Baby-Katzung-Second-Shifting-Reviewer.pdf

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#PharMasaya

4.0-02January 21, 2014

Baby Katzung(2nd Shifting Reviewer)"Realize that if you have time to whine and complain about something, then you have the

time to do something about it." Anthony J. D'Angelo

WALKTHROUGH

MAJOR DRUG CLASS Notes on the major drug class above (if any)DRUGSUBCLASS

Notes on the drug subclass on the left side DRUG

o Specific informationDRUG Specific information

LECTURER FAVORITE QUESTIONSLOYOLA Basic physiology, mechanism of actionALABASTRO Emphasized parts in pharmacokinetics, clinical uses, toxicityFILARCA Clinical uses, toxicityDIMAANO Clinical uses, toxicity, contraindicationsTORRES Drug of choice, toxicities (Di halata. Hahahaha.)

SECOND SHIFTINGGASTROINTESTINAL PHARMACOLOGY

ACID-PEPTIC DISEASES

ANTACIDS Given 1 hour after meals Short-acting (1-2 hours) Cautions: renal insufficiency Interactions: affect drug absorption by binding to other drugs or altering

intragastric pHSODIUMBICARBONATE

HCL CO2 + NaCl NaHCO3: renal insufficiencymetabolic alkalosis CO2: gastric distention, belching NaCl: heart failure, hypertension, renal insufficiency

fluid retentionMAGNESIUMHYDROXIDE +ALUMINUMHYDROXIDE

MgCl2: osmotic diarrhea AlCl3: constipation No gas formation no belching

ALGINATE Reacts with HCl forms protective viscous foam Clinical uses: heartburn, GERD

H2 RECEPTOR ANTAGONISTS ("tidine") Highly selective competitive antagonist at parietal cell H2 receptor Extremely safe (few adverse effects) Pharmacokinetics: long-acting (6-10 hours), given BID Clinical uses: prophylaxis of heartburn, PUD, stress-related gastritis No CYP450 interactions: famotidine, nizatidineCIMETIDINE Toxicity: mental status changes, gynecomastia, impotence,

galactorrhea, bradycardia, hypotension Interactions: CYP1A2, CYP2C9, CYP2D6, CYP3A4

RANITIDINE Less affinity to CYP450 than cimetidineFAMOTIDINE blood ethanolNIZATIDINE Little first-pass metabolism

~100% bioavailability

PROTON PUMP INHIBITORS ("prazole") Substituted benzoimidazoles, inactive prodrugs Active metabolite: sulfonamide cation irreversibly inactivates proton

pump (H+/K+-ATPase) Given BID on empty stomach to absorption Formulated as acid-resistant enteric-coated tablets or capsules Concentrated in parietal cell canaliculi (site of action) by Henderson-

Hasselbach trapping Short t1/2 (1.5 hours), long-acting (24 hours) DOC for acid-peptic diseases

o GERD and Barrett esophagus

o Triple therapy in H. pylori-associated peptic ulcers (10-14 dayregimen of PPI + clarithromycin + amoxicillin/metronidazole)

o NSAID-associated ulcerso Gastrinomas and hypersecretion

Toxicity: B12 and electrolyte absorption, risk of nosocomial infections,hypergastrinemia

OMEPRAZOLE Formulated as non-enteric-coated powder

MUCOSAL PROTECTANTSSUCRALFATE Reacts with water or acid forms viscous paste

Negatively-charged sucrose sulfate binds to positively-charged proteins on ulcers

Alternative to acid-inhibitory therapies (less risk ofnosocomial infections)

Cautions: renal insufficiencyMISOPROSTOL PGE1 analog stimulates mucus and HCO3 secretion,

acid DOC for NSAID-induced ulcers Toxicity: diarrhea, abdominal pain, abortifacient

BISMUTHSUBSALICYLATE

Coats ulcers and erosions Binds enterotoxins Clinical uses: traveler's diarrhea, H. pylori (second-line) Toxicity: harmless black stool, encephalopathy,

salicylate toxicity

GASTROPROKINETIC AGENTS Selectively stimulate gut motor function LES pressure (useful in GERD) GI emptying (useful in gastroparesis, post-vagotomy/antrectomy)

CHOLINERGICAGENTS

BETHANECHOLo Stimulates M3 receptors on GIT smooth muscle and

at myenteric plexus synapses NEOSTIGMINE

o Clinical uses: Ogilvie syndrome (acute colonicpseudo-obstruction)

D2 RECEPTORANTAGONISTS

Clinical uses: GERD, gastroparesis, antiemetic,postpartum lactation

METOCLOPRAMIDEo Toxicity: extrapyramidal symptoms

DOMPERIDONEo Promotes postpartum lactationo Toxicity: hyperprolactinemia

MACROLIDES

ERYTHROMYCINo Stimulates motilin receptors and facilitates MMCo Clinical uses: pre-endoscopy evacuation of blood in

patients with UGIB

CONSTIPATION

LAXATIVES Clinical uses: colonic evacuation in constipated patientsBULK-FORMINGLAXATIVES

Indigestible hydrophilic colloids Form emollient gel colonic distention, hyperperistalsis Bacterial digestion of fiber bloating, flatulence PSYLLIUM, METHYLCELLULOSE

STOOLSURFACTANTS

Given PO or rectally Minimize straining DOCUSATE

o Commonly prescribed stool surfactant MINERAL OIL

o Lubricates feces and retards water absorptiono Clinical uses: fecal impaction in children and

#PharMasaya :P Page 2 of 13

Baby Katzung (Finals Reviewer)

debilitated adultso Aspiration lipid pneumonitiso Prolonged use: vitamin malabsorption

OSMOTICLAXATIVES

NON-ABSORBABLE SUGARS OR SALTSo Clinical uses: treatment of acute constipation,

prevention of chronic constipation BALANCED POLYETHYLENE GLYCOL MAGNESIUM HYDROXIDE (MILK OF MAGNESIA)

o Most commonly used osmotic laxativeo Prolonged use: hypermagnesemia in renal

insufficiency LACTULOSE

o DOC for hepatic encephalopathyo Metabolized by bacteria flatus, cramps

MAGNESIUM CITRATE AND SODIUM PHOSPHATEo Purgativeso Toxicity: hypovolemia, electrolyte fluctuations

BALANCED POLYETHYLENE GLYCOLo Lavage solution of PEG and electroyteso Clinical uses: pre-endoscopy colonic cleansing

STIMULANTLAXATIVES

Direct ENS stimulation + colonic electrolyte and fluidsecretion colonic movement

ANTHRAQUINONE DERIVATIVES (ALOE, SENNA,CASCARA)o Chronic use: melanosis coli

DIPHENYLMETHANE DERIVATIVES (BISACODYL)o Clinical uses: acute and chronic constipation, pre-

endoscopy cleansingCHLORIDECHANNELACTIVATORS

Stimulate type 2 Cl- channels in small intestine Cl-

secretion GI motility, transit time LUBIPROSTONE

o Prostanoic acid derivativeOPIOIDRECEPTORANTAGONISTS

Inhibit GIT -opioid receptors METHYLNALTREXONE

o Opioid-induced constipation ALVIMOPAN

o Post-bowel resection ileus5-HT4RECEPTORAGONISTS

Stimulate 5-HT4 receptors in submucosal plexus TEGASEROD

o High affinity partial agonisto Withdrawn due to risk of CV events

CISAPRIDEo Partial agonisto Inhibits hERG QT prolongation

PRUCALOPRIDEo High affinity agonisto Clinical uses: chronic constipation in women

PROKINETICBENZAMIDES

ITOPRIDEo Inhibits D2 receptors and acetylcholinesteraseo gastric emptying time

GUANYLATECYCLASE CAGONISTS

LINACLOTIDEo Binds to guanylate cyclase C receptor on enterocyte

luminal surface CFTR activation fluidsecretion

DIARRHEA

ANTIDIARRHEALS Clinical uses: mild to moderate acute diarrhea Cautions: bloody diarrhea, hyperthermia, systemic toxicityOPIOIDAGONISTS

Inhibit presynaptic cholinergic neurons in entericplexuses colonic transit time, mass movement

No analgesic property LOPERAMIDE

o No CNS entry DIPHENOXYLATE

o CNS effects

o Prolonged use: dependence (combined withatropine to discourage dependence)

BILE-SALTSEQUESTRANTS

fecal excretion of bile acids Toxicity: bloating, flatulence, constipation, fat

malabsorption COLESEVELAM

o No drug interactions OTHERS (COLESTIPOL, CHOLESTYRAMINE)

