Pharmacodynamic Drug Interactions

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Pharmacodynamic Drug Interactions

• Mary Lynn McPherson, Pharm.D., BCPS
• Professor, University of Maryland School of
  Pharmacy
• mmcphers_at_rx.umaryland.edu

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Drug Interactions

• Medications are used extensively to palliate
  symptoms
• Patients with advanced illness take an average of
  5 medications (range 0-13)
• Increases risk for drug interactions
• Risk increased due to patient fragility,
  co-morbid conditions, increased age

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Defining a Drug Interaction

• A measurable modification (in magnitude or
  duration) of the action of one drug by prior or
  concomitant administration of another substance.
• Drug-drug (Rx, OTC, herbal)
• Drug-food, drug-alcohol
• Drug-lab, drug-disease, drug-chemical

Wright 1992. Drug Interactions. In Melmon and
Morrellis Clinical Pharmacology 1992
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Drug Interactions

• Pharmacodynamics
• The study of the action and effects of
  medications on physiologic function
• Pharmacodynamic drug interactions can be
• Additive (two or more analgesics)
• Synergistic
• Antagonistic (dexamethasone and glyburide)

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Pharmacodynamic Drug Interactions in Palliative
Care

• Anticholinergic effects
• Constipation
• Lowered seizure threshold
• Serotonin syndrome
• CNS depression
• QTc prolongation

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Muscarinic Receptor Subtypes
Receptor Subtype CNS Distribution Non-CNS Location
M1 Cerebral cortex, hippocampus, neostriatum Salivary glands, sympathetic ganglia
M2 Throughout the brain Smooth muscle, cardiac muscle
M3 Low levels throughout brain Smooth muscle, salivary glands, eyes
M4 Abundant in neostriatum, cortex and hippocampus Salivary glands
M5 Projection neurons of substantia nigra pars, compacta and ventral tegmental area and hippocampus Eyes (ciliary muscle)
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Antimuscarinic Pharmacologic Effects Peripheral

• Dry eyes
• Urinary retention
• Dry mouth
• Constipation

• Heat intolerance
• Tachycardia
• Decreased sweating

Carnahan et al. J Clin Pharmacol 2006461481-1486
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Antimuscarinic Pharmacologic Effects Central

• Forgetfulness
• Agitation / confusion
• Delirium
• Paranoia

• Dizziness
• Drowsiness
• Falls

Carnahan et al. J Clin Pharmacol 2006461481-1486
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Evoking Antimuscarinic Effects
Overactive bladder Oxybutynin (Ditropan) Toleradine (Detrol) Trospium (Sanctura) Solifenacin (Vesicare) Darifenacin (Enablex)
Anticholinergic / Antiparkinsons Trihexyphenidyl (Artane) Benztropine (Cogentin) Amantadine (Symmetrel)
Antivertigo / antiemetic Meclizine (Antivert) Scopolamine (TransDerm Scop)
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Evoking Antimuscarinic Effects
Gastrointestinal / Antispasmodics Diphenoxylate (Lomotil) Dicyclomine (Bentyl)
Antisecretory / Drying Agents Hyoscyamine (Levsin) Atropine (ophthalmic given PO)
Bronchospasm Ipratroptium (Atrovent) Tiotroptium (Spiriva)
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Antimuscarinic Adverse Effects
Sedating Antihistamines Diphenhydramine (Benadryl) Hydroxyzine (Vistaril)
Tricyclic Antidepressants Amitriptyline (Elavil) Nortriptyline (Pamelor) Desipramine (Norpramin) Doxepin (Sinequan)
Antipsychotic Agents Chlorpromazine (Thorazine) Olanzapine (Zyprexa) Clozapine (Clozaril) Thioridazine (Mellaril)
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Antimuscarinic Adverse Effects
Phenothiazines Prochlorperazine (Compazine) Promethazine (Phenergan)
Antiarrhythmic Agents Disopyramide (Norpace)
Muscle relaxants Cyclobenzaprine (Flexeril) Orphenadrine (Norflex)
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Anticholinergic Activity of 107 Medications
Commonly Used by Elders

• Radioassay used to measure the anticholinergic
  activity of 107 medications
• Categories included
• 0 (non-detectable)
• 0/ (no or minimal)
• (0.5-5 pmol/ml)
• (5-15 pmol/ml)
• (gt 15 pmol/ml)

