polystyrene sulfonate)
C/ P-glycoprotein induction or inhibition
•P-glycoprotein inducers:
•P-glycoprotein inhibitors:
◦Carbamazepine (Carbatrol®, Epitol®, Equetro®,
Tegretol®)
◦Dexamethasone (Decadron®)
◦Doxorubicin (Adriamycin®, Doxil®)
◦Nefazodone (Serzone®)
◦Prazosin (Minipress®)
◦Rifampin (Rifadin®)
◦St. John's wort
◦Tipranavir (Aptivus®)
◦Trazodone (Desyrel®) and trazodone ER (Oleptro™)
◦Vinblastine
◦Amiodarone (Cordarone®, Pacerone®)
◦Atorvastatin (Lipitor®, also found in Caduet®)
◦Carvedilol (Coreg®, Coreg CR®)
◦Clarithromycin (Biaxin®)
◦Cyclosporine (Gengraf®, Neoral®, Sandimmune®)
◦Darunavir (Prezista®)
◦Dipyridamole (Persantine®, also found in Aggrenox®)
◦Dronedarone (Multaq®)
◦Erythromycin
◦Grapefruit juice
◦Hydroxychloroquine sulfate (Plaquenil®)
◦Itraconazole (Sporanox®)
◦Ketoconazole (Nizoral®)
◦Lapatinib (Tykerb®)
◦Lopinavir and ritonavir (Kaletra®)
◦Mefloquine (Lariam®)
◦Nelfinavir (Viracept®)
◦Nicardipine (Cardene®)
◦Nilotinib (Tasigna®)
◦Progesterone
◦Propranolol (Inderal®, Inderal LA®, InnoPran XL®, also
found in Inderide®)
◦Quinidine
◦Ranolazine (Ranexa®)
◦Reserpine
◦Ritonavir (Norvir®, also found in Kaletra®)
◦Saquinavir (Invirase®)
◦Sunitinib (Sutent®)
◦Tacrolimus (Prograf®, Protopic®)
◦Tamoxifen (Nolvadex®)
◦Verapamil (Calan®, Calan SR®, Covera-HS®, Isoptin
SR®, Verelan®, Verelan PM®)
CONCENTRATION EFFECT
SECOND GAS EFFECT
Longnecker DE, Brown DL, Newman MF, Zapol WM: Anesthesiology 2nd ed.
Pharmacokinetic Interactions
DRUG DISTRIBUTION
drug – plasma protein binding
↓
bound (inactive) fraction + unbound (active) fraction
Albumin binds acidic and neutral molecules
Plasma concentration 35 – 50 g/L 500 – 700 μM/L
α1 acid glycoprotein binds alkaline molecules
Plasma concentration 0.4 – 1.0 g/L 9 – 23 μM/L
PLASMA PROTEINS (PB)
Change of concentration:
■ ↓ concentration of PB (catabolism, advanced age,
hepatic and renal dysfunction → ↑ concentration of
unbound drug fraction
■ ↑ concentration of PB (AAG – acute phase reactant)
→ ↓ unbound drug fraction
Change of protein binding:
■ advanced age
WARFARIN PLASMA PROTEIN
BINDING
Normal conditions:
98 % bound fraction + 2 % unbound fraction
After displacement:
96 % bound fraction + 4 % (2 x 2 %) unbound
fraction
Questionable clinical significance. Less than 1/3
of Warfarin in the body is bound to plasma
proteins
Pharmacokinetic Interactions
DRUG METABOLISM
Xenobiotics – substances foreign to the body (including drugs),
mostly metabolized by enzymes
Phase I metabolism:
♦ inactivation of active drug (enzymes - CYPs, FMO, EH)
♦ bioactivation of drug (prodrug → drug)
Phase II metabolism:
♦ production of metabolite with increased water solubility and
molecular weight ( enzymes – SULT, UGT, GST, NAT, MT)
CYTOCHROME P450 - CYP
♦ Superfamily of enzymes containing molecule of
heme noncovalently bound to polypeptide chain
♦ There are more than 50 CYPs in humans
♦ Metabolism of substrate consumes one molecule
of O2 and produces oxidized substrate and
molecule of H2O
♦ CYPs bind and metabolize multiple substrates
♦ Subfamilies CYP2C, CYP2D and CYP3A involved in
metabolism of most drugs, CYP3A4 involved in metabolism
of 50% clinically used drugs
CYP3A4
CYP3A4 [1TQN, Homo sapiens] ribbon detail. Color key: helix structures, gray; strand
structures, blue; PERF consensus, green; K-helix consensus, purple; heme-binding
consensus, orange; heme ligand, yellow
Pharmacokinetic Interactions
RENAL EXCRETION
I.