SOMATOSTATINANALOGS

OCTREOTIDEo Inhibits GIT hormone and neurotransmitter

secretion antimotility effecto Clinical uses: diarrhea 2 to hypersecretion, post-

vagotomy, dumping syndrome, VIPomao Toxicity: steatorrhea (2 to impaired pancreatic

secretion), alterations in GI motility, acutecholecystitis, hyperglycemia

OTHERS BISMUTH KAOLIN (ATTAPULGITE) AND PECTIN

o Absorb bacteria, toxins, fluids stool liquidityo Clinical uses: acute diarrhea

IRRITABLE BOWEL SYNDROME

ANTISPASMODICS DICYCLOMINE, HYOSCYAMINE

o Inhibit muscarinic cholinergic receptors

5-HT3 RECEPTOR ANTAGONISTS ("setron") 5-HT3 receptor blockade in enteric terminals motilityALOSETRON IBS with predominant diarrhea in women

Toxicity: GI toxicity, constipation, ischemic colitis

5-HT4 RECEPTOR AGONISTSTEGASEROD IBS with predominant constipation in women

CHLORIDE CHANNEL ACTIVATORSLUBIPROSTONE IBS with predominant constipation in women

NAUSEA AND VOMITING

5-HT3 RECEPTOR ANTAGONISTS ("setron") ONDANSETRON, GRANISETRON, DOLASETRON, PALONOSETRON

o Potent antiemetic properties Peripheral 5-HT3 blockade in extrinsic intestinal neurons Central 5-HT3 blockade in chemoreceptor trigger zone

o Clinical uses: post-operative and post-radiation N/Vo DOC for acute chemotherapy-induced N/V (CINV)o Not used in delayed CINVo Toxicity: headache, dizziness, constipation

PALONOSETRON Newer IV agent Higher affinity to 5-HT3 receptor Long-acting (t1/2: 40 hours)

DOLASETRON QT prolongation

CORTICOSTEROIDS WITH ANTIEMETIC ACTIVITY DEXAMETHASONE, METHYLPREDNISONE

o Enhance efficacy of 5-HT3 receptor antagonistso Clinical uses: prevention of acute and delayed CINV

NEUROKININ (NK1) RECEPTOR ANTAGONISTSAPREPITANT Central blockade in area postrema

Metabolized by CYP3A4 Combined with 5-HT3 receptor antagonists and steroids Clinical uses: acute and delayed CINV



DOPAMINERGIC ANTAGONISTS Toxicity: mental status changes, extrapyramidal symptomsPHENOTHIAZINES PROMETHAZINE, PROCHLORPERAZINE,

THIETHYLPERAZINEo Potent antiemetic and sedative activity

BUTYROPHENONES DROPERIDOLo Clinical uses: post-operative N/Vo Toxicity: extrapyramidal symptoms,

hypotension, QT prolongationPROKINETICS TRIMETHOBENZAMIDE, METOCLOPRAMIDE

ANTICHOLINERGIC H1 ANTIHISTAMINES Weak antiemetic activity Clinical uses: motion sicknessSCOPOLAMINE DOC for motion sicknessDIPHENHYDRAMINE Potent sedativeMECLIZINE Minimal anticholinergic and sedating effects

DOC for vertigo

BENZODIAZEPINESLORAZEPAM,DIAZPEAM

Given pre-chemotherapy to reduce anticipatory vomiting

CANNABINOIDS ("nabi")DRONABINOL THC analog

Clinical uses: antiemetic, appetite stimulant Interactions: phenothiazines (synergistic effect,

attenuates adverse effects of both) Toxicity: sedation, euphoria, dysphoria, hallucination,

ANS effects

INFLAMMATORY BOWEL DISEASE

AMINOSALICYLATES (5-ASA) 5-aminosalicylic acid Inhibits COX, nuclear factor-B, lymphocyte function Pharmacokinetics: rapidly absorbed from proximal small intestine, N-

acetylated to inactive metabolite in GIT epithelium and liver DOC for mild to moderate IBDAZOCOMPOUNDS("salazine")

5-ASA bound by azo bond (N=N) to inert compound or toanother 5-ASA molecule

SULFASALAZINEo 5-ASA + sulfapyridine

BALSALAZIDEo 5-ASA + 4-aminobenzoyl--alanine

OLSALAZINEo 2 molecules of 5-ASA

MESALAMINECOMPOUNDS

PENTASAo Small intestine

ASACOL, APRISOo Distal ileum, proximal colon

LIALDAo Colon

ROWASA (enema), CANASA (suppository)o Rectum, sigmoid colon

GLUCOCORTICOIDSPREDNISONE Most commonly usedHYDROCORTISONE Topical treatment of active IBD in rectum and

sigmoid colonBUDESONIDE Potent synthetic analog of prednisolone

High affinity glucocorticoid receptor agonist

ANTIMETABOLITES Clinical uses: induction and maintenance of remission in ulcerative colitis

and Crohn's disease Toxicity: myelosuppression (leukopenia, anemia)AZATHIOPRINE Nonenzymatically converted to 6-MP inhibits purine

metabolism and DNA synthesis T-lymphocyte apoptosis Toxicity: N/V, hepatotoxicity Pre-therapy monitoring: TPMT activity Interactions: allopurinol (severe leukopenia)

METHOTREXATE Inhibits dihydrofolate reductase

ANTI-TNF MONOCLONAL ANTIBODIES High affinity to TNF- prevent binding of TNF- to receptor Clinical uses: treatment of acute and chronic moderate to severe Crohn's

disease and ulcerative colitis Toxicity: infection, reactivation of latent TB, antibody formationINFLIXIMAB Chimeric mouse-human

Acute adverse infusion reactionsADALIMUMAB Fully humanizedCERTOLIZUMAB Pegylated Fab fragment

ANTI-INTEGRINNATALIZUMAB Humanized IgG4 monoclonal antibody

Blocks integrin prevents IgG binding to vascularadhesion molecules

Clinical uses: moderate to severe Crohn's disease (ifother therapies fail)

EXOCRINE PANCREATIC INSUFFICIENCY

PANCREATIC ENZYME SUPPLEMENTS Toxicity: mucositis, hyperuricosuria, renal stonesPANCRELIPASE Greater lipolytic (X12) and proteolytic (X4) activity

compared to PANCREATIN Creon: most common

GALLSTONES

URSODIOL (URSODEOXYCHOLIC ACID) hepatic cholesterol secretion cholesterol content of bile Clinical uses: dissolution of small gallstones, symptomatic gallbladder

disease, prevention of gallstones liver function deviations and improves liver histology in biliary cirrhosis

ESOPHAGEAL VARICES

HEMOSTATIC AGENTSOCTREOTIDE portal blood flow variceal pressure

Initial hemostasisARGININEVASOPRESSIN

Splanchnic arterial vasoconstriction portal venouspressure

Toxicity: CVS effects (hypertension, ischemia,hyponatremia, pulmonary edema), GIT effects (nausea,abdominal cramps, diarrhea)

TERLIPRESSINo Fewer adverse effects

NONSELECTIVEBETA BLOCKERS

PROPRANOLOL, NADOLOLo portal inflow and portal venous pressureo 2 blockade: splanchnic vasoconstriction

ALCOHOL PHARMACOLOGY

ALCOHOLSETHANOL Water-soluble, rapidly absorbed in GIT in fasting state,

peaks in blood in 30 minutes, 90% oxidized in liver



Alcohol dehydrogenaseo Primary metabolic pathway of alcoholo Converts alcohol to acetaldehyde

Microsomal ethanol oxidizing systemo Utilizes NADPH as cofactoro Low affinity for alcoholo Significantly active at BAC of >100 mg/dL

Aldehyde dehydrogenaseo Oxidizes acetaldehyde to acetate (further degraded

to CO2 + water) Acute: sedation, anxiolysis, intoxication, memory loss,

myocardial contractility, vasodilation, hypothermia Chronic: liver disease (fatty liver, alcoholic hepatitis,

cirrhosis), chronic pancreatitis, CNS effects (dependence,Wernicke-Korsakoff), CVS effects (heart failure,arrhythmia, hypertension, coronary diseases), endocrineeffects (steroid imbalance), fetal alcohol syndrome

Interactions: acetaminophen (hepatotoxicity), CNSdepressants (additive depression)

