AdrenergicsDrug Receptor Non-Selective Agonists Target Actionincrease HR (+), increase contractility, increase CO, vasoconstriction of skin, renal & splancnics, vasodilation of skeletal muscle, (-) diastolic, (++) systolic = MAP increases(+) bronchial SM relaxation, (+) mucocilliary clearance

Therapeutic Uses

Contraindications

Pharmacokinetics

CVS BP Resp. GI

Epinephrine

1, 2, 1, 2

Urinary

Eye CNS

Others

Serious acute hypersensitivity rxns SM relaxation (direct + indirect), decreased (anaphylaxis, angioedema), prevention of peristalsis, contraction of sphincters surgical bleeding , reduced absorption of local anesthetics, relaxation of detruser, contraction of laryngotracheobronchitis, asthma, openinternal sphincters & trigone, relaxation of angle glaucoma (uveosclera orute & pregnant uterus alpha-2), Cardiopulmonary resuscitiation in mydriasis (radial muscle), (-) production of cardiac arrest (increased VR from alpha-1 aqueous humor (increased outflow vasoconstriction) uveoscleral route) Indirect effects ONLY. (restlessness, aprehension) renin secretion, (-) of mast cell degranulation, platelet aggregation, (-) of insulin secretion, (+) glucagon secretion, (+) glycogenolysis & gluconeogenesis direct effects sililar to epinephrine except decrease in HR & NC/(-) in CO (reflexes from increased MAP). Vasoconstriction in all Hypotension, vasodilatory shock (spinal beds except pulmonary & coronary which trauma, spinal anesthesia, sepsis), reduce are under autoregulatory control. absorption of local anesthetics (++) diastolic, (++) systolic = MAP increases (++)

Hypertension, hyperthyroidism, angina, heart disease including myocardial infarction , cardiac arrhythmias, cerebrovascular disease, shock (except anaphylactic), diabetes mellitus

No entry into CNS. No oral bioavailability. Metabolized via MAO & COMT in the liver. Fast acting.

Norepinephrine

CVS 1, 2, 1 BP

Similar to epinephrine but much less frequent. Necrosis & sloughing could occur at site of IV or IM injection.

Similar to epinephrine

Alpha Agonists Phenylephrine Naphazoline Xylometazoline Clonadine Apraclonidine Tizanidine Granfacine Granabenz Moxonidine Rilmenidine Beta AgonistsCVS (++) HR from reflex tachy & -1; decrease After cardiac surgery where contractility & in MAP (vasodilation); other direct effects = HR are low yet TPR is high. Torsade de epi. pointes (polymorphic ventricular tachycardia). Also used in beta-blocker less hyperglycemia (no 2 inhibition of overdose. insulin release) (+) ionotropic effect, (+) HR only slightly Acute CHF or cardiogenic shock. Restlessness (especially in chldren), known hypersensitivity, cardiac arrythmias, coronary artery disease, hyperthyroidism, pheochromocytoma, siezure disorders, Diabetes mellitus, elderly. Exertional angina (from tachycardia) ; tremor (Ca++ sequestration) Administered IV infusion. As aresol actions are very short lastingl A synthesized catecholamine Synthesized catecholamine. 1 CVS (-) HR (reflex), (+) BP; usually N/C in CO because increased VR cancells out the (-) HR Low/Int. doses: hypotension (decreased SANS outflow reticulospinal tract) Postural hypotension, nasal decongestant (most common use); mydriatic, local vasconstriction (e.g. epistaxis) hypertension, cardiac disease, cerebrovascular disease, hyperthyroidism, urinary retention. Can get rebound congestion (autoregulatory function), photophobia. Longer duration (not metabolized by COMT)

CVS 2, (clonadine: +imidazoline CNS Others

Clonidine: used in neuropsychiatric disorders (e.g. Tourettes),withdrawls, and sedetive effect pre-surgery. Apraclonadine seditive effects, analgesic, spasmolytic, used in Glaucoma. Uses in neuropathic craving reduction in addicts (2 in brain) pain and 2nd choice drugs for hypertension decreased intraocular pressure (decreased production of aqueous humor)

Hypertensive crisis when withdrawn. Sedation, dwosiness, xerostomia.

At very high doses can activate alpha-1 receptors.

imidazoline

Isoproterenol

1, 2, 3 Others

Dobutamine Albuterol Salmeterol Formoterol Terbutaline

1 (high doses: 2)

CVS

2

Resp.

Bronchodilation, enhanced mucocilliary clearence, (-) release of histamine & LT's, (-) vascular permeability,

Asthma, COPD, hyperkalemia (w/ insulin), premature labor (Ritodrine also used)

Does NOT cross BBB. Given as inhalent. Albuterol: intermediate lasting. Salmeterol & Formoterol: long lasting.

D-Receptor Agonists

Dopamine

D1 (ID=D1,1, NE rel.) (HD=above + 1, D2)

CVS

Low Doses: vasodilation ----> (+) BF to renals, splanchnic, coronary beds; (-) Na+ reabsoption in PT Intermediate Doses:(+) SV & HR; N/C TPR High doses: (+) TPR w/ a (-) BF to renals, splanchnics Similar to amphetamines BUT much less pronounced Similar to Epinephrine BUT, much less potency, longer duration and with oral bioavailability displacement of NE from nerve terminal increasing sympathetic tone.

Cardiogenic, neurogenic, septic shock especially if poor renal perfusion contributes

IV administration, not active via oral route.