Active tubular secretion (proximal tubule)
Transporters responsible for the tubular secretion of drugs: Pglycoproteins (PGps), multidrug resistance-associated
proteins (MRPs), organic anion transporters (OATs),organic
cation transporters (OCTs), etc. Tubular transporters are not
highly specific and may become saturated at high drug
concentrations
II. Passive tubular diffusion
Reabsorption depends on the lipophilic properties of the drug, on
urine flow, urine pH and chelating agents
PHARMACODYNAMIC
INTERACTIONS
Pharmacodynamic interactions include the
concurrent administration of drugs having the
same or opposing pharmacologic actions and
alteration of the sensitivity or the responsiveness
of the tissues to one drug by another
DOSE – RESPONSE CURVE
RECEPTORS
Receptor is molecule on the surface or within a cell that
recognizes and binds with specific molecules, producing
a specific effect in the cell
RECEPTOR AGONISTS
Full Agonist – has receptor affinity and efficacy
Partial Agonist – has receptor affinity and reduced efficacy
RECEPTOR ANTAGONISTS
Antagonist – drug with receptor affinity, without efficacy
Competitive antagonist binds to active site of receptor
Non – competitive antagonist :
a/ irreversibly binds to active site
b/ binds to allosteric site
Uncompetitive antagonist – binds to allosteric site of receptor
already activated by agonist
Inverse Agonist – inhibits basal receptor activity
RESULTS OF
PHARMACODYNAMIC DRUG –
DRUG INTERACTIONS
 Additive effect
eA and eB → eT
eT = eA + eB
 Synergism (Potentiation)
eA and eB → eT
eT > eA + eB
Antagonism
eA and eC → eT
eT < A; eT = A - C
A,B…..agonists
C……antagonist
eT……. total effect
e………. drug effect
DRUG INTERACTIONS IN VITRO
 Drug – Drug interactions (succinylcholine and
thiopental)
 Drug – Solution interactions (ceftriaxone and LR)
 Drug – Pharmaceutical packaging material
(glass and plastics) interactions
DRUG – CONTAINER
INTERACTIONS
 Sorption - absorption to matrix or adsorption to
surface (nitroglycerin, amiodarone, insulin)
 Leaching - components of plastics migrate to
medicine (Paclitaxel leaches DEPH - Di(2
ethylhexyl)phthalate)
 Permeation – drug penetrates through container wall
(nitroglycerin)
 Polymer modification – drug modifies polymer’s
chemical structure (chlormethiazole softens PVC)
DRUG - CONTAINER
INTERACTIONS EXAMPLES
♦ Insulin adsorbs to glass and
polyvinyl chloride (PVC) surfaces
♦ Nitroglycerin (NTG) adsorbs to, absorbs
into, and penetrates the wall of plastic container
or infusion set. Polyethylene reduces NTG
concentration by 15%, PVC up to 70%.