METHANOL Metabolized by alcohol dehydrogenase Metabolites: formaldehyde, formic acid, CO2 Toxicity: "snowstorm" vision, formalin breath, sudden

cessation of respiration Management: respiratory support, hemodialysis,

alkalinization, ethanol and fomepizoleETHYLENEGLYCOL

Metabolized to toxic aldehydes and oxalates Same management in methanol poisoning

ANTI-ALCOHOLISM AGENTSDISULFIRAM Alcohol dehydrogenase inhibitor

Provokes severe discomfort (flushing, N/V, sweating,hypotension) after consuming alcohol

Interactions: alcohol-containing medicationsNALTREXONE Long-acting opioid receptor antagonist at -opioid

receptors Interactions: disulfiram (hepatotoxicity), opioids

(withdrawal syndrome)ACAMPROSATE NMDA antagonist

GABAA receptor activator Contraindications: renal impairment Toxicity: N/V, vomiting, rashes

FOMEPIZOLE Alcohol dehydrogenase inhibitor DOC for methanol or ethylene glycol poisoning

OTHERS ONDANSETRON, TOPIRAMATE, BACLOFENo craving in chronic alcoholism

RIMONABANTo CB1 receptor antagonisto Suppresses alcohol-related behaviors

CENTRAL NEUROTRANSMITTERS

AMINO ACIDSEXCITATORY GLUTAMATE

o Taken up via vesicular glutamate transporter (VgluT)o Released by Ca2+-mediated exocytosiso Converted by glutamine synthetase to glutamine

(then converted to glutamine by glutaminase)o Receptors

Ionotropic AMPA: permeable to Na+ and K+

Kainic acid: expressed in hippocampus,cerebellum, spinal cord

NMDA: present in all CNS neurons,involved in long-term potentiation

Metabotropic (G protein-coupled) Group I: postsynaptic Group II: presynaptic

INHIBITORY GAMMA-AMINOBUTYRIC ACID (GABA)o Present in CNS in GABA-releasing interneuronso Types

GABAA Ionotropic Fast component of inhibitory potentials Activators: MUSCIMOL Inhibitors: PICROTOXIN, BICUCULLINE

GABAB Metabotropic (G protein-coupled) Slow component of inhibitory potentials Either inhibit Ca2+ channels or activate K+

channels Activators: BACLOFEN Inhibitors: 2-OH SACLOFEN

GLYCINEo Interneurons in spinal cord and brainstemo Inhibitors: STRYCHININE (potent spinal cord

proconvulsant)

SEDATIVE-HYPNOTICS

BENZODIAZEPINES ("zep", "zepam", "zolam") 7-membered heterocyclic ring with carboxamide group Electronegative substituent at 7 position confers sedative-hypnotic activity Bind to benzodiazepine site of GABAA receptor frequency of channel-opening events Cross placenta and breastmilk Biotransformation: microsomal oxidation (phase I) catalyzed by CYP3A4

conjugation (phase II) to glucuronides Toxicity: tolerance and dependence, anterograde amnesia,

cardiorespiratory depressionANXIOLYTICS All are long-acting except alprazolam and oxazepam

(short-acting) Desmethyldiazepam

o Active metabolite of chlordiazepoxide,clorazepate, and diazepam

ALPRAZOLAM CHLORDIAZEPOXIDE, CLORAZEPATE

o Used in alcohol withdrawal CLONAZEPAM

o No active metaboliteo Used in epilepsy

DIAZEPAMo Used in epilepsy, alcohol withdrawal, and

muscle relaxationo Alternative DOC for status epilepticus

OXAZEPAMo Short-acting and no active metaboliteo Used in alcohol withdrawal

HYPNOTICS ESTAZOLAM, FLURAZEPAM, QUAZEPAM,TEMAZEPAM, TRIAZOLAMo Used in sleep disorders

MIDAZOLAMo Conscious sedation

ANXIOLYTIC-HYPNOTIC

LORAZEPAMo Intermediate-actingo Used in delirium tremenso DOC for status epilepticus

TRIAZOLES Triazole ring at 1,2 position Transformed to alpha-hydroxy metabolites Short-acting ALPRAZOLAM

o Used in panic attacks TRIAZOLAM

o Used in sleep disorders



Rapidly-absorbed: CLONed Dad, Father, Tatay (clonazepam, diazepam,flurazepam, triazolam)

Active metabolites: FACT MD (flurazepam, alprazolam, chlordiazepoxide,triazolam, midazolam, diazepam)

No active metabolites: CLOT (clonazepam, lorazepam, oxazepam,temazepam)

Short-acting: TRI MO (triazoles, midazolam, oxazepam)Intermediate-acting: LET (lorazepam, temazepam, estazolam)Long-acting: everything else

BENZODIAZEPINE SUBTYPE Generally rapid-acting Metabolized by CYP3A4 Clinical uses: sleep disorders (insomnia)ZALEPLON Short-acting

Hydroxylation, oxidation (no active metabolite) REM and latency of sleep risk of tolerance

ZOLPIDEM Ultra-short-acting Aldehyde dehydrogenase (no active metabolite) latency of sleep Lowest risk of withdrawal symptoms

ESZOPICLONE Intermediate-acting total sleep time No rebound insomnia

BENZODIAZEPINE ANTAGONISTFLUMAZENIL 1,4-benzodiazepine derivative

Competitive antagonist of benzodiazepines andbenzodiazepine subtype

High affinity to benzodiazepine site on GABAA receptor Rapid-acting (t1/2: ~1 hour) sedation may recur Clinical uses: BZ-induced CNS depression Toxicity: severe abstinence syndrome Interactions: tricyclics (seizures, arrhythmias)

NON-BENZODIAZEPINES

BUSPIRONE

Selective anxiolytic Partial 5-HT1A agonist with affinity to D2 receptors No depressant, anticonvulsant, relaxant properties Active metabolite: 1-(2-pyrimidyl)-piperazine Clinical uses: generalized anxiety state (not for panic

disorders) Less risk of dependence and rebound anxiety

BARBITURATES ("barbital") Bind to allosteric site on GABAA receptor duration of channel-opening events Clinical uses: sedation, hypnosis, anesthesia, anticonvulsant Toxicity: cardiorespiratory depression Contraindications: porphyria, hepatic and renal impairmentTHIOPENTAL Ultra-short-acting, very lipid-soluble (can enter CNS)SECOBARBITAL Short-acting (t1/2: 18 hours)PENTOBARBITAL Intermediate-acting (t1/2: 48 hours)PHENOBARBITAL Long-acting (t1/2: 4-5 days)

MELATONIN RECEPTOR AGONISTSRAMELTEON MT1 and MT2 receptor agonist

Metabolized by CYP1A2 Clinical uses: maintenance of circadian rhythm, reduces

latency of sleep No rebound effects or withdrawal symptoms Cautions: hypertension and diabetes Contraindications: hepatic impairment Toxicity: mental status changes (dizziness, somnolence),

hyperprolactinemia

OTHER ANXIOLYTICS AND HYPNOTICSANTIHISTAMINES Marked sedation

Long t1/2ANTIDEPRESSANTS TRICYCLICS, MIRTAZAPINE, TRAZODONEBETA BLOCKERS Clinical uses: management of physiologic

components of anxiety (tachycardia, palpitations,tremors, sweating)

No CNS depression and addiction

ANTIEPILEPTICSPARTIAL AND GENERALIZED TONIC-CLONIC SEIZURES

ANTI-MAXIMAL ELECTROSHOCK CLASS

SODIUM CHANNEL BLOCKERS Blocks voltage-gated Na+ channels (VGNC) high-frequency neuronal

firing (no effect on physiologic firing)HYDANTOINS PHENYTOIN

o Alters Na+, K+, and Ca2+ conductanceo glutamate releaseo Exhibits non-linear kineticso High protein binding (99%)o Toxicity: gingival hyperplasia, hirsutism

FOSPHENYTOINo Prodrug of phenytoin

TRICYCLICS("zepine")

CARBAMAZEPINEo DOC for complex partial seizureso Active metabolite: carbamazepine-10,11 epoxideo Toxicity: CNS effects (diplopia, ataxia),

hyponatremia OXCARBAZEPINE

o Active metabolite: 10-hydroxy metaboliteMISCELLANEOUS ZONISAMIDE

o Blocks VGNC and T-type Ca2+ channelso Toxicity: renal stones

LACOSAMIDEo Enhances slow inactivation of VGNCo Binds to CRMP-2 neuronal growth

RUFINAMIDEo Clinical uses: Lennox-Gastaut syndrome

(childhood-onset epilepsy)