Mixed Acting AgonistsCentral

Ephedrine

1, 2, 1, 2 + NE release

Peripheral

Nasal decongestant. bronchospasm, hypotension

Restlessness, insomnia, urinary retention, cardiac arrythmias taken up by adrenergic neurons and converted to Octopamine (weak adrenergic agonist). Metabolized by MAO. Methyldopa taken up by adrenergic neurons and transformed to methlynorepinephrine central effects shorter lasting but more intense than amphetamines

Tyramine

"false NT"

Used for diagnostic purposes and to localize lesion of sympathetic nerves b/c false NT only produced with intact neuron.

MAO inhibitors (anti-depressents) which could cause lethal hypertensive crisis

Methyldopa Cocaine Amphetamine (methylphenadat e) (dextroamphetam ine)

"false NT" (2 agonist)

Same final action as clonadine

sometimes used as antihypertensive

N/A

(-) reuptake of NE, 5HT, DA

local anesthetic effect

N/A

(+) release of NE, 5HT, DA in periphery + CNS (main); causing euphoria, elevation of mood, and similar peripheral effects as NE

ADD/ADHD, narcolepsy, weight reduction

AntiadrenergicsDrug Receptor Nonselective Antagonists Labetalol Carvedilol1, 1 (Pa), 2 (Pa) 1, 1, 2

Target

ActionLabetalol: (-) TPR, minimal change in HR & CO at rest (Pa activity + reflex tachycardia) ; other effects similar to other beta blockers arterial & venous vasodilation; (+) HR; response to NE is diminished. Effect of Epi. is reversed.

Therapeutic Useslocal anesthetic

Contraindications

Pharmacokinetics

CVS

No anesthetic activity

Nonselective Alpha BlockersCVS

Phenoxybenzami ne

1, 2 (irreversible) Endocrine

Preoperative management of disease (i.e. hypertensive crisis during manipulation of tumor tissue). Sympathetic dystrophy or causalgia. Hypertensive emergencies (+) insulin release, enhanced release of (pheochromocytoma) NE (alpha-2)

Urge incontinence, exertional angina (induced hypotention), all disorders leading to postural hypotension (e.g. hypovolemia, Addison's, systemic mastocytosis, mitral valve prolapse, Riley-Day syndrome, Shy-Drager)

Distributes to ALL tissues. Long lasting (irreversible binding), can be given up to a week before surgery for preoperative care.

Selective Alpha BlockersPDE Can inhibit at high doses. arterial venous vasodilation, N/C in HR Effect of NE is diminished. Effect of Epi. is reversed (unopposed 2). relaxation of trigone & sphincter of bladder

Prazosin Tamsulosin Terazosin Doxazosin Yohimbine

CVS 1 (High doses: (-) PDE) BP Urinary 2

Benign prostatic hypertrophy, overflow incontinence (e.g. urethral stricture, sphincter dyssnergia, diabetic neuropathy); Raynaud's disease, Prozasin used in hypertensive emergencies (e.g. clonidine withdraw, pheochromocytoma), heart failure sexual dysfunction

Same as non selective antagonists.

Distributes to ALL tissues. Tamsulosin shows high affinity for 1 in the prostate.

Nonselective Beta BlockersHeart Abrupt discontinuation (precipitate MI), Three main clinical uses (1) asthma, bronchitis, COPD, Hypertension, (2) cardiac bradyarrhythmias, diabetes mellitus arrhythmias, (3), exertional angina. (mask symptoms of hypoglycemia), TPR (-) initially but levels out in normal Other uses include glaucoma (Timolol), vasospastic angina, acute cardiac failure, individuals; BP is (-). local anesthetic (propranolol, pindolol), peripheral occlusive vascular disease hyperthyroidism, following acute MI, (unopposed alpha stimulation), serious bronchoconstriction hypertrophic cardiomyopathy, tremor, hepatic disease (if high first pass effect), pheochromocytoma, migraine headache (-) production of aqueous humor depression (CNS effects), elderly prophylaxis, esophageal varices (-) renin release, (-) lypolysis & (hypothermia), insomnia & prevention, anxiety & panic attack glycogenolysis, (+) VLDL, (-) HDL, nightmares. Sexual dysfunction. reduced catecholamine induced tremor, (-) K+ uptake in skeletal muscle HR, conduction, contractility all (-); CO (-), subendocardial perfusion (+) from longer diastolic time, O2 demand is decreased = increased efficiency;

Propranolol Pindolol Timolol Sotalol

1, 2 (Pindolol=Pa)

Vessels & BP Resp. Eyes Other

Sotalol can block K+ channels. Can cross BBB.

Selective Beta Blockers Atenolol Metoprolol Esmolol Butoxamine1 See above and adjust for receptor differences Metoprolol & Atenolol have local anesthetic effect. Esmolol used in cardiac emergencies b/c short half life. Esmolol has short half-life (10m). Atenolol does NOT cross BBB.

See above

2

Indirect Acting Antagonists MetyrosineN/A Tyrosine hydroxlase Inhibition pre-operative preperation in pt's with postural hypotension, diarrhea, sedation pheochromocytoma

Drug Receptor Target Muscarinic Agonists (Choline Esters)Heart Vessels

Action

Cholinergics Therapeutic Uses

Contraindications

Pharmacokinetics

vasodilation (+) peristalsis, relaxation of sphincters (direct: stim. peptidergic ganglionic neurons, indirect: NO) ; contraction of LES bronchoconstriction, increased secretions (+) peristalsis, contraction of detruser, erection, relaxation of trigone contraction of cilliary muscle (increased outflow of aqueous humor); pupillary constriction; cyclospasm (+) sweat glands arousal, excitation, headache, tremors same as Ach

GI

Acetylcholine Carbechol Bethanechol

M1, M2, M3

(+ N = Carbechol & Ach)

Lung Urinary

Antimuscarinic poisening; Carbechol used for Open Angle Glaucoma. Xerostomia, postoperative nonobstructive illeus, neurogenic bladder (Bethanechol)

Given locally = iritis, cataract, retinal detachment. Given systemically = asthma, cardiac arrhythmias, coronary artery disease, hypotension, peptic ulcer disease, GI obstruction, irritable bowel syndrome, peritonitis, urinary tract obstruction, hyperthyroidism.