It remains possible that changes in hemodynamic
status could occur in patients on NTG if a change in container
type (i.e., from PVC to glass or vice versa)
is made during the course of therapy
POLYPHARMACY IN THE
ELDERLY
Def. : 6 or more medications or a potentially inappropriate
medication(s)
+
Elderly Americans consume one-third of all the prescription
medications prescribed each year, yet they comprise less than
13% of the population (Azad 2005; CDC 2005)
CONSEQUENCES OF
POLYPHARMACY
 ↑ adverse/allergic drug events
 ↑ drug interactions
 ↑ cascade prescriptions – when side effect
of one medication is treated with other
medication(s)
American Geriatrics Society Updated Beers Criteria for
Potentially Inappropriate Medication Use in Older
Adults
The American Geriatrics Society 2012 Beers Criteria Update Expert Panel
Fifty-three medications or medication classes are divided into
three categories:
potentially inappropriate medications and
classes to avoid in older adults
II.potentially inappropriate medications and classes to avoid
in older adults with certain diseases and syndromes that the
drugs listed can exacerbate
III.medications to be used with caution in older adults
I.
INFORMATION TECHNOLOGY
(IT) IN PHARMACY
"I think there is a world market for maybe five
computers“
Thomas John Watson, Sr. the chairman and CEO of
International Business Machines (IBM), 1943
...............................
"I can assure you that data processing is a fad that won't
last the year."
Chief Business Editor, Prentice Hall, 1957
IT and PHARMACY
ENHANCED ORDER CHECKING
SYSTEM
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Drug – drug interaction order check
Allergy/Adverse reaction order check
Duplicate therapy order check
Notification of recently discontinued/expired medication
Error message when order cannot be performed
Consistency between inpatient and outpatient medications
Consistency between remote data and local medication order
MEDICATION
RECONCILIATION
Medication reconciliation is the process of
comparing a patient's medication orders to all of the
medications that the patient has been taking. This
reconciliation is done to avoid medication errors
such as omissions, duplications, dosing errors, or
drug interactions.
Joint Commission's Medication
Management standards
Medication reconciliation
comprises five steps:
I.develop a list of current medications
II.develop a list of medications to be prescribed
III.compare the medications on the two lists
IV.make clinical decisions based on the
comparison
V. communicate the new list to appropriate
caregivers and to the patient
MEDICATION RECONCILIATION EXAMPLE
MEDICATION RECONCILIATION:
Problem: XY is a 65 year old patient currently an inpatient
at the hospital. The patient was visited for the purpose of medication
reconciliation.
1. Medication interview conducted with patient. Patient confirmed that all home
prescription medications come from hospital. He reported taking all medications as
prescribed and confirmed that the above outpatient medication list is accurate
and complete.
2. Medication reconciliation performed. Comparison of home medication list to
active inpatient medication list completed. Discrepancies documented above.
3. A medication related falls assessment has been conducted for
this patient.
The following inpatient medications have been identified to
increase the risk of falls: None noted at this time.
4. Herbal/Over-the-counter/non-VA meds to be documented: None per pt report.
5. Calculated creatinine clearance (Cockcroft- Gault formula) is estimated to
be 45-50ml/min. No dosing adjustments are necessary at this time based on
renal function.
6. Significant drug interactions (inpatient orders): None identified at this
time.
7. Allergies: Patient has answered NKA.
8. Please contact pharmacy with further questions or concerns.
HERBAL SUPPLEMENTS
■ Herbal supplement are a type of
dietary supplement that contains
herbs plant or part of a plant used for
its flavor, scent, or potential
therapeutic properties
■ Herbal supplements can act in the
same way as drugs
■ Some herbal supplements are
known to interact with medications in
ways that cause health problems
PERIOPERATIVE USE OF
HERBAL SUPPLEMENS
■ 22% - 34% of preoperative adults
■ 15% of pregnant women
■ 6.4% of children scheduled for outpatient
surgery
■ 70% of patients failed to disclose
preoperative use of herbal supplements
REGULATION OF HERBAL
SUPPLEMENTS IN THE USA
The Dietary Supplement Health and
Education Act (DSHEA) 1994:
Manufacturers of dietary supplements are
not required to prove efficacy, safety, or
quality of a product prior to marketing
Manufacturers are not obligated to report
postmarketing adverse events to the FDA
U.S. Manufacturer’s disclaimer:
"This statement has not been evaluated by the
Food and Drug Administration. This product is
not intended to diagnose, treat, cure, or prevent
any disease."
