Cafer's Psychopharmacology: Visualize to Memorize 270 Medication Mascots

304 Pages·58.231 MB·English

by  Jason Cafer MD, Julianna Link PA-C

Cafer’s Psychopharmacology:
Visualize to MemorizeTM
270 Medication Mascots
First Edition, 2020
Author: Jason Cafer, MD
Editor: Julianna Link, PA-C
Cafer’s Psychopharmacology | cafermed.com 1
4/3/2021
2
Cafer’s Psychopharmacology: Visualize to Memorize 270 Medication Mascots
First Edition
Copyright 2020, CaferMed LLC
Author: Jason Cafer, MD
Editor: Julianna Link, PA-C
Illustrations: Coccus from 99Designs
Cover design: BengsWorks from 99Designs
Licensed images: Shutterstock and Wikimedia Commons
ISBN: 978-1-7350901-4-6
Contact: [email protected]
This book contains 270 medication monographs. Any prescription medication affecting the central nervous system or interacting with
psychotropic medications was considered for inclusion. Not all medications are intended for prescription by psychiatrists.
The scope of drug-interaction information is limited to what can be digested and applied to routine clinical practice. There are countless
unmentioned drug-drug interactions that could be relevant to some patients but are omitted because the amount of material would be
overwhelming.
This book is focused on medications, not overarching psychiatric care. Although chemicals are necessary for treatment of mania or
acute psychosis, pharmacologic treatment of depression/anxiety/insomnia/etc., is not always the best medicine. Always consider
interventions including cognitive behavioral therapy, diet, exercise, mindfulness, sleep hygiene, etc.
Dosing recommendations are for healthy adults, and may differ from FDA prescribing guidelines. Refer to other sources for treatment of
children, older adults, pregnancy/breastfeeding, and renal/hepatic insufficiency.
Every effort has been made to provide accurate and up-to-date information. Author/editors/publisher/reviewers disclaim all liability for
direct or consequential damages resulting from the use of this material. Readers are encouraged to confirm information with other
sources before incorporating it into your prescribing practice. Information should be compared with official instructions from the drug
manufacturer.
Cafer's Psychopharmacology | cafermed.com
Cafer's Psychopharmacology: Visualize to Memorize 270 Medication Mascots
1 Chapters 1 and 27 5 Anxiolytics/Hypnotics …….....65 9 MAOIs …..…………..……….… 117
Interactions ………………....…. 5 Buspirone (Buspar) ………………………. 66 Isocarboxazid (Marplan) …………....… 118
P-glycoprotein ……………………..………. 9 Z-drugs ……………………….……………. 67 Phenelzine (Nardil) …………..………... 119
CYP1A2 …………..………….………10, 288 DEA-controlled substances …….……….. 67 Tranylcypromine (Parnate) ………..….. 119
CYP2B6 ………..…….………………12, 290 Zolpidem (Ambien) ………………….……. 68 Selegiline transdermal (EMSAM) …..… 120
CYP2C9 …..…………….……………13, 292 Eszopiclone (Lunesta) ………..…………… 69
CYP2C19 …...………….……………. 14, 294 Zaleplon (Sonata) ………………......……. 69
CYP2D6 ...…………….………...…… 15, 296 Melatonin ……………………………….….. 70
CYP3A4 …..……………………….… 16, 298 Ramelteon (Rozerem) ……………………. 71 10 Others for depression …..... 121
UGT interactions (lamotrigine) .….... 17, 287 Tasimelteon (Hetlioz) …………….………..71 L-methylfolate (Deplin) ………..………. 121
Meds with minimal interactions ………..... 18 Orexin (hypocretin) ……………………….. 72 Ketamine (Ketalar) ……………..…...…. 122
Interaction table …………………………… 20 Narcolepsy …………………….….……….. 72 Esketamine (Spravato) …………...…… 123
27 Symbols defined ....……………….…….….. 22 Suvorexant (Belsomra) ………..….......……73 Brexanolone (Zulresso) …….…..…...…. 124
Lemborexant (Dayvigo) …………………..74 St John’s Wort (SJW) ………..…...…… 125
Sodium Oxybate (Xyrem, GHB) ……...…. 75
Propofol (Diprivan) ………………….…….. 76
2 Stabilizers/Antiepileptics ..…. 23 11 Intro to antipsychotics …... 127
Mood stabilizers ...………….........…….…… 23
Neuroleptic malignant syndrome ……..128
Lithium .…....……………………………..… 24
Antiepileptic drugs (AEDs) ..…………....... 27 6 Intro to antidepressants ……. 77 1st and 2nd generation antipsychotics ... 130
Lamotrigine (Lamictal) …..……………..… 28 Neurotransmitters ………….……………...77
Valproate (Depakene, Depakote) ….....… 29 Sexual side effects ……………………….. 80