AchE rapidly hydrolyzes Ach but does not work on Bethanechol & Carbechol. All work only in periphery (quaternary amines)

Eye

Skin

Muscarinic Agonists (Natural Alkaloids) Muscarine PilocarpineM1, M2, M3 central peripheral Xerstomia, glaucoma (pilocarpine) similar to choline esters BOTH can cross BBB. Muscarine can be found in some mushrooms.

Cholinesterase Inhibitors Neostigmine Physostigmine Edrophonium Donezipril Organophospha tes (Parathione)N/A cholinesterase (Irreversible)Symptoms related to muscarinic activation + nicotinic activation (e.g. muscle paralysis)

reduce muscle paralysis after surgery, myesthenia gravis (w/ atropine) N/A cholinesterase (Reversible) Glaucoma diagnosis of myasthenia gravis Alzheimers (selective AchE in CNS

GI obstruction, GI inflammation Physostigmine can enter CNS (tertiary or infection, peritonitis, asthma, amine). All others only act on periphery COPD, Parkinson's, peptic ulcers, (quaternary amine). Neostigmine can seizures, hyperthyroidism, actually directly stimulate Nm receptors hypotension, coronary disease as well.

Enters ALL tissues

Cholinesterase Reactivators Pralidoxime ObidoximeN/A cholinesterase effects most pronouned at NMJ, less at ANS ganglia, abscent in CNS Mainly for irreversible AchE Inhibiter poisening (organophosphates). Reversible AchE poisening (cannot regenerate AchE blocked by carbamates + itself acts as weak AchE)

Antimuscarinics & Ganglionic DrugsDrug Receptor Target Actionrelaxation of cilliary muscle (cycloplegia), mydriasis, decreased lacrimal secretions funduscopic exams (mydriasis), refractive error exams (cycloplegia), iritits, irritable bowel syndrome, diarrhea, malorrhea, renal colic, enuresis, urge incontinence, preoperative uses, sinus (+) conduction (A-V) & contractility (atria), bradycardia, A-V block, (+) HR, (-) refractoriness, minimal cardiopulmonary resucitation due to ventricular effects vagal reflexes, Parkinsons (Trihexyphenidyl), Motion sickness Bronchial smooth muscle relaxation, (scopolamine), overactive vagal decreased secretions and mucus clearence responses (-) peristalsis, (-) secretions HCl & HCO3-, relaxation of LES, relaxation of detruser int. doses: mild vagal stimulation, fatigue, depression of vestibular function, reduces parkinsonian tremor & rigidity Same as above but with NO change in secretions and mucocilliary clearence Glaucoma, prostatic hypertrophy, urinary tract obstruction, GI tract obstruction, adynamic ileus, gastric ulcer, severe infectious diarrhea, Ulcerative colitis, Crohn's disease (toxic megacolon can ensue), Tacyarrhythmias, coronary artery disease, cardiac failure, hyperthyroidism, children, elderly, GERD

Therapeutic Uses

Contraindications

Pharmacokinetics

Antimuscarinic (Tertiary Amines)Eye

Atropine Scopolamine

M1, M2, M3

CNS

Heart

Teritiary amines cross BBB. Scopalamine administered as a patch. AchR's are not on ventricles so will not increase workload of the heart that much.

Darifenacin

M3

Respiratory GI/Urinary

Antimuscarinic (Quaternary Ammoniums)Ipratropium Glycopyrrolat eM1, M2, M3, N Respiratory bronchospastic disorders visceral hypermotility, preanesthetic, cardiovascuar see above Do NOT cross BBB. Ipratropium only used via inhalatory route.

Ganglionic StimulantsCNS (+) respiratory center, (+) emetic center, (+) ADH secretion, mild (+) attention & memory at low doses, (+) reticular formation at low doses, RF (-) at high doses (+) BP, (+) CO & HR from (+) Nn on adrenal medulla, constriction of skin & splanchnic vessels, dilation of muscular vessels Large doses can cause Nn depolarization blockade.Acute poisening can result in cold sweat.

Nicotine

Nn ganglionic

CVS GI/Urinary Respiratory Endocrine Other

Tx of nicotine addictions

(+) N(E) from adrenal medulla

Gagnlionic Blockers Hexamethoni um Nn post synaptic ganglionic Mecamylamin eCVS moderate (+) HR, (-) CO b/c venus pooling, (+)skin BF, (-) splanchnic & renal BF, upright hypotension Use predominate tone to figure out response Mecamylamine: Tx of Tourettes, nicotine & cocaine addiction. Hexamethonium does NOT enter brain (quaternary amine). Mecamylamine enters CNS (secondary amine).

Others

AutocoidsDrug Receptor Target Action Therapeutic Uses Contraindications Pharmacokinetics

Histamine Inhibitors-2 agonists Theophylline Cromolyn Glucocorticoidsrespiratory allergic disorders (Cromolyn) Cromoloyn used as an inhalent.