Chew et al. JAGS 2008561333-1341.
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Anticholinergic Activity of 107 Medications
Commonly Used by Elders

• (gt 15 pmol/ml)
• Amitriptyline, doxepin
• Clozapine, thioridazine
• Atropine, dicyclomine, hyoscyamine
• (5-15 pmol/ml)
• Nortriptyline, paroxetine
• Diphenhydramine
• Chlorpromazine, olanzapine
• Oxybutynin

Chew et al. JAGS 2008561333-1341.
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Anticholinergic Activity of 107 Medications
Commonly Used by Elders

• (0.5-5 pmol/ml)
• Citalopram, escitalopram, fluoxetine, mirtazpine
• Quetiapine
• Tempazepam
• Ranitidine
• Lithium

Chew et al. JAGS 2008561333-1341.
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Anticholinergic Activity of 107 Medications
Commonly Used by Elders

• 0/ (no or minimal)
• Celecoxib, fentanyl, hydrocodone, propoxyphene
• Duloxetine, metformin
• Amoxicillin, cephalexin, levofloxacin
• Diazepam, donepezil
• Digoxin, furosemide
• Phenytoin, topiramate
• Diphenoxylate, lansoprazole

Chew et al. JAGS 2008561333-1341.
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Anticholinergic Activity of 107 Medications
Commonly Used by Elders

• 0 (non-detectable)
• Acetaminophen, aspirin, codeine, ibuprofen,
  morphine, tramadol
• Bupropion, sertraline, trazodone, venlafaxine
• Glipizide, pioglitazone, rosiglitazone
• Cetirizine, fexofenadine, loratadine
• Ciprofloxacin, sulfamethoxazole, trimethoprim
• Aripiprazole, haloperidol, perphenazine,
  risperidonem ziprasidone

Chew et al. JAGS 2008561333-1341.
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Anticholinergic Activity of 107 Medications
Commonly Used by Elders

• 0 (non-detectable)
• Alprazolam, buspirone, lorazepam, oxazepam,
  zaleplon, zolpidem
• Beta-blockers, CCB, statins, ACE inhibitors,
  ARBs, nitroglycerin
• Galantamine, memantine, rivastigmine
• Bisacodyl, famotidine, loperamide, omeprazole,
  pantoprazole, rabeprazole

Chew et al. JAGS 2008561333-1341.
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Anticholinergic Activity of 107 Medications
Commonly Used by Elders

• 0 (non-detectable)
• Baclofen, carbidopa, clopidogrel, darbepoetin,
  dipyridamole, epietin, levodopa, levothyroxine,
  megestrol, warfarin
• Carbamazepine, gabapentin, lamotrigine, valproate

Chew et al. JAGS 2008561333-1341.
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Estimated Anticholinergic Activity (AA) for
Therapeutic Doses of Nortriptyline at Estimated
Mean Peak Concentrations (Cmax) in a Typical
Geriatric Patient
Total Daily Dose (mg) Cmax (ng/ml) In Vitro AA (pmol/ml)
10 12 0.8
25 29 3.5
50 59 8.2
100 117 18.0
150 175 29.0
Chew et al. JAGS 2008561333-1341.
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Cognitive Impact of Anticholinergics

• 27 studies reviewed
• Consistent correlation seen between SAA and
  worsening performance on cognitive testing
• Acute (delirium)
• Chronic (mild cognitive impairment)
• Deficits in processing, speed, psychomotor
  performance, concentration/attention, problem
  solving and language skills

Campbell et al. Clinical Interventions in Aging
20094225-233.
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Cognitive Impact of Anticholinergics

• Delirium - identified by disorientation, altered
  consciousness, disorganized thinking, fluctuating
  alertness
• Variable deficits in recalls identified
• Minimal changes in global measures of cognitive
  functioning with exposure to anticholinergics

Campbell et al. Clinical Interventions in Aging
20094225-233.
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Anticholinergics Conclusion

• Patients at risk
• Older adults, advanced disease, fall risk
• BPH, asthma
• Taking other medications with similar adverse
  effects
• Alzheimers disease and other dementias
  (anticholinergics antagonize cholinesterase
  inhibitors)
• Consider non-drug interventions