POTASSIUM CHANNEL AGONISTSRETIGABINE K+ channel opening hyperexcitability

Toxicity: CNS effects (dizziness, somnolence, confusion,blurred vision, dysarthria)

GABA AGONISTSBENZODIAZEPINES DIAZEPAM

LORAZEPAMo Longer-acting than diazepamo DOC for status epilepticus

BARBITURATES PHENOBARBITALo inhibitory and excitatory transmissiono DOC for seizure in infants, also used in febrile

seizures PRIMIDONE

o Active metabolites: phenobarbital,phenylethylmalonamide (PEMA)

GABA ANALOGS("gaba")

VIGABATRINo Irreversibly inhibits GABA aminotransferase GABA degradation GABA levels

o DOC for infantile spasms (West syndrome)o Toxicity: drowsiness, dizzinesso Prolonged use: visual field defectso Contraindications: psychosis



GABAPENTINo Enters CNS via L-amino acid transportero Modifies release of GABAo Clinical uses: dystonia, migraine

PREGABALINo Clinical uses: fibromyalgia

TIAGABINEo Inhibits GABA uptake in neurons and gliao Prolongs inhibitory action of synaptically-

released GABAo Toxicity: cognitive slowing

PLEIOTROPICS Multiple mechanisms of action Clinical uses: partial seizuresLAMOTRIGINE Suppresses sustained rapid firing

Voltage- and use-dependent inactivation of Na+

channels Inhibits voltage-gated N and P/Q Ca2+ channels Bipolar disorder Toxicity: skin rash

LEVETIRACETAM Binds to synaptic vesicular protein SV2A glutamateFELBAMATE Use-dependent block of NR1-2B NMDA receptor

Blocks strychnine-insensitive glycine site on NMDA complexTOPIRAMATE AMPA receptor antagonist

ABSENCE SEIZURESANTI-PENTYLENETETRAZOL CLASS

CALCIUM CURRENT INHIBITORS T-type Ca2+ current in thalamic neurons Clinical uses: absence seizuresSUCCINIMIDES ETHOSUXIMIDE

o DOC for absence seizuresMISCELLANEOUS VALPROIC ACID

o K+ channel agonisto Blocks voltage-gated Na+ channelo Blocks NMDA receptor-mediated excitationo Facilitates glutamic acid decarboxylase

GABA synthesiso High protein bindingo Displaces phenytoin from plasma proteinso DOC for Lennox-Gastaut syndromeo Second line for absence seizureso Toxicity: hepatotoxicity, spina bifida

OXAZOLIDINEDIONES TRIMETHADIONEo seizure thresholdo Active metabolite: dimethadioneo Toxicity: sedation

OTHER ANTIEPILEPTICS

CARBONIC ANHYDRASEINHIBITORS

ACETAZOLAMIDEo Produces mild acidosis in the brain

anticonvulsant effectHORMONES PROGESTERONE

PARKINSON'S DISEASE

DOPAMINE PRECURSORSLEVODOPA(L-DOPA)

Enters CNS via L-amino acid transporter Decarboxylated to dopamine Extracerebral metabolism only 1-3% enters CNS Metabolites: homovanillic acid (HVA),

dihydroxyphenylacetic acid (DOPAC) Toxicity: GIT effects (N/V, anorexia), CVS effects

(arrhythmias, hypotension), dyskinesias

Prolonged use: fluctuations in responseo Wearing-off reaction: timing-relatedo On-off phenomenon: characterized by "off" periods of

akinesia with "on"periods of dyskinesia, non-timing-related

Interactions: MAOA inhibitors (hypertensive crisis)CARBIDOPA Peripheral dopa decarboxylase inhibitor

L-dopa metabolism available L-dopa for CNSSINEMET LEVODOPA + CARBIDOPASTALEVO LEVODOPA + CARBIDOPA + ENTACAPONE

DOPAMINE RECEPTOR AGONISTS Monotherapy in younger patients No toxic metabolites incidence of fluctuations Toxicity: GIT effects (N/V, anorexia), dyskinesias, mental disturbancesERGOTDERIVATIVES

BROMOCRIPTINEo D2 agonist

PERGOLIDEo D1 and D2 agonisto "on" periods in fluctuatorso Toxicity: cardiac valvulopathies

NON-ERGOTDERIVATIVES

PRAMIPEXOLEo D3 agonist

ROPINIROLEo D2 agonisto Metabolized by CYP1A2

APOMORPHINEo Pharmacokinetics: SQ route, rapid absorptiono Clinical uses: temporary relief (rescue) from "off"

periods of akinesiao Toxicity: persistent nauseao Pre-therapy: trimethobenzamanide (anti-nausea)

SELECTIVE MONOAMINE OXIDASE B INHIBITORS ("giline") Clinical uses: mild parkinsonism or children with parkinsonism Interactions: L-dopa or tyramine (hypertensive crisis), SSRI or tricyclic

antidepressants (serotonin syndrome) Contraindications: analgesics, OTC cold medicationsSELEGILINE Inhibits MAOA at high doses

on-off or wearing-off fluctuations Metabolites: desmethylselegiline (neuroprotective),

amphetamines (causes adverse effects)RASAGILINE Early symptomatic treatment of Parkinson

CATECHOL-O-METHYLTRANSFERASE INHIBITORS ("capone") Clinical uses: severe parkinsonism or on-off phenomenonENTACAPONE Peripheral COMT inhibitor

No CNS entryTOLCAPONE Central and peripheral COMT inhibitor

Capable of CNS entry Longer-acting, more potent Toxicity: hepatotoxicity ( liver enzymes)

OTHER ANTIPARKINSONIANSAMANTADINE Potentiates dopaminergic functions

Inhibits adenosine effects at adenosine A2A receptors disinhibition of D2 receptor function

iatrogenic dyskinesias Toxicity: mental status changes, livedo reticularis,

peripheral edemaANTICHOLINERGICAGENTS

BENZTROPIN, BIPERIDEN, ORPHENADRINE,PROCYCLIDINE, TRIHEXYPHENIDYLo Muscarinic receptor antagonists in basal gangliao tremors and rigidityo Little effect on bradykinesia



THERAPY FOR NON-MOTOR MANIFESTATIONS OF PARKINSONRIVASTIGMINE, MEMANTINE, DONEPEZIL Cognitive decline (dementia)ANTIDEPRESSANTS, ANXIOLYTICS Affective disordersMODAFINIL Excessive daytime sleepiness

DEPRESSION AND ANXIETY DISORDERS

SELECTIVE SEROTONIN REUPTAKE INHIBITORS Highly selective SERT blockade Little effect on NET and adrenoceptors All protein-bound and highly lipophilic Potent CYP2D6 inhibitors: fluoxetine, paroxetine Clinical uses: generalized anxiety, post-traumatic stress, OCD, panic, bulimia First-line therapy for depression Interactions: MAOI (serotonin syndrome), tricyclic antidepressants (toxicity)CITALOPRAM Significant improvement in anxiety symptomsESCITALOPRAM Most potent SSRIFLUOXETINE Longest half-life

Toxicity: weight lossFLUVOXAMINE Highest bioavailability

Clinical uses: OCD, panic disorder Most drug interactions

PAROXETINE Anticholinergic effects Highest volume of distribution Toxicity: weight gain, cardiac septal defects

SERTRALINE Nausea

SEROTONIN-NOREPINEPHRINE REUPTAKE INHIBITORS Moderately selective SERT and NET blockade serotoninergic and

noradrenergic effects Clinical uses: major depression, generalized anxiety, neuropathies,

fibromyalgia Interactions: MAOI, tricyclic antidepressantsDULOXETINE HepatotoxicityMILNACIPRAN Highest bioavailability

Shortest t1/2VENLAFAXINE Weak NET inhibitor

Lowest protein binding antidepressant Cardiotoxicity

TRICYCLIC ANTIDEPRESSANTS ("triptyline", "ipramine") Oldest antidepressants Mixed/variable SERT and NET blockade Clinical uses: depression unresponsive to other antidepressants, pain

conditions, enuresis, migraine Toxicity: anticholinergic effects, blockade (orthostatic hypotension), H1

antagonism (weight gain, sedation), discontinuation syndrome Interactions: benztropin, diphenhydramine, antihypertensivesAMITRIPTYLINE Prototype tricyclic antidepressantMORE AFFINITY TO SERT CLOMIPRAMINE

o Sexual effects IMIPRAMINE

o Shortest t1/2MORE AFFINITY TO NET DESIPRAMINE, NORTRIPTYLINE

o No active metaboliteso Wide therapeutic window

5-HT2A RECEPTOR ANTAGONISTS ("zodone") Inhibit 5-HT2A receptor Little effect on NET, weak-moderate presynaptic blocker, modest H1

receptor antagonistNEFAZODONE Weak SERT and NET inhibitor

Potent CYP3A4 inhibitor Toxicity: hepatotoxicity Interactions: triazolam and simvastatin ( levels of both)

TRAZODONE Weak selective SERT inhibitor More bioavailable Clinical uses: hypnosis Toxicity: sedation, priapism Interactions: ritonavir and ketoconazole ( trazodone)

Exception to the rule: vilazodone is classified as an SSRI.