Histamine Antagonists1st Generation Drugs Diphenhydramine H1 (+muscarinic, -adrenergic, Promethazine serotonergic) Cyproheptadine Meclizine 2nd Generation Drugs Loratadine Fexofenadine Cimetidine FamotidineCNS skin BP CNS H1 central antimuscarinic effects (pronouced antiemetic & sedation w/ Promethazine) (1) allergic rhinitis, hay fever, urticaria (2) motion sickness (1st gen.) partial inhibition of histamine induced (3) hypotension vestibular disturbances (1st gen) (4) Parkinsonism do not enter brain (5) systemic mastocytosis reduced itching & edema Glaucoma, prostatic hypertrophy (1st gen.), urinary tract infection (1st gen.), GI tract obstruction, ileus, 1st generation can cross BBB, 2nd infectious diarrhea, asthma, COPD, generation cannot cross. Mainly use w/ antidepressents, metabolized by the liver often tachyarrthmias, severe hepatic producing active metabolites. disease, children (restlessness & hyperthermia), pregnancy

H2

GI

Reduces gastric acid & pepsingen secretion

Duodenal/gastric/stress/drug ulcers, Cimetidine inhibits P450 GERD, esophagitis, Zollinger-Ellison, renal disease, concommitent use of thereby increasing activity of other systemic mastocytosis, pyrosis, drugs metabolized via P450 drugs. At higher doses it can also hiatal hernia block -adrenergic receptors.

Serotonin AgonistsVessels vasoconstriction of cerebral vessels moderate to severe migraine 5-HT 1B/1D (Activation) cerebrovascular disease, peripheral vascular disease, heart disease, use w/ other 5-HT agonists, SSRI's or MAO inhibitors, pregnancy, can cause chest tightness

Sumatriptin

Serotonin AntagonistsCyproheptadine Ondansetron5HT2A (+H1, muscarinic adrenergic) 5HT-3 relaxes smooth muscle of corprus cavernosus can increase appetite by blocking 5HT intetinal hypermotility of carcinoid, receptors in hypothalamus migraine prophylaxis antiemetic erectile dysfunction, maintain patency of ductus arteriosus NSAID induced ulcer, abortion PGE2 PGF2 eye increased uveoscleral outflow reducing intraoccular pressure increased force & frequency of contraction, (at high doses can cause contracture) vasoconstriction of cerebral vessels increase release of DA vasoconstriction of cerebral vessels increased force & frequency of contraction, (at high doses can cause contracture) hallucinogen moderate to severe migraine, post partum hemmorhage hyperprolactinemia, Parkinson's Low therapuetic index = easier to Cerebrovascular disease, obstructive overdose. Ergotamine & vascular disease, coronary disease, bromocriptine have negligable oral collagen disease, renal disease, bioavailability. Ergot alkaloids sepsis, pregnancy, use with SSRI's or have large vasoconstrictive MAO inhibitors, exertional angina properties. abortion, induce labor, cervical ripening Glaucoma eye drop Works in Area postrema.

ProstaglandinsAlprastadil Mesoprostol Dinoprostone LatanoprostPGE1 Reproductive

Ergot AlkaloidsErgotamine5HT (+) (Pa/An) Alpha (++) (Pa/An) 5HT (+) (An) DA (+++) (A) Alpha (+) (An) 5HT (+) (Pa/An) DA (+) (Pa/An) Alpha (+) (Pa) 5HT 1A, 2A, 2C Uterus CNS moderate to severe migraine

Bromocriptine

CNS CNS Uterus CNS

Ergonovine Lysergic acid Diethylamide (LSD)

Drug

Receptor

TargetActionCNS high doses (+) of respiratory center, toxic doses (-) respiratory center high doses cause compensated respiratory alkalosis followed by uncompensated respiratory & metabolic acidosis at toxic doses

NSAID's Therapeutic Uses

Contraindications

Pharmacokinetics

Salicylic Acid Derivatives

Aspirin Sodium Salicylate Mesalamine

Inhibition of COX (Aspirin: Irreversible)

Gastritis, peptic ulcer, alcohol, coagulation disorders, G6PD Inflammatory diseases e.g. rheumatoid deficiency, decreased hearing arthritis, ankylosing spondylitis, (only capacity, renal disease, gout, mesalamine for ulcerative colitis, Crohn's advanced heart failure, severe low/moderate doses: (-) tubular uric acid disease), antipyresis, nonspecific analgesia, hypertension, serious hepatic disease, secretion; high doses: (-) tubular uric acid Urinary thromboembolic disease prophylaxis (e.g. MI, asthma, hay fever, nasal polyps, rabsorption & (-) GFR (from inhibition of transient iscemia, stroke) ; local urticaria, methotrexate therapy, viral PG induced BF to kidney) dermatological uses (keratolytic, antifungal) illness in children, pregnancy, breast feeding; can cause pseudoallergic GI (+) gastric secretions, (+) bile secretions rxn hyperthermia (uncoupling of Oxphos in Others skeletal muscle) ; (-) platelet aggregation; Resp.

Distributed to ALL tissues. Salicylic acid follows zero order kinetics so clearence becomes dose dependent. Renal secretion via same carrier as other weak acids e.g. methyltrexate, uric acid. Salicylates also displace substances e.g. bilirubin, other drugs from albumin. Aspirin acetylates COX (irreversible)

Propionic Acid DerivativesIbuprofen Ketoprofen NaproxenInhibition of COX (Ketoprofen: + LO) similar to salicylates but less pronounced. Naproxen shown to (-) luekocyte migration Distributed to ALL tissues.