OCaxcrbaarbmaazzeeppininee ( T(Treilegpretatol)l )… …..…………..….………...…... 3313 SQeTr optroonloinn gsaytniodnro …me… ………….…..………….....…….… 81…, .1 2882 12 1Hsatl oGpeerindo Al (nHatildposl)y …c…ho…t…ic…s .....….…… .1 13312
Gabapentin (Neurontin) …...……………... 34
Chlorpromazine (Thorazine) …….….... 133
Pregabalin (Lyrica) …...………………..…. 35
Perphenazine (Trilafon) ……….…….... 134
Topiramate (Topamax) …...……..……..…. 36
Fluphenazine (Prolixin) ……….………. 136
Levetiracetam (Keppra) ………………...... 37 7 Tricyclics (TCAs) ………….…. 83
Thiothixene (Navane) …………..……... 137
Phenytoin (Dilantin) …..………………...... 38 Amitriptyline (Elavil) ………………………. 84
Loxapine (Loxitane) ………….…..……. 137
Zonisamide (Zonegran) ...………………... 39 Nortriptyline (Pamelor) …………..……….. 85
Trifluoperazine (Stelazine) ….…….….. 138
Lacosamide (Vimpat) ..……….…………... 40 Doxepin (Sinequan, Silenor) ………..…… 86
Thioridazine (Mellaril) ………....………. 139
Ethosuximide (Zarontin) …...…………….. 40 Imipramine (Tofranil) ………………….….. 87
Pimozide (Orap) ……………..…..…….. 140
Eslicarbazepine (Aptiom) ………………… 41 Clomipramine (Anafranil) ……..…….…….. 88
Molindone (Moban) …….….………..…. 140
Rufinamide (Banzel) ……………………… 41 Desipramine (Norpramin) ………………... 89
Antiemetics that block D2 receptors .... 141
Felbamate (Felbatol) ……………………... 42 Protriptyline (Vivactil) …………………….. 89
Prochlorperazine (Compazine) ……..... 141
Brivaracetam (Briviact) …………………… 42 Amoxapine (Asendin) ……….……………. 90
Promethazine (Phenergan) ……….….. 142
Tiagabine (Gabitril) ……………………….. 43 Maprotiline (Ludiomil) …………………..… 91
Metoclopramide (Reglan) ……….….… 143
Perampanel (Fycompa) ………………….. 43 Trimipramine (Surmontil) …………...……. 91
Trimethobenzamide (Tigan) …….……. 143
Cenobamate (Xcopri) …………………….. 44 Toxicity of medication overdose ………....92
Vigabatrin (Sabril) ………………………… 45
Cannabidiol (CBD, Epidiolex) …………… 46
Epileptogenic drugs …………………….…47 13 2nd Gen Antipsychotics ….. 145
Virtual darkness therapy …………….…… 48 8 Modern Antidepressants …... 93 Quetiapine (Seroquel) ……………...….146
Sertraline (Zoloft) …………………….…… 94 Aripiprazole (Abilify, Maintena, Aristada) 147
Escitalopram (Lexapro) ………………….. 95 Risperidone (Risperdal, Consta) .….....148
Citalopram (Celexa) ……………………… 96 Olanzapine (Zyprexa) ……….....…….…149
3 Barbiturates ……...………..…. 49 Fluoxetine (Prozac) ………………………. 97 Lurasidone (Latuda) …………………...150
Phenobarbital (Luminal) …………..………. 50 Paroxetine (Paxil) ………………………… 98 Ziprasidone (Geodon) …………..……..151
Primidone (Mysoline) …………………….. 50 Fluvoxamine (Luvox) …………………….. 99 Clozapine (Clozaril) …………..…..……152
Butabarbital (Butisol) ……………………... 51 SNRIs / atypical antidepressants …....... 100 Brexpiprazole (Rexulti) ………….……. 153
Mephobarbital (Mebaral) ……...….……… 51 Duloxetine (Cymbalta) ……………..…… 101 Cariprazine (Vraylar) ……………….…. 154
Butalbital combo (Fioricet) ………..………. 52 Venlafaxine (Effexor) ………....…………. 102 Paliperidone (Invega, Sustenna)………155
Secobarbital (Seconal) …………………… 52 Desvenlafaxine (Pristiq, Khedezla) ……. 103 Iloperidone (Fanapt) ……………...…… 156
Pentobarbital (Nembutal) ………………… 52 Milnacipran (Savella) ………………..….. 104 Asenapine (Saphris, Secuado) …….… 157
Amobarbital (Amytal) …………….……….. 53 Levomilnacipran (Fetzima) ……….…….. 105 Lumateperone (Caplyta) ………..……..158
Thiopental (Sodium Pentothal) …...……… 53 Trazodone (Desyrel, Oleptro) ………….. 106 Pimavanserin (Nuplazid) ……..….……..159
Nefazodone (Serzone) ………….......….. 107 Long-acting injectables ………….….…. 160
Mirtazapine (Remeron) …………………. 108
California Rocket Fuel ………………….. 109
4 Benzodiazepines ………….…. 55 Vortioxetine (Trintellix) ………………..… 110
Alprazolam (Xanax) ………………………. 57 Vilazodone (Viibryd) …………………….. 111
Clonazepam (Klonopin) ………………….. 58 Serotonin discontinuation syndrome …... 112
Lorazepam (Ativan) ………………………. 58 NRIs, NDRIs, DNRIs ……………………. 113
Diazepam (Valium) ……………………….. 59 Atomoxetine (Strattera) ………………..... 114
Temazepam (Restoril) ………….………… 59 Bupropion (Wellbutrin) ……………….…. 115
Chlordiazepoxide (Librium) ……………… 60
Note that antidepressant
Triazolam (Halcion) ………………………. 60
chapters are color-coded with
Clorazepate (Tranxene) ………….……….. 61
various shades of “the blues”.
Oxazepam (Serax) ……………………….. 61
Flurazepam (Dalmane) …………………... 62
Estazolam (Prosom) ……………………… 62 Antipsychotic chapters are
Quazepam (Doral) ………………………... 63 green. A psychotic patient may
Clobazam (Onfi) …………………………... 63 see “little green men”.