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Constipation

• 40 of all ADR affect the GI tract
• Drug-induced constipation occurs at therapeutics
  doses of drugs and is dose-related
• Medications most likely to cause constipation
  include
• Antispasmodics (11.6)
• Antihistamines (9.2)
• Antidepressants (8.2)
• Diuretics (5.6)
• Aluminum antacids (3.0)
• Opioids (2.6)

Talley NJ et al. Amer J Gastroenterology
2003981107-1111.
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Drug-Induced Constipation
Therapeutic Category Examples
Analgesics Opioids (morphine), NSAIDs (ibuprofen)
Anticholinergics TCA, antipsychotics (haloperidol), antiparkinsonian agents (benztropine), antihistamines (H1 diphenhydramine), antispasmodics (dicyclomine)
Cation-containing agents Aluminum (antacids, sucralfate), calcium (antacids, supplements), bismuth, iron supplements, lithium
Chemotherapy Vinca alkaloids (vincristine), alkylating agents (cyclophosphamide)
Antihypertensives CCB (verapamil, nifedipine), diuretics (furosemide), centrally-acting (clonidine), antiarrhythmics (amiodarone), beta blockers (atenolol)
Bile acid sequestrants Colestyramine, colestipol
5HT3-receptor antagonists Ondansetron
Laxatives Chronic abuse
Branch RL, Butt TF. Drug-induced constipation.
Adverse Drug Reaction Bulletin 2009257.
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Drug-Induced Constipation
Therapeutic Category Examples
Excess fiber Dietary or prescribed
Other antidepressants Monoamine amine oxidase inhibitors
Other antiparkinsonian agents Dopamine agonists
Other antispasmodics Peppermint oil
Anticonvulsants Carbamazepine
Miscellaneous Barium sulphate, octreotide, polystyrene resins, oral contraceptives
Vitamin C tablets, 131I thyroid ablation, erythropoietin, baclofen
Pamidronate, alendronic acid, PPI and H2 antagonists
Branch RL, Butt TF. Drug-induced constipation.
Adverse Drug Reaction Bulletin 2009257.
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Analgesics - Opioids

• Mediated through either µ or d-opioid receptors
  on enteric nerves, epithelial cells and muscle.
• Reduces intestinal motility (via µ-receptors)
• Reduces intestinal secretion (via d-receptors)
• And increases absorption of water (via µ and
  d-receptors)

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Analgesics - NSAIDs
Inhibit cyclooxygenase, blocking production of
PGE both centrally and peripherally.
PGE Effects Inhibition of PGE Effects
Decreases gastric acid secretion Increased gastric acid secretion
Increases gastric mucus secretion Decreased mucus secretion
Causes GI smooth muscle contraction GI smooth muscle relaxation
?
Constipation
NSAID discontinuation is more often due to
constipation than dyspepsia.
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Other Drug-Induced Constipation

• Anticholinergics
• Inhibit PSNS, preventing Ach from binding to the
  M2 muscarinic receptor, resulting in decreased
  intestinal tone and motility.
• Leads to a delay on colonic transfer time
• Includes TCAs, MAOIs, antipsychotics,
  antiparkinsonian agents
• Antispasmodics (peppermint oil)
• Dose-related effect on smooth musculature caused
  by interference of menthol with the movement of
  calcium across the cell membrane.
• Reduces influx of extracellular calcium ions
  through voltage-dependent channels reduces
  gastroduodenal motility by decreasing the number
  and amplitude of contractions.

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Other Drug-Induced Constipation

• Cation-containing agents
• Aluminum has an astringent effect and may cause
  intestinal obstruction in high doses.
• 17-30 of aluminum chloride produced from
  aluminum hydroxide is absorbed remainder
  unabsorbed from gut, producing constipating
  effect.
• Calcium-containing antacids 90 calcium
  carbonate is converted to insoluble calcium salts
  in small intestine, not absorbed, and cause
  constipation
• Bismuth (bismuth subsalicylate BSS)
• BSS is an antidiarrheal agent decreases flow of
  fluid and electrolytes into bowel, reducing
  inflammation in the intestine and killing
  organisms that cause diarrhea
• Reduces number of formed stools by 50
• Iron, Lithium

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Other Drug-Induced Constipation