TETRACYCLIC AND UNICYCLIC ANTIDEPRESSANTS Least associated with sexual side effects: bupropion, mirtazapineAMOXAPINE NET > SERT inhibition

Shortest t1/2 Toxicity: parkinsonism

BUPROPION NE and DA activity Biphasic elimination Toxicity: agitation, insomnia, anorexia, seizures Interactions: cyclophosphamide, desipramine, MAOI

MAPROTILINE Interactions: fluoxetine (additive anticholinergic andantihistaminic effects)

MIRTAZAPINE NE and 5-HT release H1 receptor antagonist Toxicity: sedation

MONOAMINE OXIDASE INHIBITORS Block MAOA and MAOB Toxicity: orthostatic hypotension, weight gain, amphetamine-like effects,

discontinuation syndrome Interactions: SSRI (serotonin syndrome), tyramine (hypertensive crisis)IRREVERSIBLENONSELECTIVEINHIBITORS

PHENELZINEo Toxicity: sexual side effects, sedation

TRANYLCYPROMINESELECTIVE MAOAINHIBITORS

SELEGILINE

OTHERS ISOCARBOXAZID, MOCLOBEMIDE

PSYCHOTIC DISORDERS

TYPICAL ANTIPSYCHOTICS Primarily block D2 receptors but can also block , muscarinic, H1, and 5-HT2 Clinical uses: schizophrenia, Tourette syndrome Toxicity: parkinsonism (2 to dopamine antagonism)PHENOTHIAZINES("azine")

ALIPHATIC (CHLORPROMAZINE)o 1 = 5-HT2A > D2 > D1o Toxicity: orthostatic hypotension, impaired

ejaculation, lens deposits PIPERIDINES (THIORIDAZINE)

o Toxicity: cardiotoxicity, retinal deposits PIPERAZINES (FLUPHENAZINE)

o Toxicity: risk of tardive dyskinesiaBUTYROPHENONES("peridol")

HALOPERIDOLo High potency among typical antipsychoticso D2 > 1 > D4 > 5-HT2A > D1 > H1o Toxicity: severe extrapyramidal symptoms,

cardiotoxicity (torsades)DIBENZOXAPINES LOXAPINE

THIOXANTHENE THIOTHIXENEo Less risk of tardive dyskinesiaDIHYDROINDOLONES MOLINDONE

ATYPICAL ANTIPSYCHOTICS Clinical uses: manic phase of bipolar affective disorderCLOZAPINE Advantages: suicidal tendencies

Disadvantages: agranulocytosis, seizure threshold,diabetes mellitus

High affinity to M1 anticholinergic effects High affinity to 1 orthostatic hypotension High affinity to 5-HT weight gain



RISPERIDONE Shortest peak time (1-1.5 hours) Moderate affinity to D2 extrapyramidal symptoms

OLANZAPINE Highest volume of distribution (10-20 L/kg)QUETIAPINE High affinity to 1 and H1 sedation

Lowest affinity to M1ZIPRASIDONE Highest protein binding (>99%)

Advantages: least weight gain (low affinity to 5-HT2) Disadvantages: QT prolongation

ARIPIPRAZOLE Advantages: no hyperprolactinemiaMISCELLANEOUS PIMOZIDE

BIPOLAR DISORDERS

MOOD STABILIZERS Inhibit inositol monophosphate (rate-limiting enzyme in inositol recycling)LITHIUM Classic mood stabilizer

Inhibits IP and glycogen synthase kinase-3 Narrow therapeutic window Long-term risk of hypothyroidism Clinical uses: manic phase of bipolar disorder,

schizoaffective disorder, unipolar depression Toxicity: ECG changes, dermatologic effects (acne,

rashes), hypothyroid and hyperparathyroid state,teratogenic effects (septal and valve defects), GITeffects (anorexia, N/V, diarrhea), granulocytosis,cognitive tremors, nephrogenic diabetes insipidus

CARBAMAZEPINE Monotherapeutic alternative to lithium Prophylaxis and treatment of bipolar disorder

VALPROIC ACID Inhibits IP and GSK-3 Anti-manic effect Initial treatment and maintenance of bipolar disorder

GENERAL ANESTHESIA

INHALATION ANESTHETICS Meyer-Overton principle: nonspecific interactions with lipid matrix of

neuronal membrane ion flux neuronal activity Minimal alveolar concentration (MAC)

o MAC potencyo Minimum concentration resulting in immobility in 50% of patients even

with surgical stimulus or incisiono Additive in nature (used in balanced anesthesia)o Elderly or CNS depressants (opioids, sedative-hypnotics) lower MAC

Factors DIRECTLY related to uptakeo Anesthetic concentration in inspired air

anesthetic concentration in gas mixture faster inductiono Pulmonary ventilation

Hyperventilation uptake Factors INVERSELY related to uptake

o Solubility Index: blood-gas partition coefficient Low solubility or blood-gas partition coefficient rapid onset

and recoveryo Pulmonary blood flow

pulmonary blood flow faster induction of anesthesiao Arteriovenous concentration gradient

AV gradient faster equilibration Route of elimination: lungs (primary), liver Toxicity: hepatotoxicity, nephrotoxicity, malignant hyperthermiaLOW-SOLUBILITY NITROUS OXIDE

o Least potent inhaled anesthetic (MAC: 100%)o Lowest brain-blood partition coefficient (1.1)o Not metabolized

DESFLURANEo Highest blood-gas partition coefficient (0.42)o Brain-blood partition coefficient: 1.3o MAC: 6-7%

o Least metabolized among fluranesHALOTHANE High-solubility

Oxidized to trifluoroacetic acid and chlorotrifluoro-ethyl free radical halothane-induced hepatitis

OTHERS SEVOFLURANE, ENFLURANE, METHOXYFLURANEo Metabolized to fluoride ions nephrotoxicity

INTRAVENOUS ANESTHETICS Clinical uses: rapid induction of general anesthesia, ICU sedation,

maintenance of anesthesia Organ level effects: cerebral vasoconstriction CBF and ICP, CMRO2,

cardiorespiratory depressionBARBITURATES THIOPENTAL, METHOHEXITALPROPOFOL Potentiates Cl- current mediated through GABAA

receptor complex Relatively short context-sensitive t1/2 even with

prolonged infusion up to 8 hours DOC for induction and maintenance of anesthesia

BENZODIAZEPINES MIDAZOLAMo Rapid onset, short context-sensitive t1/2o DOC for "conscious" sedationo Preoperative medication (anxiolysis,

anterograde amnesia)ANALGESICS KETAMINE

o Blocks glutamate effects on NMDA receptoro Lowest protein binding among IV anestheticso Clinical uses: dissociative anesthesia (eyes

wide open with slow nystagmic gaze)o Causes psychotomimetic effects (emergence

reactions: vivid dreams, hallucinations)o Minimal respiratory depression

FENTANYLo Opioid analgesico Clinical uses: neurolept anesthesia (combined

with droperidol and nitrous oxide)o Toxicity: chest wall rigidity

ETOMIDATE GABA potentiator Short context-sensitive t1/2 Minimal hemodynamic effects Toxicity: adrenocortical suppression (inhibits 11-

hydroxylase)DEXMEDETOMIDINE Highly-selective 2 agonist

Stimulates 2 receptors in locus ceruleushypnosis

LOCAL AND REGIONAL ANESTHESIA

LOCAL ANESTHETICS Goal: localized analgesia Block voltage-gated Na+ channels (in active or inactive state but not in

rested state) but can also act on other ion channels (K+, Ca2+), enzymes, andreceptors (NMDA, G protein, 5-HT3, NK1)

Structure: lipophilic (aromatic) ring + intermediate chain (ester or amide) +ionizable group (tertiary amine)

Non-ionized (non-protonated) form: biologically active form Routes: parenteral, topical (transdermal, transmucosal) Pharmacokinetics

o More vascular site rapid absorptiono Vasoconstrictors (epinephrine) blood flow less systemic

absorption and toxic effects, better uptakeo Smaller and more lipophilic local anesthetics faster interactiono Metabolism: plasma butyrylcholinesterase (esters), hepatic amidase