Midazolam (Versed) ……………….……… 64
Flumazenil (Romazicon) …………………. 64
4
18 DA depleting agents ……... 197 22 Opioids ……………..…….. 245
Tardive dyskinesia treatment ……...…. 197 Constipation treatment ……………... 246
Anticholinergic effects are VMAT inhibitors ………………...……… 198 Morphine (MS Contin) ………...……. 247
famously described as "Hot Tetrabenazine (Xenazine) ……...…….. 199 Hydromorphone (Dilaudid) ………… 247
as a hare, dry as a bone,
Deutetrabenazine (Austedo) ………..... 200 Oxymorphone (Numorphan) …….…. 248
blind as a bat, red as a
beet, and mad as a hatter" Valbenazine (Ingrezza) ……………….. 200 Hydrocodone/APAP (Vicodin) ……... 248
Reserpine (Serpasil) ……….…..………. 201 Oxycodone/APAP (Percocet) …….... 249
Codeine/APA (Tylenol #2,3,4) ……... 250
Heroin (diamorphine) ………..……… 251
Meperidine (Demerol) …………..….. 252
14 Anticholinergics ……….….. 161 19 Parkinson’s disease……..... 203 Fentanyl (Duragesic) ……………….. 252
Anticholinergic burden scale …….….... 162 Carbidopa - Levodopa (Sinemet) ….… 206 Methadone (Dolophine) ……………. 253
Antihistamines ……………….…….…... 163 Ropinirole (Requip) ………………….... 207 Tramadol (Ultram) ……………..……..254
Diphenhydramine (Benadryl) ….…...… 164 Pramipexole (Mirapex) …………….….. 208 Tapentadol (Nucynta) ………………. 255
Doxylamine (Unisom) ………….….…... 164 Apomorphine (Apokyn) …………….…. 209 Levorphanol (Levo-Dromoran) ……. 256
Hydroxyzine (Vistaril, Atarax) ………... 165 Rotigotine (Neupro) …………………… 209 Naltrexone (ReVia) …………………. 257
Meclizine (Antivert) ……………….….... 166 Bromocriptine (Parlodel) …………...…. 210 Naltrexone LAI (Vivitrol) ………….… 258
Dimenhydrinate (Dramamine) ……...... 166 Cabergoline (Dostinex) ……………….. 210 Low dose naltrexone …………….…. 258
Cyproheptadine (Periactin) …………… 167 Entacapone (Comtan) ……………….… 211 Contrave (naltrexone + bupropion) .. 259
Anticholinergics ………………….…..… 168
Tolcapone (Tasmar) …………….….….. 211 Naloxone (Narcan) ……………..…… 260
Benztropine (Cogentin) …………….….169
Trihexyphenidyl (Artane)....................... 170 Selegiline PO (Eldepryl) ………………. 212 Buprenorphine (Subutex, Suboxone) 261
Dicyclomine (Bentyl) ………………...... 171 Rasagiline (Azilect) ……………….…… 213 Butorphanol (Stadol) ………….……. 264
Hyoscyamine (Anaspaz, Levsin) ….…. 171 Safinamide (Xadago) …………………. 213 Pentazocine (Talwin) ……….………. 264
Scopolamine (Transderm Scōp) …..…. 171 Amantadine (Symmetrel) ………...…… 214 Nalbuphine (Nubain) ………….……. 265
Glycopyrrolate (Robinul) …………….... 172 Istradefylline (Nourianz) ………..….….. 215 Loperamide (Imodium) …………...… 266
Glycopyrronium (Qbrexza) ….…..…..... 172 Diphenoxylate/Atropine (Lomotil) …. 266
Oxybutynin (Ditropan) …………….…... 173
Tolterodine (Detrol) ……………...….… 173
Solifenacin (Vesicare) ………….……... 174 20 Stimulants …………...…….. 217
Fesoterodine (Toviaz) ………….……... 174 Treatment of ADHD ……………..…….. 218 23 Sexual dysfunction …….. 267
Darifenacin (Enablex) ………..……….. 175 Methylphenidate (Ritalin) ……………... 220 Flibanserin (Addyi) ………….………. 267
Trospium (Sanctura) ………………….. 175 Dexmethylphenidate (Focalin) …..…… 221 Bremelanotide (Vyleesi) ……………. 268
Atropine (Atropen, Atropisol) ……….… 176 Concerta …………………………….….. 221 Sildenafil (Viagra) ………….………... 269
Pupils – mydriasis and miosis ….…..… 176 Aptensio XR ………………………...….. 222 Tadalafil (Cialis) ………………….….. 270
Jornay PM …………………………..….. 222 Vardenafil (Levitra) ……...………….. 270
Adhansia XR ……………………..…….. 223 Avanafil (Stendra) ………………..…. 270
15 Cognitive enhancers …….. 177 Cotempla XR-ODT ……………….……. 223
Daytrana …………………………..……. 224
Cognitive enhancers ……………….…. 177
Amphetamine salts (Adderall) …......… 225
Cholinergics ………………….……….... 177
Dextroamphetamine (Dexedrine) ……. 226 24 Antimicrobials …………... 271
Donepezil (Aricept) ……………………. 178
Adzenys XR-ODT ………………….….. 226 Fluconazole (Diflucan) …….……….. 271
Rivastigmine (Exelon) ……………..….. 179
Lisdexamfetamine (Vyvanse) ………... 227 Minocycline (Minocin) ………………. 272
Galantamine (Razadyne) ………….…. 179
Mydayis ……………………….………… 227 Clarithromycin (Biaxin)…....………… 272
Bethanechol (Urecholine) ………….…. 180
Evekeo ………………………………..… 228 Fluoroquinolones ………………..….. 273
Pilocarpine (Salagen) …………………. 181
Methamphetamine (Desoxyn) ……….. 228 Rifampin (Rifadin) ……………….….. 273
Memantine (Namenda) ……………….. 182
Modafinil (Provigil) ……………….……. 229
Namzaric (memantine + donepezil) …. 182
Armodafinil (Nuvigil) …………………... 230
Solriamfetol (Sunosi) …………..………230
Phentermine (Adipex) ………………… 231 25 Hormones ……………...… 275
16 Sympatholytics ….…..….... 183 Qsymia (phentermine + topiramate) .... 231 Levothyroxine (Synthroid, T4) …….. 276