Acetic Acid DerivativesDiclofenac KetorolacSimilar to most NSAIDs. Diclofenac has a greater anti-inflammatory ability than most. Ketorolac has a greater analgesic effect than most. Acute musculoskeletal pain (most common), imflammatory conditions of eye, long term Tx of rhuematoid arthritis, ankylosing spondylitis acute postoperative pain

Inhibition of COX

similar to other NSAIDs used parenterally

OxicamsPiroxicam MeloxicamCOX-1 > COX-2 mainly COX-2 One of the most effective COX inhibitors analgesic, antipyretic, anti-inflammatory similar to other NSAIDs Long half life (50hrs) permiting daily dosing

Indole DeravitivesIndomethacinInhibition of COX (most potent) Others (-) ecoisanoid production, (-) PMN migration, (-) T& B cell proliferation Parkinsons, seizure disorder, Management of patent ductus arteriosus, Similar to other NSAIDs but depression, renal disease, heart failure, drug of choice for acute gout, Artters antiinflammatory effect greater diabetes, lupus, pregnancy. Not syndrome, pleurisy, rhematoid arthritis, in some cases. High incidence of recommended for analgesia b/c high osteoarthritis, bursitis, tendinitis. dose related adverse effects toxicity.

Selective COX-2 InhibitorsCelecoxibCOX-2 good antiinflammatory with minimal platelet & GI effects Rhuematoid arthrlitis sulfonamides,

Analgesic-AntipyreticsAcetaminophe ninhibition of COX (periphery: weak) (CNS: strong) Inhibition is stronger in the CNS and weaker in the periphery. The CNS effect can make up for the loss in the periphery in analgesia. Does NOT effect platelet function (i.e. BT) Antipyretic, analgesic for mild to moderate pain. Can be given to children, pt's with platelet problem and pt's with gout. Very few when given at therapeutic levels. At high doses can cause liver and renal necrosis (free radical production from P450 metabolism, which means inducers of P450 e.g. alcohol could enhance effect). Must treat poisening with aceylcysteine very weak antinflammatory (peripheral tissue) (only anitanalgesic, antipyretic) (also means no Reye's, no uric acid effects, etc.) Mainly metabolized via liver.

Glucocorticoidsinhibition of PA2 & COX inhibits accumulation of fluids in tissues stimulate surfactant synthesis

Cell Cycle SpecificDrug Mechanism Phase Terapeutic Uses Toxicities Antidote/Adjuvant Pharmacokinetics

CCS- AntimetabolitesFolate Analogues(1) Body cavities (pleural/peritoneal) if expanded can act as storage and release site toxic effects. (2) 50% plasma bound and displacable. (3) Urine Excretion (alkalinisation useful). (4) IC activation (polyglutamated). (5) Oral, IV, or intrathecal (brain met). (6) does NOT enter brain (7) Resistence.

Methotrexate*

competitive (-) DHFR FH4 FH2 polyglutamate (toxic metabolite)

S

(1) Solid tumors, (2) Osteogenic sarcoma (3) ALL (4) Immunosupressive (graft rejection, RA, SLE ) (5) abortifacient (risk factor X), (6) Psoriasis

(1) Nephrotoxicity (7-OH-MT) (2) Meylosuppression (DL) (3) Rescues: (1) Pulmonary toxcicity (4) Leucovorin (2) Hepatotoxicity (long term) (5) Filgrastim (G-CSF) GIT-mucositis

Purine Analogues Mercaptopurine Azathioprine Fludarabine Thioguanine Pentostatin Pyrimidine Analogues 5-Fluorouracil* Floxuridine(1) dysfunctional RNA (2) inhibit thymidylate synthase* [as FdUMP] inhibitionof DNA synthesis (-) thymidylate synthase* [as FdUMP] inhibition of DNA synthesis same as above but not myelotoxic (-) DNA polymerase (put on end) elongation (DNA synthesis ONLY) S S (1) Metastatic breast carcinoma (2) Hepatoma (3) cancers of bladder, prostate, pancreas, oropharangeal, colon, GI, ovary (1) Metastatic colon Ca (via hepatic artery) (2) renal carcinoma (1) breast cancer (pt's resistent to paclitaxel & doxorubicin) (2) Pancreatic cancer (newer) Acute myleocytic leukemia (AML) (1) Above + Neurotoxcicity IC activation required (cytidine monophosphate) Adjuvant: Leucovorin (GI cancers) (1) inhibit PRPP synthase (2) inhibit PRPP amidotransferase (both = de novo & salvage purine pathway) (1) ALL remissions (mercaptopurine) (2) immunosuppressive (anti-arthritic) (3) Chronic lymphcytic leukemia (fludarabine=DOC) (1) Meylosuppression (DL) (3) hepatotoxic (mercaptopurine) (4) neurotoxicity (fludarabine) (1) IC Activatin required: into nucleotides which requires addition of ribose group via HGPRT (2) toxicity w/ allopurinol (3) mercaptopurine does NOT cross BBB

S

(-) adenosine deaminase (deoxy) inosine DNA synthesis

S

Hairy cell leukemia (DOC)

(1) Myelosuppresion (DL)

(1) anorexia, (2) nausea, alopecia, (3) stomatitis, diarrhea, (4) myelosuppression (DL) (except capecitabine)

(1) 3% of pop. lack dihydropyrimdine dehydrogenase (inactivates FU) 5-FU. (2) IC activation required (nucleotide) (3) crosses BBB (4) not given orally

Capecitabine** Cytarabine** Others Asparaginase* Hydroxyurea** Vinca alkaloids Vincristine* Vinblastine* Topoisomerase Inhib. Etoposide**

S

S

hydrolyzes L-asparagine (deprives cancer cell) (lymphocyte specific) (-) ribonucleotide reductase ( conversion of RNA's DNA's)

S

Acute Lymphoblastic Leukemia

(1) Hypersensitivity Rxns (2) CNS toxicity coma,hemmorhage (3) clotting abnormalities Meylosuppression

(1) IV = route (2) potentiation w/ vincristine

S

Myeloproliferative disorders (melanoma, CML)