(amides) Factors affecting local block

o Preferential blockade of small-diameter fibers (type B and C),myelinated fast-firing fibers (type C) over large-diameter (type A) ormotor fibers



o Motor fibers blocked first in large mixed nerve trunkso Sensory fibers blocked first in extremities

Clinical uses: local infiltration, blockade of peripheral nerves, regionalanesthesia (Bier block, short surgical procedures)

Toxicity: CNS effects (dizziness, sensory disturbances, nystagmus),neurotoxicity, tachyphylaxis, allergic reaction (2 to PABA from esters)

AMINOESTERS(one i)

COCAINEo First local anesthetico Restricted to topical anesthesia of EENTo Vasoconstrictory property bleedingo Toxicity: adrenergic effects from NET blockade

(vasoconstriction, hypertension, arrhythmia) BENZOCAINE CHLOROPROCAINE

AMINOAMIDES(two I's)

ARTICAINEo Dental anesthetic

BUPIVACAINEo DOC for regional spinal anesthesia, also used in

epidural infusions for labor analgesia and post-operative pain control

o Toxicity: cardiotoxicity (antidote: lipid emulsion) LIDOCAINE

o Intermediate-acting anesthetico Reference standard agent of local anestheticso Toxicity: transient neurologic syndrome (sudden

transient pain or dysthesia) PRILOCAINE

o Spinal anesthetico Highest clearance systemic toxicityo Metabolized to o-toluidinemethemoglobinemia

ROPIVACAINEo Same clinical uses as bupivacaine but less

cardiotoxic

BIOLOGIC TOXINSMARINETOXINS

TETRODOTOXIN (puffer fish), SAXITOXIN (dinoflagellates)o Bind externally to "ready" state of Na+ channels

conductionOTHERS BATRACHOTOXIN (frogs), CIGUATOXIN (moray eel)

o Bind internally to receptors in Na+ channel Na+ influx persistent depolarization

SKELETAL MUSCLE RELAXANTS

NONDEPOLARIZING NEUROMUSCULAR BLOCKERS Reversed by acetylcholinesterase inhibitors (neostigmine, pyridostigmine)ISOQUINOLINEDERIVATIVES("curium")

d-TUBOCURARINEo Prototype neuromuscular blockero Paralyzes small muscles before large muscles

(abdominal, paraspinous, diaphragm) ATRACURIUM, CISATRACURIUM

o Spontaneous chemodegradation (Hofmannelimination) into laudanosine and quarternary acid

MIVACURIUMo Shortest-acting nondepolarizing blockero Competitively inhibits acetylcholine at NM receptoro Blocks prejunctional Na+ channelso Rapidly cleared by plasma cholinesterase

STEROIDDERIVATIVES("curonium")

PANCURONIUMo Long-actingo Most potent nondepolarizing blocker

INTERMEDIATE-ACTING (ROCURONIUM, VECURONIUM)o ROCURONIUM: fastest-onset nondepolarizing

blocker (60-120 seconds), reversed by sugammadex

DEPOLARIZING NEUROMUSCULAR BLOCKERSSUXAMETHONIUM(SUCCINYLCHOLINE)

2 acetylcholine molecules linked together Extremely short duration of action (5-10 minutes) Hydrolyzed by plasma cholinesterase Pharmacodynamics

o Phase I block: fasciculation and flaccidparalysis, augmented by cholinesteraseinhibitors

o Early phase II block: desensitizationo Late phase II block: reversed by cholinesterase

inhibitors DOC for procedures requiring short-term

relaxation (intubation, electroconvulsive therapy) Toxicity: malignant hyperthermia, cardiac effects,

hyperkalemia, IOP, GI regurgitation, myalgias

SPASMOLYTICSDIAZEPAM tonic output of -motor neuronsBACLOFEN GABA analog

Activates GABAB receptors K+ conductancehyperpolarization presynaptic inhibition

Inhibits release of excitatory neurotransmitters in CNS andsubstance P in spinal cord (analgesic effect)

TIZANIDINE 2 adrenoceptor agonist (similar to clonidine but has lessantihypertensive property)

Reinforces presynaptic and postsynaptic inhibition inspinal cord

DANTROLENE Binds to ryanodine receptor RyR1 (in skeletal muscle) Ca2+ release from SER

DOC for malignant hyperthermiaOTHERS PROGABIDE

o GABAA and GABAB agonist GLYCINE (endogenous inhibitory neurotransmitter) IDROCILAMIDE, RILUZOLE

o Clinical uses: amyotrophic lateral sclerosis BOTULINUM TOXIN

o Clinical uses: ophthalmology, relief of local spasm,aging-associated wrinkles, generalized spasm ofcerebral palsy

ANALGESIA AND INFLAMMATION

OPIOIDS Organ level effects: analgesia (, , ), euphoria (), sedation and

respiratory depression (), cough suppression, miosis, truncal rigidity, N/V,hyperthermia () or hypothermia (), bradycardia (except in meperidine),hypotension, constipation, urinary retention, peripheral effects (prolongedlabor, neuroendocrine effects, pruritus, lymphocyte proliferation)

ENDOGENOUSPEPTIDES

ENDORPHINS ( AGONISTS)o Precursor: preproopiomelanocortin (POMC)o Present in CNSo Pain modulation

ENKEPHALINS ( AGONISTS)o Precursor: preproenkephalin (PPE-A)

DYNORPHINS ( AGONISTS)o Precursor: leucine-enkephalin (PPE-B)o DYNORPHIN A: found in dorsal horn

OPIOID AGONISTS Primarily act on the opioid receptor Chemical classifications

o PHENANTHRENES ("phine", "codeine", "codone"): morphine, codeine,nalbuphine, buprenorphine

o PHENYLHEPTYLAMINES: methadone, propoxypheneo PHENYLPIPERIDINES: meperidine, fentanyl, diphenoxylate, loperamideo MORPHINANS ("orphanol"): levorphanol, butorphanolo BENZOMORPHANS: pentazocine



o MISCELLANEOUS ("adol"): tramadol, tapentadol Routes: rectal suppositories, transdermal, intranasal, transmucosal,

parenteral (patient-controlled analgesia) Clinical uses: analgesia, acute pulmonary edema, cough, diarrhea,

shivering, preoperative anesthesia Toxicity: tolerance (2 to repeated doses), dependence (2 to withdrawal),

hyperalgesia (2 to persistent opioid administration) Interactions: sedative-hypnotics (CNS and respiratory depression),

antipsychotics (sedation), MAOI (hyperpyrexic coma)STRONGAGONISTS

MORPHINEo Clinical uses: moderate to severe pain

MEPERIDINEo Only opioid analgesic with antimuscarinic activity tachycardia

METHADONEo Blocks NMDA receptors and monoaminergic uptake

transporters (DAT, NET, SERT)o Clinical uses: difficult-to-treat pain (neuropathic or

cancer pain)o DOC for opioid dependenceo Detoxification of opioids and heroin

FENTANYLo SUFENTANIL: more potento ALFENTANIL: less potent, rapid-onset, short-actingo REMIFENTANIL: short t1/2

MILD TOMODERATEAGONISTS

CODEINE, OXYCODONE, DIHYDROCODEINE,HYDROCODONEo Combined in formulations containing aspirin,

acetaminophen, and others DIPHENOXYLATE, LOPERAMIDE

PARTIALOPIOIDAGONISTS-ANTAGONISTS

NALBUPHINEo Strong agonisto antagonist

BUPRENORPHINEo High affinity but low intrinsic activity at receptoro antagonisto Binds to orphanin receptor ORL1o Alternative to methadone for detoxification and

maintenance of opioid and heroin abuse PENTAZOCIN

ANTITUSSIVES DEXTROMETHORPHANo Levorphanol derivativeo Strong opioid agonist

LEVOPROPOXYPHENEOTHERS TRAMADOL

o Centrally-acting analgesic (SERT blockade)o Weak agonisto Toxicity: seizures, nausea, dizziness

TAPENTADOLo Modest affinity to receptoro Significant NET blockade

OPIOID ANTAGONISTS Morphine derivatives with bulkier substituent at N17 position Reverses opioid effects within 1-3 minutes Inert, no tolerance or withdrawal Toxicity: abstinence syndromeNALOXONE Short-acting (1-2 hours)