Lorcaserin (Belviq) ………….…………. 232 Liothyronine (Cytomel, T3) ………… 277
Clonidine (Catapres, Kapvay) …..…….1 83
Pitolisant (Wakix) …………………..….. 233 Armour Thyroid ………………..….…. 277
Guanfacine (Tenex, Intuniv) ……..…… 184
Caffeine ……………………………....… 234 Oxytocin (Pitocin) ………………..….. 278
Lofexidine (Lucemyra) …………….….. 185
Tamoxifen (Nolvadex) …………..….. 279
Dexmedetomidine (Precedex) ……….. 185
Raloxifene (Evista) ………………….. 280
Prazosin (Minipress) ………………….. 186
Propranolol (Inderal) ………………….. 187 21 Addiction medicine …….… 235
Amlodipine (Norvasc) …………………. 188
Nicotine …………………………………. 236
Nimodipine (Nimotop) ……………….... 188 Varenicline (Chantix) …………..……… 237 26 Leftovers …………………. 281
Dronabinol (THC, Marinol) ……...……. 238 Metformin (Glucophage) …………… 281
Disulfiram (Antabuse) ……………….… 239 Acetylcysteine (NAC) …………...….. 282
17 Muscle relaxants ...……….. 189 Acamprosate (Campral) ………………. 240 Ondansetron (Zofran) …………..….. 283
Dextromethorphan (DXM) ……………. 241 Sumatriptan (Imitrex) ………………. 284
Cyclobenzaprine (Flexeril) ………….... 190
Nuedexta (DXM + quinidine) ……….... 242 Rizatriptan (Maxalt) ………………… 284
Baclofen (Lioresal) ………………..…… 191
Hallucinogens …………………….……. 243 Fremanezumab (Ajovy) ………..……285
Methocarbamol (Robaxin) ……….…… 192
LSD ………………………………….….. 244 Galcanezumab (Emgality)……......... 285
Tizanidine (Zanaflex) ……………….…. 192
Erenumab (Aimovig) ……………….. 285
Metaxalone (Skelaxin) …………..……. 193
Omeprazole (Prilosec) …………..…. 286
Orphenadrine (Norflex) ………..……… 193
Meprobamate (Miltown) ………………. 194
Carisoprodol (Soma) …………..………195 The color code for Addiction
Methaqualone (Quāālude) ……………. 196 Mcheadpicteinr eis c phuarpptleer, aans din O “pPiuoridpsle 27 Interaction Wrap-up…….. 287
Drank” or opium poppies.
Chapter 1 – Interactions
5
PHARMACODYNAMICS VS PHARMACOKINETICS PHARMACOKINETIC INTERACTIONS
Drug-drug interactions fall into two main categories: Kinetics involves the rate at which a drug gets into or out of the body or
pharmacokinetic and pharmacodynamic. brain.
Pharmacodynamics is what a drug does to the body. Drug-drug Interactions involving absorption are generally straightforward.
Pharmacodynamic interactions are based on the drugs’ mechanisms For instance, anticholinergics slow gut motility and delay gastrointestinal
of action and do not involve alteration in blood levels of either absorption of other medications.
interacting drug.
Kinetic interactions involving rate of elimination from the body are
Pharmacokinetics is what the body does to a drug. Kinetic derives challenging to learn and daunting to memorize. It is important to consider
from the Greek verb kinein, "to move”. In this case we’re talking these interactions to avoid underdosing or overdosing certain
movement into and out of the body, for instance absorbing the medications. This book tackles these tricky elimination interactions by
chemical from the gut and processing it for excretion in urine or illustrating:
feces. Pharmacokinetic (PK) interactions are generally manifested by
alteration of blood levels of one of the interacting drugs. ❖Phase I metabolism involving the six most important cytochrome P450
(CYP450) enzymes
For simplicity’s sake, let’s drop the pharmaco- prefix and refer to
these concepts as kinetic interactions and dynamic interactions. ❖Phase II metabolism involving UGT enzymes, as applicable to
lamotrigine (Lamictal)
PHARMACODYNAMIC INTERACTIONS ❖Renal clearance of lithium (page 26)
Dynamic interactions are intuitive if you understand how the A mysterious type of kinetic interaction involves drugs getting across the
interacting drugs work. Although dynamic interactions are blood-brain barrier, as is necessary for a psychiatric medication to take
understandable without silly pictures, here are a couple anyhow. effect. If such an interaction is occurring, the effect will not be detectable
in serum drug levels. This will be discussed in the context of
Dynamic interactions can be additive/synergistic, with enhanced P-glycoprotein (page 9).
effects brought about by combining medications with similar or
complementary effects.
CYTOCHROME P450 ENZYMES
In the liver, kinetic interactions predominantly involve CYtochrome P450
enzymes, CYP enzymes for short, which can be pronounced “sip”.
Like-minded “dynos” ganging up to reduce blood pressure, Instead of concerning yourself with the origin of P450 nomenclature, take
which is an additive/synergistic effect. a moment to contemplate this picture of Ken (kinetic) taking a “sip”
(CYP).