• Chemotherapeutic agents
• Vinca alkaloids 50 of patients treated due to
  neurologic changes in ANS or enteric NS
• Alkylating agents (cyclophosphamide) denature
  proteins including in GIT. Changes in intestinal
  mucosa can cause constipation or diarrhea.
• Antihypertensive agents
• CCB (verapamil, nifedipine) reduce intestinal
  motility
• Diuretics (HCTZ) decreased motility and excess
  fluid removal
• Centrally-acting (clonidine) stimulated
  absorption and inhibits secretion of fluids and
  electrolytes, prolongs intestinal transit time by
  interacting with receptors on enteric neurons
• Amiodarone
• Bile-acid sequestrants

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Drug-Induced Seizures

• 6-9 of seizures are drug-induced
• Drugs can cause seizures directly
• At or above therapeutic concentrations
• Drugs can cause seizures indirectly
• Reducing the effectiveness of AED
• Hypoglycemia, hyponatremia, hyperpyrexia
• Due to adverse effects (hypoxia, arrhythmia or
  cerebral edema

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Thundiyil JG et al. J Medical Tech 2007315-19.
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Thundiyil JG et al. J Medical Tech 2007315-19.
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Drug-Induced Seizures

• Cases involving TCAs, cocaine and theophylline
  have shown a marked decrease
• Newer causes of drug-induced causes have emerged
  including bupropion, tramadol, and venlafaxine

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Drug Withdrawal-Induced Seizures

• Anticonvulsant agents
• Benzodiazepines
• Barbiturates
• Opioids
• Baclofen

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Serotonin Syndrome

• A potentially life-threatening condition caused
  by excess serotonergic stimulation of the central
  nervous system.
• Caused by
• Drug interactions
• Intentional overdose
• Symptoms occur within minutes to hours after
  starting a second drug

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Serotonin Syndrome

• Classic triad of symptoms
• Altered mental status
• Neuromuscular hyperactivity
• Autonomic hyperactivity
• All three features are not always present together

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Clinical Features of Serotonin Syndrome

• Neuromuscular hyperactivity
• Akathisia
• Tremor
• Clonus
• Myoclonus
• Rigidity
• Nystagmus

• Autonomic hyperactivity
• Diaphoresis
• Fever
• Tachycardia
• Tachypnea
• Altered mental status
• Agitation
• Excitement
• Confusion

Sun-Edelstein. Expert Opin Drug Safe
20087587-596
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Boyer EW et al. NEJM 3521112-1130.
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Drug-Induced Serotonin Syndrome
TheraCategory Examples
SSRIs Paroxetine, sertraline, fluoxetine, fluvoxamine, citalopram
SNRIs Venlafaxine, milnacipran, duloxetine, sibutramine
TCAs Clomipramine, imipramine
Misc Antidepress Mirtazapine, trazodone, St. Johns Wort
Maoist Trancylcpromine, phenelzine, isocarboxazid
Antiparkinsons Selegilene
Anti-infectives Linezolid, furazolidone
Opioids Meperidine, fentanyl, methadone, tramadol, pentazocine, dextromethorphan
Antihistamines Chlorpheniramine, brompheniramine
CNS stimulants / Psychedelics Amphetamine, sibutramine, methylphenidate, cocaine, MDMA (ectasy), LSD
Triptans (/-) Sumatriptan, zolmitriptan, rizatriptan, almotriptan, frovatriptan
Sun-Edelstein. Expert Opin Drug Safe
20087587-596
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Suspecting Serotonin Syndrome

• Was a serotonergic agent administered in the past
  five weeks?
• No stop Yes continue
• Experienced one of the following
• Tremor and hyperreflexia
• Spontaneous clonus
• Muscle ridigity, temperature gt 38C and either
  ocular clonus or inducible clonus
• Ocular clonus, and either agitation or
  diaphoresis
• Inducible clonus and either agitation or
  diaphoresis
• No stop Yes possibly serotonin syndrome

Boyer EW et al. NEJM 3521112-1130.
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Drug-induced CNS depression

• Sedation, agitation, confusion
• May progress to respiratory depression
• Opioids, benzodiazepines
• Non-benzodiazepine sedative-hypnotics
• Barbiturates, alcohol, antipsychotics
• Antidepressants, antihistamines (H1)
• Antiemetics, anticonvulsants, illicit drugs