CCS- Natural Products(1) Pediatric leukemia (ALL) (2) Hodgkin's (MOPP) & Non-Hodgkins (CHOP) (3) Rhabdomyosarcoma (4) Lymphoma (5) Neuroblastoma (1) Hodgkin's (AVBD) (2) Testicular carcinoma

bind to tubulin (-) microtubule assembly

M

Neurotoxic (DL) (bm sparring)

M

Myelotoxic (DL) (neuro sparring)

(1) Do NOT cross BBB. (2) Vincristine = longer half-life. (3) Resistence (mdr gene) (4) IV (5) vincristine potentiated by asparaginase

(1) Testicular cancer (VBE) (2) Diffuse stabalizes topoisomerase II-DNA complex S/G2 lymphomas (3) Hodgkins disease (4) Oat cell dsDNA breaks carcinoma (small cell lung Ca)

Camptothectans** stabalizes topoisomerase I-DNA complex (1) Colorectal, ovarian, small cell lung S/G2 (Topotecan, ssDNA breaks cancers Irinotecan) Taxanes

(1) Myelotoxic = may cause AML (2) Leukopenia (DL) (3) hypersensitivity rxns (1) Neutropenia (DL) (2) thrombocytopenia (DL) (3) dose-limiting mucositis, diarrhea

(1) Resistence (mdr & mutations in TI's) (2) Etopiside = NO BBB Topotecan = BBB (3) IV infusion

Paclitaxel* Docetaxel

bind -tubulin (-) MT dissasembly microtubular plates dysfunctional spindles

M

(1) hypersensitivity rxns (2) Meylosuppression (DL) (3) (1) Primary tx in 1 & met. ovarian cancer cardiac conduction defects (4) (2) metastatic breast cancer (3) other cancers N,V,A (5) Neuropathy = (4) locally advanced or met NON-small cell paclitaxel docetaxel (6) nail & lung cancer = docetaxel skin (7) toxic accumulation of fluid

(1) Highly insoluble --> must be solubilized with cremophor which could (+) allergy (2) Paclitaxel clearence (-) by cisplatin (3) NO BBB

CCS/CCNS- Cytotoxic AntibioticsAnthracyclines(1) Solid tumors (breast, endometrium, testes) (1) Meylosuppression (2) Cardiomyopathy (arrhythmia) (2) Hodgkins (ABVD) (3) Non-Hodgkins (DL) (3) erythemia (Adriamycin CCS (CHOP) (4) sarcomas (osteogenic, Ewing's, soft flare) (4) N,V,A (5) mutagenic & CCNS tissue) (5) metastatic carcinoma thyroid carcinogenic; (6) cholestasis (w/ azathioprine) (7) may cause red urine Acute Myelognous Leukemia Antidotes: (1)Dimethyl sulphoxide (free radicals) + (2) Dexrazoxane (iron chelator--heart) (1) Fast running IV infusion (vesication) (2) synergistic toxicity w/ azathioprine (3) IV only (4) Resistence (mdr & decreased activation)

Doxorubicin*

(1) (-) topoisomerase II (prevents resealing) (2) free radical formation (3) Intercalating b/t BP's (-) transcription

Daunorubicin* Others Dactinomycin**(1) binds DNA helix (-) transcription (2) single strand breaks (e-'s)

(1) Myelosuppression (DL) (2) CCS (1) Rhabdomyosarcoma (2) Wilm's tumor (3) Pancytopenia-dose limiting (3) CCNS Ewing's tuor (4) Kaposi's Sarcoma N,V,A (1) Pulmonary toxcity (DL) (2) (1) Testicular cancers (2) squamous carcinomas hyperthermia (3) skin problems (3) Hodgkin's (AVBD) (hyperpigment)

Bleomycins*

free radical formation fragments DNA

G2

(1) Made of 2 copper chelating peptides. (2) Meylosuppression is rare.

Cell Cycle Non-SpecificCCNS- Alkylating AgentsNitrogen Mustards(1) Myelosuppression (DL) (thrombocytopenia less severe) (2) amenorrhea & azoospermia (3) leukemogenic (4) Cardiotoxic (high dose) (5) renal & bladder toxcity (6) chemical cystitis (acrolein) (7) SIADH (8) pulmonary toxicity (1) (+) ADH secretion. (2) Liver activation by P450 (3) Oral or IV, not intrathecal (activation). (4)Acrolein = chemical cystitis (hemorrhagic). (5) Given w/ high water (kidney protection). (6) Resistence. (7) crosses BBB

Cyclophosphamide cyclophosphamide nitrogen mustard + acrolein alkylation DNA = inactivation *

(1) Chronic Leukemias (2) soft tissue cancers (breast, ovary) (3) Non-hodgkin's lymphoma, (5) neuroblastoma (6) immunosuppressent (graft rejection, SLE)

Antidote: (1)Mesna (acrolein urine) (2) demeclocycline (SIADH Tx)

Mechlorethamine Chlorambucil

bifunctional alkylating agent

(1) Hodgkins = Mechlorethamine (2) Leukemia, lymphomas = chlorambucil

typical alkylating agent lung-pulmonary fibrosis, hyperpigmentation, adrenal suppression (stress coping), cataracts (high doses) thrombocytopenia Myelosuppression (DL)

(1) powerful vesicant (used in WW1)

Busulfan Procarbazine Nitrosoureas Carmustine** Lomustine Others Temozolamide**

alkylating agent

CML (b/c selectivity), AML, pre-Tx for bone marrow transplants to clear host bm. Hodgkin's (MOPP)

conventional doses = ONLY meylosuppressive

free radical formation fragments DNA

bifunctional alkylator (BOTH DNA strands)

(1) Brain tumors (2) melanomas (3) GIT tumors.