Clonidine Quetiapine
(Catapres) (Seroquel)
CYP
“Sip” (CYP) enzyme interactions are
(pharmaco) “Ken-etic”
antihypertensive orthostasis as side effect
CYP enzymes, which reside primarily in the liver, make chemicals less
Other dynamic interactions are antagonistic, for instance combining lipid-soluble so they can be more easily excreted in urine or bile. Of over
a dopaminergic such as pramipexole (for restless legs) with an 50 CYP enzymes, six play a major role in the biotransformation of
antidopaminergic like haloperidol (antipsychotic). Here’s another medications: 1A2, 2B6, 2C9, 2C19, 2D6 and 3A4. Our visual mnemonics
example: will be built on the following phraseology:
Fighting “dynos” involved in an antagonistic interaction. 1A2 - One Axe To (grind)
CYP 2B6 - Tube Socks
Donepezil Diphenhydramine
(Aricept) (Benadryl) 2C9 - To See Nice(ly)
2C19 - To See Nice Things
2D6 - Too Darn Sexy
3A4 - Three A’s For (fishing)
cholinergic for antihistamine with strong
Alzheimer’s anticholinergic effects The three most important CYPs are 1A2, 2D6 and 3A4. For psychiatrists,
2C19 can be important, while 2B6 and 2C9 are rarely significant.
Cafer's Psychopharmacology | cafermed.com 5
6 SUBSTRATES
Increased concentration of
A drug that is biotransformed by a particular enzyme is referred to substrate (and increased ratio of
as a substrate of that enzyme. When the substrate is serum substrate:metabolite)
biotransformed (metabolized) it is then referred to as a metabolite.
H for High and Hurried, within 2–4
hours, although the effect may not
be clinically evident for 2–4 days
inHibitor
biotransformation
InHibitors of CYP enzymes will be represented by:
substrate metabolite
Unspecified inHibitor
Each CYP enzyme can metabolize several substrates and most
substrates can be metabolized by several CYP enzymes. Substrates
are the “victims” of the interactions described in this chapter.
Throughout this book we use the following visuals for CYP
1A2 inhibitor - Axe body spray
substrates:
Unspecified substrate - sub 2B6 inhibitor - thick calf
2C9 inhibitor - monocle
1A2 substrate - tree
2C19 inhibitor - watering can
2B6 substrate - sock
2D6 inhibitor - air pump
2C9 substrate - eyeball
3A4 inhibitor - fishing hook & bobber
2C19 substrate - flower “3 A’s for
fishing”
2D6 substrate - beach ball
3A4 substrate - fish The magnitude to which an inHibitor increases the serum concentration
of a specific substrate depends on the number of alternative pathways
available to metabolize the substrate. If the drug is a substrate of, e.g.,
1A2, 2D6 and 3A4, then inhibiting one of the three pathways should be of
“Aggressor” medications affect how long victim substrates linger in no consequence. Such substrates may be described as multi-CYP.
the blood, and the relative serum concentration of parent drug
(substrate) to metabolite. For a given enzyme, interfering For a substrate metabolized by a single pathway, the effect of inhibition
medications (aggressors) are either inDucers or inHibitors. InDucers (and induction) will be dramatic. An example is lurasidone (Latuda),
stimulate (inDuce) production of metabolic enzymes. InHibitors which is contraindicated with strong 3A4 inhibitors or inducers.
interfere with an enzyme’s ability to metabolize other medications.
Some inhibitors are stronger than others. In general, expect blood levels
of susceptible substrates to increase in the ballpark of:
ENZYME INHIBITION
❖ mild inhibitor ~ 25% - 50% increase
InHibition of an enzyme occurs when one drug (the inHibitor) binds ❖ moderate inhibitor ~ 50% - 100% increase
more tightly to the enzyme than the victim substrate binds. The ❖ strong inhibitor > 100% increase
inHibitor itself may be metabolized by the enzyme, or act as a
non-competitive inhibitor. When an inhibitor is bound to an enzyme, Expect these numbers to vary widely between substrates and individuals,
the victim substrate must find another enzyme to metabolize it, or often unpredictably. Note that magnitude of inhibition tends to be
hope that it can eventually be excreted unchanged. Strong inhibitors dose-related over the dosage range of the inhibitor.
may cause the victim substrate to linger longer, prolonging the
victim’s half-life and elevating its concentration in the blood. For
victim substrates that cross the blood brain barrier (as is necessary
to be psychoactive), inhibition leads to increased drug concentration
The “fluffers” – notorious strong inHibitors:
in the central nervous system.
❖❖ fluvoxamine (Luvox) - SSRI
Why is H being emphasized? Well, when an inHibitor is added to an ❖❖ fluoxetine (Prozac) - SSRI
individual’s medication regimen, levels of victim drugs can escalate ❖❖ fluconazole (Diflucan) - antifungal
(H for High). InHibition takes effect quickly, within Hours (H for ❖❖ ketoconazole (Nizoral) - antifungal
Hurried), although the effect may not be clinically evident for 2 to 4
days, until the victim substrate accumulates.
The last two are “cone”-azole antifungals.
Some (but not all) substrates are also competitive inHibitors of the
same CYP enzyme.
6
Cafer's Psychopharmacology | cafermed.com
ENZYME INDUCTION Can shredding be problematic even if the patient is not taking a victim
medication? Consider this: 7
The opposite of inHibition is inDuction. InDuction occurs when an
inDucer stimulates the liver to produce extra enzymes, leading to
enhanced metabolism and quicker clearance of victim drugs.
The D is for Down, i.e., Decreased serum concentrations of victim
substrates. Unlike inHibition (H for Hurried), inDuction is Delayed, not Long-term use of a shredder
taking full effect for 2 to 4 weeks while we… leads to decreased bone mineral
wait for the liver to ramp up enzyme production. density. This is presumably due
to inDuction of enzymes that
inactivate 25(OH) vitamin D.
inDucer
D for Down and Delayed (2–4 weeks) bone shredding machine
REVERSAL OF INHIBITION/INDUCTION
Decreased serum concentration of
substrate (and decreased serum ratio All things being equal, it is best to avoid prescribing strong inducers or
of substrate:metabolite) inhibitors. Even if there is no problematic interaction at the time, having
a strong inhibitor or inducer on board may complicate future medication
management.