Clinical uses: acute opioid overdoseNALTREXONE Blocks effects of injected heroin

Maintenance of addictionNALMEFENE Parenteral naltrexone derivativeMETHYLNALTREXONE Opioid-induced constipationALVIMOPAN Post-bowel resection ileus

NOVEL ANALGESICSLIDOCAINE,MEXILETINE

Block tetrodotoxin-resistant voltage-gated Na+ channels

GABAANALOGS

GABAPENTIN, PREGABALIN

ZICONOTIDE Blocks voltage-gated N-type Ca2+ channels

NONSTEROIDAL ANTI-INFLAMMATORY DRUGS sensitivity of blood vessels to bradykinin and histamine, lymphokines,

reverse vasodilation, inhibit platelet aggregation Newer NSAID

o Anti-inflammatory, antipyretic, analgesico Less GI irritation

Pharmacokinetics: enterohepatic circulation, renal elimination Found in synovial fluid Toxicity: tinnitus, abdominal pain, GI ulcers, hepatotoxicity (abnormal liver

function tests), asthma, pruritus, nephrotoxicity (renal insufficiency) Greatest toxicity: indomethacin, tolmetin Least toxicity: salicylates, ibuprofenNONSELECTIVECOXINHIBITORS

ACETYLSALICYLATE (ASPIRIN)o Irreversibly inhibits COX inhibits platelet

aggregationo incidence in TIA, unstable angina, coronary

thrombosis with MI or post-CABGo Valuable in preeclampsia-eclampsiao Toxicity: Reye's syndrome in children (fatal

fulminant hepatitis with cerebral edema) NON-ACETYLATED SALICYLATES (MAGNESIUM AND

SODIUM SALICYLATE, SALICYL SALICYLATE)o Alternative to aspirin if with renal insufficiency

SELECTIVECOX-2INHIBITORS("coxib")

CELECOXIBo Alternative to aspirin in patients with high risk of GI

bleedingo Interactions: sulfonamides (rashes)

ROFECOXIB, VALDECOXIBo Withdrawn due to CV thrombotic events

MELOXICAMo "Preferentially" selective but not highly selective

COX-2 inhibitor NIMESULIDE

o Relatively selective COX-2 inhibitoro Analgesic and antipyretic properties

OTHERS (ETORICOXIB, PARECOXIB)NONSELECTIVENSAIDS

DIFLUNISALo No CNS entry (no antipyretic effect)o Clinical uses: rheumatoid arthritis, cancer pain with

bone mets, pain post-third molar surgery FLURBIPROFEN

o Clinical uses: EENT (inhibits intraoperative miosis,perioperative analgesia in minor ear, nose, andneck surgeries)

o Toxicity: cogwheel rigidity IBUPROFEN (PHENYLPROPIONIC ACID)

o DOC for closure of patent ductus arteriosus inpreterm infants

INDOMETHACINo Inhibits phospholipase A and Co neutrophil migration and lymphocyte

proliferationo Clinical uses: patent ductus arteriosus closure,

initial treatment of gout, ankylosing spondylitis,ophthalmic uses, postlaminectomy syndrome

o Toxicity: pancreatitis KETOPROFEN

o Cyclooxygenase and lipooxygenase inhibitor KETOROLAC

o Substitute to morphine in mild to moderate post-



operative paino opioid requirement

MEFENAMIC ACIDo Relief of mild-moderate pain in patients 14 y/oo Clinical uses: primary dysmenorrhea, menorrhagiao Contraindications: status post-CABG, GI ulcers,

renal disease NABUMETONE

o Lone nonacid NSAID NAPROXEN

o DOC for tumor fever PHENACETIN

o Withdrawn due to nephrotoxicity (acute tubularnecrosis, papilary necrosis)

PHENYLBUTAZONEo Withdrawn due to aplastic anemia and

agranulocytosis PIROXICAM

o Inhibits PMNL migration and lymphocyte functiono oxygen radicals

SULINDACo Clinical uses: rheumatic disease, familial

adenomatous polyposis, risk of cancero Toxicity: Stevens-Johnson syndrome, toxic

epidermal necrolysis TOLMETIN

o Ineffective in gout OTHERS (DICLOFENAC, ETODOLAC, OXAPROZIN)

DISEASE-MODIFYING ANTI-RHEUMATIC DRUGSMETHOTREXATE Inhibits aminoimidazole carboxamide (AICAR)

transformylase and thymidylate synthetase First-line therapy for rheumatoid arthritis Clinical uses: arthritis, psoriasis, ankylosing

spondylitis, polymyositis, dermatomyositis,Wegener's granulomatosis, giant cell arteritis,SLE, vasculitis

Toxicity: nausea, mucosal ulcersGOLD SALTS AURANOFIN, AUROTHIOGLUCOSE

o Inhibits Schwartzmann phenomenonIMMUNOSUPPRESANTS AZATHIOPRINE

CHLOROQUINE CYCLOPHOSPHAMIDE CYCLOSPORINE LEFLUNOMIDE MYCOPHENOLATE MOFETIL SULFASALAZINE

o IgA and IgM rheumatoid factorsGLUCOCORTICOIDS Management of extra-articular manifestations

of rheumatoid arthritis (pericarditis, eyeinvolvement, exacerbation)

Clinical uses: SLE, vasculitis, giant cell arteritis,Wegener's granulomatosis, sarcoidosis, gout

ANALGESICS ACETAMINOPHENo Phenacetin derivativeo Weak nonselective COX inhibitoro No significant anti-inflammatory activityo Metabolized to N-acetyl-p-benzoquinone

(hepatotoxic and nephrotoxic)o Clinical uses: mild analgesiao Toxicity: Reye's syndrome, severe

hepatotoxicity with centrilobular necrosis(>15 g paracetamol)

o Antidote: N-acetylcysteine

BIOLOGICAL ANTI-RHEUMATIC DRUGS Toxicity: risk of bacterial infections (e.g. pulmonary tuberculosis) and

lymphomasANTI-TNF ADALIMUMAB

o Effective as monotherapy or in combination withmethotrexate and other DMARD

INFLIXIMABo Concurrent therapy with methotrexateo Contraindications: multiple sclerosis

ETANERCEPTo Monotherapyo Clinical uses: rheumatoid arthritiso risk of latent TB activation than other anti-TNF

OTHERS ABATACEPTo Inhibits T cell activation

RITUXIMABo Anti-CD20o Combined with methotrexateo Clinical uses: rheumatoid arthritis refractory to anti-TNFo Toxicity: infusion reactions (pre-treat with IV

glucocorticoids) TOCILIZUMAB

o Anti-IL-6o Moderate to severe rheumatoid arthritiso Same clinical uses as rituximab

ANTI-GOUTCOLCHICINE Binds to intracellular protein tubulinmicrotubule

polymerization Clinical uses: relief of pain and inflammation of gouty

arthritis in 12-24 hours, prophylaxis of recurrentepisodes of gouty arthritis

Overdose: burning throat pain, bloody diarrheaANALGESICS Inhibit prostaglandin synthase and urate crystal

phagocytosis INDOMETHACIN OXAPROZIN

o Very long t1/2 (50-60 hours)o renal excretion of uric acido Contraindications: renal stones

URICOSURICAGENTS

PROBENECID, SULFINPYRAZONEo Organic acidso Act at anion transport sites of renal tubuleso urate pool sizeo Reabsorbs tophaceous urate depositso Clinical uses: tophaceous gout, increasingly

frequent gouty attackso Toxicity: GI irritation (in sulfinpyrazone),

nephrotic syndrome (in probenecid), aplasticanemia (in both)

ALLOPURINOL Isomer of hypoxanthine Purine inhibitor of xanthine oxidase uric acid Combined with colchicine or NSAID Clinical uses: long-term or lifelong treatment DOC for intercritical period (between acute attacks) Toxicity: N/V, diarrhea, allergic reaction Interactions: mercaptopurine, probenecid

FEBUXOSTAT Nonpurine inhibitor of xanthine oxidase Clinical uses: chronic gout, prophylaxis of gout flares

(combined with colchicine or NSAID pre-therapy)PEGLOTICASE Recombinant mammalian uricase

Converts uric acid to allantoin Clinical uses: refractory chronic gout

GLUCOCORTICOIDS Clinical uses: severe symptomatic goutIL-1 INHIBITORS ANAKINRA, CANAKINUMAB, RILONACEPT



TRADITIONAL MEDICINES

BOTANICALSEchinaceapurpurea

Constituents: flavonoids, water-soluble polysaccharides andconjugates

Uses: immunomodulatory (colds, respiratory infections),anti-inflammatory, antimicrobial