(1) Myelosuppresion (DL) (2) Neurotoxcicity (3) hepatotoxcity

lipophilic (cross BBB); passive cellular uptake

NON-crosslinking "alkylating agent" (methylation)

malignant gliomas

Triazine

HormonalDrug Mechanism(1) blocks binding of estrogen to receptor (Pa) (2) agonist actions (e.g. bone) (1) estrogen receptor antagonist ALL tissues

Phase

Terapeutic Uses

ToxicitiesN & V, hot flashes, vaginal bleeding, disease flare, hypercalcemia, ocular dysfuncition, peripheral edema

Antidote/Adjuvant

Pharmacokinetics

Estrogen AntagonistsTamoxifen* Fulvestrant**(1) Breast cancer (2) Infertility (3) Gynecomastia (4) prophylactic in women w/ high risk of met. (1) Tamoxifen resistent breast cancer Acts as agonist at endometrial receptors = increased risk for endometrial cancer. High resistence development.

Anastrazole* Flutamide Cyproterone Ketoconazole Glutethimide Finasteride**

(-) aromatase (-) estrogen synthesis (-) translocation of steroid receptors into nucleus (-) binding of dihydrotestosterone to intracellular receptors (-) testosterone synthesis in adrenals (-) 5--reductase conversion of testosterone to DHT

(1) breast cancer NON-steroidal androgen antagonist (NSAA) Steroidal androgen antagonist (SAA) Prostate Cancer (early stages testosterone dep.)

Androgen Antagonists

AnaloguesMedroxyprogester one Megestrol Acetate Fluoxymesterone Leuprolide** Goserelin NaferelinProgestin analogue (1) metastatic hormone dependent breast cancer (2) previously treated endometrial cancer Advanced breast cancer (1) bone & back pain (2) gynecomastia (3) hematuria (4) impotence (5) testicular atrophy

Androgen analogue Pa GnRH agonist inhibits LH & FSH release (administered at constant dose)

Prostate cancer

OthersDrug Cisplatin* Carboplatin Oxaloplatin Mechanism Phase Terapeutic Uses Toxicities Antidote/Adjuvant Pharmacokinetics

Platinum Coordination Complex -Alkylating-Like Drugsdiffuses into cell activated via displacement of Cl- w/ H2O cross links DNA breaks & miscoding (-) repl/transc. (1) Solid tumors (testis, ovary, bladder, lung, (1) Nephrotoxicity (PT) (DL) (1) Ondansetron etc) (2) Neuroblastoma (3) osteogenic sarcoma (2) Electrolyte disturbances (4) (vomiting) (2) Marked V & N (5) Amifostine (eNeurotoxicity (hearing & scavenger) periph.) (6) proinflammatory colorectal cancer (1) Rapid injection IV. (2) Reacts with Alluminum (needles). (3) Vigorous hydration before administration. (4) Resistence (repair mechanisms)

Monoclonal AntibodiesRituximab** Trastuzumab* (Herceptin) Imatinib mesylate** (Gleevec)anti-CD20 antibody (follicular B-cells) Non-Hodgkins lymphoma (CHOP) With paclitaxel in pt's with metastatic breast cancer CML Nausea, vomiting, chills, fevers, headaches, cardiac dysfunction CD20 found on both malignant and normal NOTE: EGFR family expressed in many tumors

IgG1 anti-HER2 receptor antibody

anti-BCR-ABL tyrosine kinase antibody

ImmunosuppressivesDrug MechanismConversion to 6-thioinosinc acid: (1) Inhibits PRPP synthase (2) inhibits PRPP amidotransferase (3) (-) lymphokine production [salvage & de nova=clonal expansion B & T cells]

Therapeutic Uses

Adverse Effects

Pharmacology(1) Oral (main), IV (2) inactivation in liver (50% in urine w/in 24hrs) (3) toxic build up when given with allopurinol (4) converted to mercaptopurine then 6-T (5) nonselective for any rapidly dividing cell

Indiscriminately Cytotoxic DrugsAzathioprine(1) Prevent graph rejection (1) meylosuppression (2) hepatotoxicity (2) autoimmune diseases (cholestasis) (3) carcinogenic (4) increased (3) Tx of Type IV hypersensitivity infections (5) hypersensitivity

Lymphotoxic DrugsAntilymphocytic Globulin Antithymocytic Globulin Rho(D) Immune Globulin Immune Globulin IV Muromonab-CD3 (Orthoclone)binds lymphocytes activating complement lysis (1) prophylaxis kidney rejection (2) acute rejection Tx. for kidneys (3) GVH prophylaxis in BMT (4) aplastic anemia (BMT incapable pt's) (1) Acute renal transplant rejection crisis (1) Hemolytic disease of newborn (1) Autoimmune Disease (2) Kawasaki Disease (3) refractory thrombo-cytopenia purpura (4) Hepatitis A--measles (1) Cytokine release syndrome (2) (1) acute renal graft rejection crisis (2) pulmonary edema (3) blood dyscrasias (4) steroid resistent cardiac/hepatic rejection hearing loss (5) hypersensitivity (5) imparied vision (1) rasied to serum of many human donors (1) hypersensitivity (2) serum sickness (2) rash, joint pains (1) raised in horses to human lymphocytes

binds T-cells destroyed by complement binds to Rho(+) RBC's in mother to prevent Ab production against Rho Ag passive immunization (no specificity)