InDucers will be depicted by: Consider an individual on an established medication regimen who
stops taking an inducer or inhibitor. The serum concentration of victim
substrate(s) will change due to the reversal of induction/inhibition.
Unspecified inDucer After an inDucer is withdrawn, the concentration of a victim substrate
will increase gradually (D for Delayed) over a few weeks because the
extra CYP enzymes are degraded without being replenished.
1A2 inducer - axe When an inHibitor is stopped, levels of a victim substrate will decrease
as soon as the aggressor exits the body. “Hurriedly” does not mean
immediately, because it takes about five half-lives for the inhibitor to
be completely cleared.
2B6 inducer - lighter
For a patient on several psychotropic medications, reversal of inhibition
or induction can really throw things out of whack.
2C9 inducer - eyepatch
2C19 inducer - shears While ePrescribe systems may warn the doctor
when starting an interacting medication, there will
be no warning when stopping a medication will
2D6 inducer - N/A (2D6 is not subject to inDuction) lead to a reversal situation.
3A4 inducer - anvil “3 A’s for
For an example of reversal of inHibition, consider a patient taking
fishing”
alprazolam (Xanax, 3A4 substrate) who suddenly stops fluvoxamine
(Luvox, 3A4 inHibitor). In absence of the inhibitor, alprazolam levels
drop (from double) to normal. Since fluvoxamine has a short elimination
More often than not, an inducer is itself a substrate of the enzyme. half-life of 15 hours, it should be out of the body at 75 hours (15 hr x 5).
For example, carbamazepine (Tegretol) is represented as both an So, you would expect the patient on Xanax to become more anxious 3
anvil and a fish on page 31. days after stopping Luvox. It may be difficult to discern whether the
patient’s emerging distress is due to serotonin withdrawal or decreased
THE SHREDDERS alprazolam levels.
An example of reversal of inDuction involves tobacco, which is a 1A2
inDucer. A patient taking clozapine (1A2 substrate) stops smoking,
The “shredders” are four strong inDucers of several CYPs, reversing inDuction and causing clozapine levels to potentially double
which cause countless chemicals to be quickly expelled from over the first week (which is faster than occurs with other inducers).
the body: The individual may become obtunded, hypotensive, or even have a
seizure. To avoid this, the recommendation is to decrease clozapine
❖❖ carbamazepine (Tegretol) - antiepileptic dose by 10% daily over the first four days upon smoking cessation, and
❖❖ phenobarbital (Luminal) - barbiturate to check clozapine blood levels before and after the dose adjustment.
❖❖ phenytoin (Dilantin) - antiepileptic Note that nicotine products (gum, patches, e-cigs) do not induce 1A2.
❖❖ rifampin (Rifadin) - antimicrobial Although reversal of inHibition is typically faster than reversal of
induction, this does not apply to inhibitors with extremely long half-lives.
Dr. Jonathan Heldt refers to the shredders as “Carb & Barb” For instance, fluoxetine (Prozac) has a long elimination half-life of
about 7 days, keeping itself around for about 35 days (7 days x 5).
in his book Memorable Psychopharmacology.
Consider a patient with schizophrenia on aripiprazole (Abilify, 2D6
substrate) who stops Prozac (2D6 inHibitor). The patient is doing well
at one month, but becomes paranoid two months out. Unless the
St John’s Wort (herbal antidepressant) also inDuces several CYPs, prescriber anticipated this possibility, no one will realize what
but does so with less potency than the four shredders. happened.
Cafer's Psychopharmacology | cafermed.com 7
8 PRODRUGS
Phase I metabolism typically involves biotransformation of an active Phase I Phase II
drug to an inactive (or less active) chemical.
Phase I Phase II glucuronic
substrate substrate acid
The responsible enzyme is UDP-glucuronosyltransferase, abbreviated
biotransformation UGT, as in “U Got Tagged” with glucuronic acid.
*
Medications metabolized primarily by Phase II are relatively immune to
active substrate inactive metabolite drug interactions. Examples of clinically relevant Phase II interactions are
those involving lamotrigine (Lamictal) as a substrate, as featured on page
*Note the lack of a propeller. 17.
RENAL CLEARANCE
For a few medications, the parent drug has low therapeutic activity
until it is biotransformed by a CYP enzyme. In such cases, the A few medications are excreted in urine without being metabolised. Such
substrate is called a prodrug, and the biotransformation process can drugs are not subject to Phase I or II interactions, but may be victims of
be referred to as bioactivation. kinetic interactions. Renal “aggressors” act by slowing or hastening the
rate of excretion of the victim drug in urine.
Interactions affecting renal clearance of
victim drugs are also considered
*
bioactivation (pharmaco)“Ken”etic.
inactive substrate active metabolite
(prodrug)
The aggressor in a renal interaction is not referred to as an inducer or
inhibitor, because no enzyme is involved. Nor is the victim called a
substrate, because it is not being biotransformed.
For most medications (active parent drug to inactive metabolite)
inDuction decreases (D for Down) effect of the drug and inHibition (H Lithium, excreted unchanged in urine, is subject to victimization as
for High) amplifies the therapeutic effect and/or side effects. illustrated on page 26.
With prodrugs, the opposite effect is observed clinically. Induction
increases and inhibition decreases the medication’s effect(s). CYP GENETIC PROFILES
Don’t let prodrugs confuse you. InHibitors increase and InDucers
Genetic polymorphisms can influence an individual’s medication kinetics,
decrease the levels of substrate regardless of whether the parent
which is most relevant for 2D6 and 2C19. Let’s talk about 2D6, arguably
drug is pharmacologically active.
the most consequential example.