REGULATION OF HERBAL
SUPPLEMENTS IN EU
 A 2004 EU directive requires manufacturers of
all over-the-counter herbal products to register
and license the product with the European
Agency for the Evaluation of Medicinal Products
 Manufacturers have to provide the premarket
evaluation of quality and safety of the product
 Companies need to carry out post-marketing
surveillance and report serious adverse events
St. John’s Wort
Hippocrates documented the use of St. John's Wort for
mood ailments in the 5th century BC
St. John’s Wort
 Active compounds: hypericin and hyperforin
 Indications: treatment of mild to moderate depression
 Mechanism of action: inhibition of serotonin, dopamine and noradrenalin
reuptake, activation of GABA and Glutamate receptors
 Side effects: photosensitivity, anxiety, palpitations, headaches
 Pharmacokinetic Interactions: CYP3A4 and CYP2C9 induction,
P-glycoprotein induction
 Pharmacodynamic Interactions: antidepressants
 Recommendations: discontinuation at least 5 days prior to surgery
particularly in patients on warfarin and waiting on organ transplantation
Drug Interactions with St. John’s Wort
DRUG
SUBSTRATE
Alprazolam
CYP3A4
triazolam) may be
Cyclosporine CYP3A4, P-gp
concentrations.
Digoxin
P-gp
Erlotinib
CYP3A4
Fexofenadine CYP3A4
Glipizide
CYP2C9
Ibuprofen
CYP2C9
Imatinib
CYP3A4
Indinavir
CYP3A4
protease inhibitors
Methadone
Nifedipine
felodipine,
INTERACTION
COMMENTS
↓AUC 40%
Other benzodiazepines (e.g., midazolam,
↓AUC 30%-75%
↓AUC 25%-30% Monitor plasma concentration.
↓AUC 66%
Avoid use.
↓AUC 40%-50%
↓AUC 33%
Glyburide may be similarly affected.
↓AUC 30%
Other NSAIDs may be similarly affected.
↓AUC 30%-40% Avoid concurrent use.
↓AUC 60%
Ritonavir, saquinavir, nelfinavir and other
CYP2B6, CYP2C19 ↓AUC 47%
CYP3A4, P-gp
↓AUC 45%
nitrendipine, verapamil
Omeprazole
CYP2C19, CYP3A4 ↓AUC 40%-50%
Oral contraceptives:
CYP3A4
Simvastatin
CYP3A4
similar manner
Tacrolimus
CYP3A4
tacrolimus
similarly affected.
Transplant rejection may occur; monitor CsA
likely to be similarly affected.
Potential to affect fentanyl, oxycodone
May also affect amlodipine, bepridil, diltiazem,
isradipine, nicardipine, nimodipine,
Larger effect in CYP2C19; EMs, may also affect
esomeprazole, pantoprazole, lansoprazole
Loss of efficacy Use alternative contraception; avoid SJW.