Toxicity: flu-like symptoms, unpleasant taste, GIT upset Interactions: immunodeficiency disorders, tuberculosis,

alcohol-based medications (disulfiram-like reaction)Ginkgobiloba

Constituents: flavone glycosides, terpenoids Pharmacologic effects: vascular effects ( blood flow,

blood viscosity, vasodilation), antioxidant, CNS effects(dementia of Alzheimer type)

Miscellaneous uses: bronchoconstriction, short-termmemory, erectile dysfunction, hearing disturbances, maculardegeneration

Hypericumperforatum

St. John's wort Constituents: hypericin Uses: antidepressant, antiviral, anticarcinogenic Toxicity: photosensitization, mania Interactions: antidepressants

Serenoarepens,Sabalserrulata

Saw palmetto Constituents: phytosterol, aliphatic alcohols, polyprenic

compounds, flavonoids Uses: benign prostatic hyperplasia Toxicity: GIT upset, hypertension, libido, abdominal pain,

back pain, urinary retention, headache No drug interaction reported

PURIFIED NUTRITIONAL SUPPLEMENTSCOENZYME Q10 CoQ, CoQ10, uboquinone

Potent antioxidant found in mitochondria Clinical uses: cardiovascular diseases (hypertension,

heart failure, ischemic heart disease), prevention ofstatin-induced myopathy

Interactions: warfarin (CoQ10: similar to vitamin K)GLUCOSAMINE Derived from crustaceans (e.g. crabs)

Substrate for articular cartilage production Facilitates glycosaminoglycans (GAG) synthesis Clinical uses: knee osteoarthritis Interactions: warfarin ( INR and bleeding)

MELATONIN N-acetyl-5-methoxytryptamine (serotonin derivative) Produced by the pineal gland (suppressed in daylight) Regulates sleep-wake cycle Inhibits reproductive function ( ovulation in females

and sperm quality in males) Clinical uses: jetlag, insomnia Toxicity: day-after drowsiness, fatigue, dizziness,

headache, irritability Interactions: nifedipine ( BP)

GLUTATHIONE Major endogenous antioxidant Neutralizes free radicals and reactive oxygen species Maintains exogenous antioxidants (vitamin C and E) in

their reduced (active) forms Clinical uses: prevents toxic effects of chemotherapy,

aging, alcoholism, cancer, heart and liver disease,Alzheimer's and Parkinson's disease

Toxicity: rashes, stomachache, thyroid disease, fataleffects (renal failure, SJS, toxic epidermal necrolysis)

Contraindications: allergy to milk protein, organtransplant

PAPAYA SEEDS Uses: anti-inflammatory, anti-parasitic (ringworminfections), analgesic (stomachache)

Toxicity: allergic reaction (skin irritation)

HERBAL MEDICINESAKAPULKO(Cassia alata)

Constituents: saponins (laxative) Uses: antifungal, ringworms, scabies, eczema,

stomatitis, expectorant, anti-asthma, diuretic, laxative Toxicity: GIT effects (N/V, diarrhea)

AMPALAYA(Momordicacharantia)

Constituents: flavonoids, alkaloids (antihyperglycemic) Uses: antihyperglycemic, antirheumatic, antiseptic,

antihelminthic, immunomodulatory Toxicity: abortifacient

ATIS (Anonasquamosa)

Uses: gastrointestinal (dysentery, diarrhea), colds,fever, antirheumatic, dizziness and fainting,antipediculosis

Toxicity: blindness (seeds), abortion (paste)BANABA(Lagerstromiaspeciosa)

Queen's flower, crepe myrtle Constituents: corosolic acid (insulin-like effect) Uses: antihyperglycemic, obesity, blood pressure Cautions: antidiabetics

BAWANG (Alliumsativum)

Constituents: alliin Uses: antihypertensive, antifungal, fibrinolytic Toxicity: nausea, hypotension, allergy, bleeding Cautions: anticoagulants

BAYABAS(Psidiumguajava)

Uses: wound disinfectant, antiseptic gargle,astringent, vaginal wash

GUMAMELA(Hibiscus rosa-sinensis)

China rose or hibiscus Uses: expectorant, diuretic, emollient, anti-infective

and anti-inflammatory (boils, swelling, abscesses,mumps), antipyretic, sedative

Toxicity: abortifacient in large dosesLAGUNDI (Vitexnegundo)

Constituents: chrysoplenol D (antihistamine, musclerelaxant)

Uses: respiratory uses (asthma, pharyngitis, cough,colds, flu, bronchopulmonary disorders), boils,symptomatic management of chicken pox,antihelminthic

LUYA (Zingiberofficinale)

Uses: analgesic (rheumatic and muscle pain,toothache), alleviates sore throat and colds, GI uses(tympanism, flatulence, intestinal worms, diarrhea, gaspains, dyspepsia), serum cholesterol, PTB treatment

Contraindications: pregnancy (testosterone inhibition)MABOLO(Diospyrosblancoi)

Uses: gastrointestinal uses (stomach pains, diarrhea,dysentery), cardiovascular uses (heart disease,hypertension), cough, fever, skin ailments, diabetes

MALUNGGAY(Moringaoleifera)

Horse radish Uses: nutrient supplement (source of Ca2+, iron,

vitamin C, phosphorus), antioxidant, antidiabetic,antihypertensive, analgesic (rheumatic pain, headache,migraine), purgative, antifungal

MAKABUHAY(Tinosporarumphii Boerl)

Heavenly elixir Uses: antimalarial, wound cleansing, diarrhea,

indigestion, scabiesNIYOG-NIYOGAN(Quisqualisindica)

Chinese honey suckle Uses: antiparasitic

OREGANO(Origanumvulgare)

Winter marjoram Constituents: antioxidants Uses: respiratory uses (cough, colds, asthma), anti-

aging, arthritis, GI uses (upset stomach, dyspepsia,indigestion), UTI, dermal uses (heals wounds, insectbites or stings)

PANDAN(Pandanustectorius)

Fragrant screw pine Uses: analgesic, antiseptic and antibacterial

PANSIT-PANSITAN(Peperomiapellucida)

Ulasimang-bato Uses: arthritis, gout, skin diseases (boils, abscesses,

acne), headache, abdominal pain, kidney problems



SABILA OR ALOEVERA(Barbadensismiller)

Uses: skin conditions (acne, psoriasis, bites, minorburns), analgesic, antihypertensive, anti-aging,diabetes, eradicates intestinal bacteria and parasites,helps prevent cancer and tumors

SALUYOT(Corchoruscapsularis)

Constituents: Ca2+, phosphorus, iron, K+, vitamin A,thiamine, riboflavin, ascorbic acid, fibers

Uses: antioxidant, reduce wrinkles, anti-inflammatorySAMBONG(Blumeabalsamifera)

Uses: diuretic, kidney stones, hypertension,rheumatism, colds, fever, GI uses (diarrhea, stomachpains, dysentery), worms, boils, sore throat

Toxicity: hypokalemia (take with bananas or potatoes)SILYMARINE ORMILK THISTLE(Silybummarianum)

Constituents: silymarin (polyphenolic flavonoid withantioxidant properties)

Uses: hepatoprotection (improves liver function incirrhosis and chronic hepatitis), Amanita phalloidespoisoning, antidiabetic, anticholesterol, reducesgrowth of cancer cells (breast, prostate, cervix, skin),antioxidant

Nontoxic (no overdose symptoms)TANGLAD(Andropogoncitratus DC)

Lemon grass Uses: cleansing, stomach discomfort, antibacterial and

antifungal, antiuricemic, detoxifierTSAANG- GUBAT(Ehretiamicrophylla)

Forest or wild tea Uses: GI uses (gastroenteritis, intestinal motility,

dysentery, diarrhea or LBM, mouth gargle), body washYERBA BUENA(Menthacardifolia)

Uses: analgesic (headache, stomachache, rheumatic orarthritic pain, menstrual and gas pains), dental uses(swollen gums, toothache), nausea, fainting, pruritus

PHARMACOLOGY TRANSCRIPTION TEAM

Martin Joseph A. Calaunan@MARTINidazoleTransmaster/Editor

Nikka Mae A. Larcia@NIKKArdipine

Nina Carmela P. Pescante@PESKYcide

Marc Christopher F. Barbin@phenoBARBital

Clarice B. Palma@CLArithromycin

Ron Michael N. Olaguera@interfeRON

Documents

Baby-Katzung-Second-Shifting-Reviewer.pdf