Most individuals are genetically equipped with 2D6 genes that produce
normal 2D6 enzymes that metabolize 2D6 substrates at the usual rate.
The following are prodrugs activated by 2D6: These normal individuals are said to have a 2D6 extensive metabolizer
(EM) genotype, resulting in a 2D6 EM phenotype.
❖Codeine - metabolized to morphine
❖Tramadol (Ultram) - weak opioid
❖Tamoxifen - anti-estrogen for breast cancer
Here is a cute representation of how a normal
The bowling ball is explained on page 15. individual, i.e., 2D6 extensive metabolizer
(EM), processes 2D6 substrates. The air
inside the beach ball represents the substrate,
which is being expelled from the ball as
EM
metabolite at the usual rate. 2D6 substrates
will have typical elimination half-lives.
PHASE II METABOLISM
About 5% of the population have extra copies of 2D6 genes, resulting in
Phase II metabolism occurs in an ultrarapid metabolizer (UM) phenotype. These individuals clear 2D6
the liver and is subject to substrates quickly.
kinetic interactions. CYP
enzymes are not involved.
Two Kens without a
For 2D6 ultrarapid metabolizers (UM), the
bottle to “CYP” (sip)
air (2D6 substrate) flows out of the ball
quickly as metabolite. 2D6 substrates could
be ineffective for these individuals (with the
Phase II reactions typically involve conjugation of a substrate with exception of 2D6 prodrugs, which could be UM
glucuronic acid. This makes the drug water-soluble and prepped be too strong).
for renal excretion.
8
Cafer's Psychopharmacology | cafermed.com
About 10% of individuals have defective 2D6 enzymes resulting in a THE NATURE OF THIS INFORMATION 9
2D6 poor metabolizer (PM) phenotype. This condition may be found
on a diagnosis list as “Cytochrome P450 2D6 enzyme deficiency”. The information presented in the remainder of this chapter is a
synthesis of sources including the OpeRational ClassificAtion (ORCA)
system (as presented in The Top 100 Drug Interactions by Hansten &
For 2D6 “POOR Horn, 2019), Lexicomp, DrugBank, Flockhart Table, ePocrates, Carlat
ME”tabolizers (PM), air Medication Fact Book, Stahl’s Essential Psychopharmacology, The
accumulates, resulting in Medical Letter, Current Psychiatry, GeneSight, Genecept, various
unexpectedly long half-lives research papers and FDA prescribing information for the individual
for 2D6 substrates. These Poor me! drugs.
individuals are more likely to
report side effects. PM Reputable sources are often at odds with each other regarding the
strength of specific inducers/inhibitors, the vulnerability of specific
substrates to induction/inhibition, or even which CYPs are relevant to a
specific medication. CYP interactions are continuously being discovered
and clarified. Even with the freshest information and full knowledge of a
An individual taking a strong as if! patient’s genotype, the magnitude of a specific CYP interaction is
2D6 inHibitor (pump as difficult to predict.
illustrated on page 15) will
OO
metabolize 2D6 substrates P R HOW TO APPLY THIS INFORMATION
as if the individual had a
2D6 PM genotype. Refer to the tables on pages 20 and 21. Highlight the medications that
you prescribe. First acquaint yourself with the inDucers because the list
is short. Memorize the bolded inducers (shredders) and those that you
highlighted. After you know the inducers, move to the inHibitor column.
In summary, genetic testing of CYP polymorphisms will interpret the Memorize the bolded inhibitors (fluffers) and your highlighted
individual’s metabolizer profile for a given enzyme as either: medications.
❖ Extensive metabolizer (EM) - normal
❖ Ultrarapid metabolizer (UM) - fast clearance of substrates When it comes to substrates, memorization is less important.
❖ Poor metabolizer (PM) - slow clearance of substrates Substrates are only relevant when an inducer or inhibitor is on board, or
if the patient has a special metabolizer genotype. Of the medications
A genetic test result of intermediate metabolizer (IM) means that you prescribe, be aware of the more susceptible substrates.
enzyme activity is likely to be a bit lower than that of an EM, i.e., an
intermediate between EM and PM. Generally, IM individuals can be Consider running an interaction check whenever a patient is taking a
clinically managed normally, like an EM individual. shredder, fluffer, systemic antifungal, HIV medication, or cancer
medication. ePocrates.com and the ePocrates app are adequate, and
Standalone 2D6 genotyping costs at least $200. GeneSight or free.
Genecept panels cost about $4,000 and report the six relevant CYPs
Keep things simple. When choosing new medications, avoid major
and two UGT enzymes (UGT1A4 and UGT2B15). 23andMe ($199)
inducers and inhibitors if suitable alternatives are available. For the
reports 1A2, 2C9, and 2C19, among 100s of other genes. 23andMe
complicated psychiatric patient on several medications, try to avoid
does not report the most relevant CYP genotype, 2D6, because the
carbamazepine (shredder inducer) and the fluffer SSRIs (fluoxetine
genetics of 2D6 metabolism is more complicated.
and fluvoxamine). Among SSRIs, escitalopram (Lexapro) and sertraline
(Zoloft) are good choices—they are 2C19 substrates but do not affect
Genotyping may be useful when choosing which medication to
the metabolism of other medications.
prescribe an individual patient. With GeneSight, about 1 in 5 patients
have a genetic variation relevant to their treatment. For an individual
Also think about choosing less vulnerable substrates. Each drug mascot
already established on a medication, serum drug levels may be more
on pages 18 and 19 is depicted in box/bubble because it is generally
useful than genotyping. There are situations when knowing the actual
not involved in clinically significant kinetic interactions (although
blood levels of clozapine, risperidone, olanzapine, aripiprazole,
dynamic interactions almost always apply). You don’t have to worry
haloperidol, lamotrigine, etc. are clinically relevant. Unfortunately,
much about benzodiazepine interactions if you stick to the “LOT”
these tests usually must be sent to an outside lab, and it may take a
benzos—lorazepam, oxazepam and temazepam. Most antipsychotics
week to see the results. Levels of lithium, carbamazepine, phenytoin,
are susceptible substrates, but not so much for ziprasidone, loxapine
and valproic acid are usually reported the same day.
and paliperidone.