↓AUC 50%
May also affect lovastatin and atorvastatin in a
↓AUC 50%-60% Transplant rejection may occur; monitor
EPHEDRA
Ephedra also called ma huang, is an herb that has been used in
Traditional Chinese Medicine for more than 5,000 years,
primarily to treat asthma or bronchitis
EPHEDRA
 Active compounds: ephedrine, pseudoephedrine, norephedrine,
methylephedrine and norpsedoephedrine
 Indications: asthma, bronchitis, nasal congestion, weight reduction
 Mechanism of action: direct and indirect sympathomimetics
(α1 β1 β2 )
 Side effects: coronary and cerebral vasospasms, hypertension,
seizures, in vitro platelets aggregation inhibition, dysrhythmias
 Pharmacodynamic Interactions: inhibitors MAO, sympathomimetics,
parasympatholytics, halothane
 Recommendation: discontinuation at least 24 hours prior to
surgery/anesthesia
ECHINACEA
Native American medicinal plant called named for the prickly scales in its
large conical seed head, which resembles the spines of an angry hedgehog
(echinos is Greek for hedgehog)
ECHINACEA
•
Active compounds: phenols (cichoric acid , caftaric acid), polysaccharides and
alkylamides
•
Indications: sore throat, headache, wounds
•
Mechanism of action: immunostimulating (or immunosuppressive) and
antimicrobial effects
•
Side effects: hepatotoxicity, anaphylactic reactions
•
Pharmacokinetic Interactions:
inhibition CYP1A2 - ↑ plasmatic concentration of warfarin, verapamil,
acetaminophen, amitriptyline, clopidogrel, clozapine, diazepam, estradiol,
olanzapine, ondansetronu, propranolol and theophylline)
induction CYP3A - ↓ plasmatic concentration of midazolam
•
Recommendations: not recommended in surgical patients
GARLIC
Garlic has been used as both food and medicine in many cultures
for thousands of years, dating back to ancient Egypt
GARLIC
alliinase
Active compounds:
↓
alliin → allicin
Traditional use:
Healing power and protection against evil spirits in
ancient Egypt
Vampire repellent – even before Stoker’s Dracula
In early 18th-century France, crushed garlic in wine was
believed to protect gravediggers from the plague
During both World Wars I and II, soldiers were given
garlic to prevent gangrene
On the eve of St. Lucia day, people all over Slovakia ate garlic
for protection from witches
GARLIC
Pharmacology:
Plasma lipid profile - ↓ total cholesterol ↓ LDL
↓ triglycerides ↑ HDL (? inhibition of HMG-CoA)
Circulation - ↓ blood pressure (↓ SVR, ↓ PVR)
Glycemic control - ↑ release of insulin, ↑ response to insulin
Coagulation (ajoene) – irreversible inhibition of platelet aggregation in
dose-dependent fashion
Antimicrobial effect – against bacteria and fungi
Antioxidant
Side effects:
gastrointestinal irritation
Recommendations:
discontinue at least 7 days prior to surgery/neuraxial analgesia
GINKGO BILOBA
Ginkgo leaf and seed have been used in Chinese herbal medicine
to enhance memory for thousands of years
GINKGO BILOBA – I.
 Active compounds: flavonoids and terpenoids
 Indications: cognitive disorders – Alzheimer dz. and multi-infarct
dementia, age related macular degeneration, PVD, cerebrovascular
dz., Raynaud’s dz., vertigo, tinnitus, altitude sickness
 Mechanism of action:
- antioxidant
- platelet-activating factor inhibition
- thromboxane synthase inhibition
- improvement of cholinergic transmission
- nonselective MAO inhibition
- inhibition of neuronal reuptake of serotonin, dopamine and
norepinephrine

GINKGO BILOBA – II.
 Side effects: bleeding related to antiaggregation effect,
nausea, dyspepsia
 Theoretical Interactions: acetylcholinesterase inhibitors,
anticoagulants, antiplatelet agents, NSAIDs,
MAO inhibitors, SSRIs, vasodilators
 Recommendations: discontinuation 36 hours prior to surgery
GINSENG
ADAPTOGENS
Adaptogens can be defined as a pharmacological group of herbal
preparations that increase tolerance to mental exhaustion and enhance
attention and mental endurance in situations of decreased performance
The key point of action of phytoadaptogens appears to be their upregulating and stress-mimetic effects on the "stress-sensor" protein
Hsp70, which plays an important role in cell survival and apoptosis
Panossian A, Wikman G. Evidence-based efficacy of adaptogens in fatigue, and
molecular mechanisms related to their stress-protective activity. Curr Clin
Pharmacol. 2009 Sep;4(3):198-219.
ASIAN AND AMERICAN GINSENG
Ginseng was considered for generations to be a
panacea by the Chinese and Koreans
ASIAN AND AMERICAN GINSENG I.
• Active compounds: ginsenosides (> 20 steroidal saponins)
• Indications:
adaptogen - helps the body better cope with physiologic,
emotional and environmental stress
• Mechanism of action:
- stimulation of ACTH secretion
- stimulation of RNA transcription
- immunostimulating effect on reticuloendothelial
system
- may prolong QTc interval
ASIAN AND AMERICAN GINSENG II.