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Drug-induced CNS depression

• Less obvious causes
• Cimetidine
• Anticholinergic agents
• Drugs that reduce GFR
• NSAIDs
• ACE inhibitors
• Fall risk increased with
• Sedatives, hypnotics, antidepressants,
  benzodiazepines

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Opioid-Induced Sedation

• Occurs in 20-60 patients taking opioids
• Sedation is defined as depression of brain
  functioning by a medication, mainfested by
  sleepiness, drowsiness, fatigue, slowed brain
  activity, reduced wakefulness, and impaired
  performance.
• Dose-dependent effect
• Tolerance within a few days
• Dont confuse with catch-up sleep

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Opioid-Induced Respiratory Depression

• Quantified by
• Observed changes in breathing frequency
• Severe respiratory depression considered to be
  breathing rate of less than 8-10 breaths/minute
• And/or oxygen saturation
• Slowed and irregular respiration leads to
  hypercapnia and hypoxia

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Factors that modulate opioid-induced respiratory
depression

• Drug interactions
• Propofol, midiazolam
• Sleep obstructive sleep apnea
• Opioids increase stage 2 sleep (light sleep) and
  decrease stage 4 (deep sleep) and REM sleep
• Methadone and benzodiazepines
• Pain stimulated respiration

Pattinson KTS. Br J Anaesth 2008100747-758.
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Factors that modulate opioid-induced respiratory
depression

• Genetics
• Polymorphisms affecting MOP receptor activity and
  opioid bioavailability
• Polymorphisms affecting opioid metabolism

Pattinson KTS. Br J Anaesth 2008100747-758.
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Atypical Opioids and Respiratory Depression

• Tramadol
• Causes less respiratory depression than
  meperidine or oxycodone at equivalent doses
• Reported in patients with renal failure
• Buprenorphine
• Partial agonist may cause less respiratory
  depression than conventional opioids at
  equivalent doses

Pattinson KTS. Br J Anaesth 2008100747-758.
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Drug-Induced QTc Prolongation

• QT interval prolongation is an abnormality of the
  electrical activity of the heart that places
  individuals at risk for ventricular arrhythmias.
• gt 450 msec in men gt 470 msec in women
• Increase in QTc gt 60 msec from baseline after
  medication administration, or
• QTc values gt 500 msec after medication
  adminstration
• Potential risk for arrhythmia, including Torsades
  de Pointes (TdP)

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Risk Factors for Drug-Induced QTc Prolongation

• Female sex
• Hypokalemia
• Severe hypomagnesemia
• Bradycardia
• Recent conversion from atrial fibrillation
• Congestive heart failure

• Subclinical long QT syndrome (LQTS)
• Baseline QT interval prolongation
• Ion-channel polymorphisms
• Medications / high serum concentrations / rapid
  infusion

Wood AJJ. NEJM 20043501013-1022.
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Drugs that may cause TdP

• Drugs commonly involved
• Disopyramide, dofetilide, ibutilide
• Procainamide, quinidine, sotalol, bepridil
• Other drugs
• Amiodarone, arsenic trioxide, cisapride
• Erythromycin, clarithyromycin, halofantrine,
  pentamidine, sparfloxacin, chloroquine
• Domperidone, droperidol
• Chlorpromazine, haloperidol, thioridazine
• Methadone

Gupta A et all Am Heart J 2007153891-899.
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Methadone and LQTS and TdP

• Increasingly prescribed for chronic pain
• Associated mortality rising disproportionately
  relative to other opioids
• Potent blocker of delayed rectifier potassium ion
  channel
• Results in QT-prolongation and TdP in susceptible
  individuals

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Risk Factors for Methadone and Prolonged QTc

• Dose-related
• Inappropriate initial dosing (including drug
  diversion) or conversion calculation
• Sleep apnea, heart/lung/liver disease
• Use of other drugs that increase risk

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www.torsades.org

• Arizona CERT Center for Education and Research
  on Therapeutics
• Drugs with known risk of TdP
• Drugs with possible risks of TdP
• Drugs for LQTS patients to avoid
• Drugs unlikely to cause TdP

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Pharmacodynamic Drug Interactions in Palliative
Care

• Anticholinergic effects
• Constipation
• Lowered seizure threshold
• Serotonin syndrome
• CNS depression
• QTc prolongation

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Questions