This book uses picture association as a memorization technique. Pages
P-GLYCOPROTEIN
10 through 17 establish a visual mnemonic framework for various
kinetic interactions that will be reinforced by a mascot for each of 270
P-glycoprotein (P-gp) is a gatekeeper at the gut lumen and the
medications. The mascots serve a double purpose of helping you
blood-brain barrier. P-gp pumps P-gp substrates out of the
remember US trade name/generic name pairings.
brain—“Pumpers gonna pump”.
Since you probably won’t be mentioning CYP nomenclature in casual
conversation, you might want to bypass the technical naming system
altogether. Instead of keeping a list of “3A4 substrates” in your memory
bank, you could just learn the school of “fish”.
“Pumpers
I hope this book empowers you to understand and memorize topics that
gonna pump”
P-gp substrates P-gp are otherwise daunting, so you can use your knowledge to improve
out of the brain substrate patient care. Without further ado, let’s start our journey to becoming a
superhero of psychotropic medication management.
An example of a relevant P-gp interaction involves the OTC opioid
antidiarrheal loperamide (Imodium). Loperamide does not cause
central opioid effects under normal circumstances. If the individual
takes a potent P-gp inhibitor, megadose loperamide can stay in the
brain long enough to cause euphoria. The P-gp inhibitor typically
used the achieve this recreational effect is omeprazole (Prilosec).
Cafer's Psychopharmacology | cafermed.com 9
1A2 accounts for 10–15% of Cytochrome P450 1A2 (CYP1A2) 52% of individuals are 1A2 page
10 CYP activity in the liver ultrarapid metabolizers; 288
“One Axe to Grind; One Axe to Grow” < 1% are poor metabolizers
“1 Axe to 2 Grind” “1 Axe 2 Grow”
inHibitor = High
inDucer = Down
Increased substrate
1A2 Substrate
levels
1A2 inducer 1A2 Sub1sAt2rate aisDnunedbdcus rcrteetriaavosteneer sodleen vsse eltss 1A2 aawinsniHt dhtih birneeit ivHioneonhru sihbreasistp o =apr seHis nus sor roiend
slowly =
1A2 cleared from the body
Delayed*
Inhibitor (five half-lives of the
inhibitor)
Hydrocarbons from smoked herbs such as tobacco and cannabis are
moderate potency 1A2 inducers. All other 1A2 inducers are weak. Fluvoxamine (Luvox) is the only strong 1A2 inhibitor.
weak 1A2 s t ro n g
TEGRETOL (Carbamazepine) 1A2 cannabis also LUVOX inhibitor
antiepileptic, mood stabilizer inducer Tobacco imndoudceerar te fluvoxamine
1A2 not nicotine patch or gum 1A2 SSRI for OCD
* Induction by smoking takes about 3 days to
DILANTIN (Phenytoin) 1wAe2a k sliktaer t—thneo tiocteh ethr e aaxxees . ha sU npoo ns pcinensisnagt iownh eoefl 11AA22 im n ho i db ei tr oa r t e
antiepileptic inducer smoking, induction reverses over the first CIPRO
week. This is much faster than with other ciprofloxacin
1A2
inducers. 10 cigarettes daily is sufficient for 1A2
maximum induction effect. quinolone
antibiotic
First Generation Antipsychotics Second Generation Antipsychotics “-pine” trees Antidepressant
NAVANE HALDOL STELAZINE CYMBALTA
Thiothixene Haloperidol Trifluoperazine Duloxetine
ZYPREXA CLOZARIL SAPHRIS
Olanzapine Clozapine A s e n a p i ne
minor
minor minor ~ 50% increase 3-fold increase negligible decrease 3-fold increase
by Luvox by Luvox by smoking by Luvox
Melatonin agonists Methylxanthines Spasmolytic
ROZEREM HETLIOZ Melatonin Theophylline Caffeine NOURIANZ ZANAFLEX
Ramelteon Tasimelteon Istradefylline Tizanidine
“TREE
-ophylline”
up to 100-fold 3-fold increase > 10-fold increase
increase by Luvox by Luvox by Luvox
Contraindicated with Luvox
Contraindicated with Luvox or Cipro
Conclusion: Keep in mind that 52% of individuals have a 1A2 ultrarapid
Tobacco metabolizer genotype, and everyone who smokes has an ultrarapid
Decreases metabolizer phenotype. Smokers may need to take higher doses of 1A2
To b acco OClalonzozaarppininee 50% bt”hploeinoseed ttlreweveoes l”s of aosusf bmlsoetnrmagt oearsisz. ay tToiohune .r eeMmffeeemcmto boreifz ras ttmioo onrku ionnf g ao onthn ei nrot le1arAna2zca tsipouinnb esc thraaentcedks c oilson z oaaf pnloiyn weme iers d pwircioaortrtiiohtyny,
by about 50%. regimen that includes Luvox. Consider keeping Luvox out of the mix
entirely—it is nonessential for treatment of OCD because other SSRIs are
similarly effective at high doses (page 99).
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Cafer's Psychopharmacology | cafermed.com