Side effects:
- unintended hypoglycemia in both DM type 2
and nondiabetes patients
- inhibition of platelet aggregation
Recommendations:
Discontinue –
a/ 24 hours before surgery due to potential
hypoglycemia
b/ 7 day before surgery due to antiplatelet effect
SIBERIAN GINSENG
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Eleutherococcus senticosus, also known as eleuthero
Active compounds: eleutherosides
Indications: mental and physical stress, cold, flu
Mechanism of action: adaptogen, immunostimulat,
anti – viral action (colds, flu, herpes)
VALERIAN
Valerian has been used as a sedative, hypnotic and
anxiolytic since the second century A.D.
VALERIAN
 Active compounds: sesquiterpenes, valeric acid…
 Indications: insomnia, sedation, anxiolysis, restless leg
syndrome, muscle spasm, premenstrual syndrome
 Mechanism of action: modulation of GABA neurotransmission
 Side effects: risk of benzodiazepine – like withdrawal after
abrupt discontinuation
 Recommendations: continue preoperatively or wean gradually
over several weeks
KAVA KAVA
Kava kava has been used as a ceremonial
drink
in the Pacific Islands for hundreds of years .
KAVA KAVA
 Active compounds: kavalactones
 Indications: insomnia, anxiety
 Mechanism of action: modulation
of
GABA transmission in limbic system, local anesthetic effect, Ca 2+ and
Na+ channel blocking, MAO-B inhibition
 Side effects: hepatotoxicity, thrombocytopenia, lymphopenia,
pulmonary hypertension, myocardial depression, ↓ SVR
 Pharmacodynamic Interactions: kava potentiates effect of CNS
depressants (sedatives/hypnotics, alcohol, anesthetics)
• Recommendations: discontinue at least 24 hours prior to surgery
Ann Intern Med.February 1955;42(2):417-424
________________________________________
Insel R, Roy B, Cohen R, Murphy D: Possible
development of the serotonin syndrome in man. Am J
Psychiatry 1982; 139:954-955.
SEROTONIN SYNDROME
Serotonin syndrome is a potentially life threatening
drug reaction caused by severely elevated serotonin (5HT) levels in the body
The 5-HT1A and 5-HT2A receptors appear to be crucial in
the pathogenesis of the serotonin syndrome
Clinical manifestation:
alteration of mental status
autonomic hyperactivity
neuromuscular dysfunction
SEROTONERGIC DRUGS
MECHANISM OF ACTION
AGENT
Increased serotonin formation
L-tryptophan
Increased serotonin release
Cocaine
Ecstasy
Amphetamines
Alcohol
Dopamine agonists
Reduced serotonin reuptake
SSRIs
SNRIs
TCAs
Meperidine
Tramadol
Fentanyl
Ondansetron/Granisetron
St. John’s wort
Inhibits serotonin metabolism
MAOIs
Serotonin agonists
Triptans
Ergot alkaloids
LSD
Increases sensitivity of the postsynaptic
receptor
Lithium
ANTIDEPRESSANTS
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Monoamine oxidase inhibitors (MAOI)
Tricyclic antidepressants (TCA)
Tetracyclic antidepressants (TeCA)
Selective serotonin reuptake inhibitors (SSRI)
Serotonin-norepinephrine reuptake inhibitors (SNRI)
Noradrenergic and specific serotonergic antidepressants
(NaSSA)
Norepinephrine reuptake inhibitors (NRI)
Norepinephrine-dopamine reuptake inhibitors (NDRI)
Selective serotonin reuptake enhancers (SSRE)
Norepinephrine-dopamine disinhibitors (NDDI)
avoiding depression...
CLINICAL PRESENTATION OF
SEROTONIN SYNDROME
 Alteration of mental status: anxiety,
restlessness, delirium
 Autonomic hyperactivity: tachycardia,
hypertension, hyperthermia, diaphoresis,
vomiting, diarrhea
 Neuromuscular dysfunction: hyperreflexia,
clonus, tremor, bilateral Babinski signs
DIAGNOSIS OF SEROTONIN
SYNDROME
Recently introduced serotonergic agent and the presence of
any of the following (Hunter criteria):
A. tremor and hyperreflexia
B. spontaneous clonus
C. muscle rigidity, temperature greater than 38°C,
and either ocular clonus or inducible clonus
D. ocular clonus and either agitation or diaphoresis
E. inducible clonus and either agitation or
diaphoresis
LABORATORY FINDINGS IN
SEROTONIN SYNDROME
 Leukocytosis
 ↑ Creatine phosphokinase
 Metabolic acidosis
Severe cases:
Rhabdomyolysis
Disseminated intravascular coagulation
Myoglobinuria
DIFFERENCIAL DIAGNOSIS OF
SEROTONIN SYNDROME
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neuroleptic malignant syndrome
malignant hyperthermia
anticholinergic toxicity
sympathomimetic toxicity
meningitis, encephalitis
TREATMENT OF SEROTONIN
SYNDROME
 discontinuation of the provoking agents
 supportive care – hydration, oxygenation, sedation with
benzodiazepines
 physical cooling for hyperthermia > 38o C
 neuromuscular paralysis with nondepolarizing agents for
severe neuromuscular hyperreactivity and hyperthermia
 treatment of hypertension and tachycardia – β-blocker, nitrates
 cyproheptadine (5-HT receptor antagonist), methylsergide
(nonspecific serotonin antagonist )
NEUROLEPTIC MALIGNANT
SYNDROME (NMS)
 Life threatening neurologic emergency
associated with use of neuroleptics,
antiemetics, and antiparkinson medication
withdrawal.
 NMS is associated with dopamine receptor
blockade or dopamine deficit in CNS
NEUROLEPTIC MALIGNANNT
SYNDROME TIME COURSE
RISK FACTORS ASSOCIATED
WITH NMS
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High potency agents
Parenteral drug administration
Concomitant use of lithium
Dehydration ?
Acute medical illness
LABORATORY FINDINGS IN NMS
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↑ serum creatine kinase (CK > 1000 IU/L)
Leukocytosis
↑ liver function tests
Acid – base and electrolyte abnormalities:
MAC, ↓Ca , ↓Mg ,↑K , ↓↑Na
 ↓ serum Fe
TREATMENT OF NMS
 Discontinuation of causative agent
 Supportive care aims– stabilization of
cardiovascular and respiratory systems,
normovolemia, normothermia, sedation
 Medical therapy:
- dantrolene
- amantadine
- bromocriptine
ANTICHOLINERGIC TOXICITY
 Anticholinergic toxicity is caused by
overdosing or combination of antimuscarinic
agents
 Over 600 prescription and nonprescription
drugs and plants have antimuscarinic
properties
ANTIMUSCARINIC COMPOUNDS
Belladonna alkaloids: atropine, scopolamine
Tertiary and quaternary amine compounds: procaine,
cocaine, dicyclomine, cyclopentolate, homatropine
Antihistamines: diphenhydramine
Antipsychotics: haloperidol, droperidol
Antiparkinson drugs: benztropine, trihexphenidyl
TCA: imipramine, amitriptyline
Opioids: meperidine, methadone
CLINICAL PRESENTATION
Mental status: anxiety, agitation, delirium,
seizures, coma
Hemodynamics: tachycardia
Skin: red (vasodilation), dry (anhidrosis) and hot
( hyperthermia)
Eyes: nonreactive mydriasis, blurry vision
Urinary retention
TREATMENT OF
ANTICHOLINERGIC TOXICITY
 Supportive care
 Benzodiazepines for seizures and agitation
 Physostigmine – only in pure anticholinergic
poisoning
Relative contraindications – reactive airway,
epilepsy, intestinal obstruction, cardiac
conduction abnormalities
ĎAKUJEM ZA
POZORNOSŤ