(1) hypersensitivity

(1) raised in rabits to human thymocytes (2) selectively inhibits cellular immunity

monoclonal antibody to CD3

hits primed and unprimed T-cells

Subpopulation Specific DrugsCyclosporin Tacrolimus (FK506) Sirolimus (Rapamycin ) Mycophenolate mofetil Leflunomide(1) NEPHROTOXICITY (2) neurotoxicity (3) (1) Prevention of graft rejection (2) GVH in Hirsuitism (4) hepatotoxicity (5) ginival BMT (3) Uveitis (4) AD's (e.g. Psoriasis) (5) hyperplasia -----*USMLE* (6) osteoporosis glomerular nephritis (long term tx.) (7) hyperurecima (8) LDL (1) nephrotoxicity (not as bad) (1) complexes w/ FKBP12 (-) calcineurin (1) same as cyclosporin (2) Atopic (2) neurotoxicity (-)NFAT IL-2/receptor = T-cell proliferation dermatitis, psoriasis (3) hyperkalemia (4) hyperglycemia (1) complexes w/ FKBP12 binds mTOR (1) same as cyclosporin (1) cholesterol & TAG's (DL) (2) blocking T-cell response to cytokines & (-) (2) tx. of stenosis (coronary heart meylosuppression (3) hepatotoxicity (4) B-cell proliferation (hence Ig's) disease) hypertension (1) nausea, vomiting, diarrhea, abdominal pain (1) immunosuppressive therapy (2) meylosuppressive (3) hypertension (4) As mycophenolic acid: (1) (-) inosine (substitute for azathioprine) (2) prophylaxis increased infections (cyomegalavirus) (5) not monophosphate dehydrogenase [ B-& Tin transplant rejection (3) off lable tx SLE, suitable for pregnancy (6) shown to reduce cell dependent de nova guanine synthesis] erythemia multiforme (4) acute rejection effects of estrogens (reduced effectiveness of oral contraceptive) (-) dihydroorotate reductase de nova rhuematoid arthritis pyrimidine synthesis (1) complexes w/ cyclophilin-A (-) calcineurin (-) NFAT IL-2/receptor = Tcell proliferation (2) expression TGF- (1) highly lipophilic (diffusion into lymphocyte) (2) Oral, IV, IM (3) metabolized by P450 (1) 10-100x potent than cyclosporin (2) given preoperatively (3) not as toxic as cyclosporin (4) metabolized by P450 (1) oral

(2) P450 metabolism

(1) prodrug converted to mycophenolic acid (2) NOT inhibit salvage path = selective lymphocytes

Cytokine/Receptor Target DrugsEtanercept Infliximab Daclizumab (Zenapax) Thalidomide(1) binds TNF- inhibtits proinflammatory events (1) Rheumatoid arthitis (2) methotrexate regimes (3) immunosuppressent (4) experimental use for psoriasis (1) hypersensitivty (2) headaches (3) serum sickness (1) dyspnea, fever, GI, hypertension, chest pain (2) hpersensitivty (3) heart problems highly teratogenic (1) fusion protein acts like receptor

(1) binds TNF- inhibits pro-inflammatory (1) Crohn's Disease (2) RA events (+methotrexate) (1) binds CD25 (component of IL-2R) on Tcells prevents activation (1) reduces circulating levels of TNF- (2) blocks bFGF inhibiting angiogenisis (1) acute rejection after transplant restricted distribution (1) lupus (2) erythema nodosum leprosum

(1) monoclonal antibody (2) IV

GlucocorticoidsPrednisone Methylprednisone(1) IL-1, IL-6 T-& B-cell act/pro (2) (-) PA2 (lipocortin) (3) anti-inflammatory effects (1) maitanance chemo (2) w/ other drugs-prevent graft rejection (3) AD (5) acute rejection crisis bone marrow toxicity (1) do not alter phagocytic ability (2) cellular immunity affected more than humoral but prolonged use can [IgG] (3) prednisone must be activated to prednisolone in the liver to be active

ImmunostimulantsDrug Mechanism Therapeutic Uses Adverse Effects Pharmacology

Levamisole (Ergamisole) Bacillus Calmette Guerin (BCG)

stimualtes maturation/proliferation of T-cells

(1) colon cancer (Duke stage C) (adjunctive) (2) Nephrotic syndrome (nonapproved) (1) intravescical therapy of bladder cancer

(1) neutropenia, thrombocytopenia (2) agranulocytosis (3) anemia (4) encephalopathy (demylination) (1) Flu like symptoms (2) systemic infection (rare)

(1) potentiates 5FU & leucovorin

activation of immune response (macrophages, T-&B-cells, NK-cells)

viable strain of Mycobacterium bovis

InterferonsINF- INF- INF-(1) antiviral ( MHC-1, MHC-II) (2) antiproliferative (3) immunostimulant (1) Hairy cell leukemia (2) Hep B & C (3) melanoma (4) condyloma acuminatum (genital warts) (1) MS (1) Chronic granulomatous disease (2) activation of phagocytes

InterluekinsAldesleukin Oprelvekin(+) proliferation B-&T-cells, NK, LAK's (1) renal cell carcinoma (2) melanoma (1) thrombocytopenia (1) capillary leak syndrome (hypotension, tachycardia, edema) (2) renal failure (reduced (1) recombinent version of IL-2 perfusion) (3) neurotoxicity (4) nausea/vomiting (5) anemia, thrombocytopenia (1) recombinant form of IL-11

stimulates platelet formation (1) (+) production of neutrophils (lineage specific) (2) (+) peripheral blood stem cells (1) (+) macrophage & granulocyte proginators (Non-lineage specific) (2) (+) mature cells

CSFFilgrastim (Neupogen) Sargramostim (ProKine/Leukine) Epoetin- (Erythropoetin) Thrombopoetin(1) (+) BM recovery during chemo (1) non-Hodgkins lymphoma (2) ALL (3) Hodgkins pt's undergoing BMT (4) meyloid recover after chemo or BMT (5) neutropenia associated with AIDS (2) anemia Recombinant Fusion Protein: (1) anemia, neutropena, thrombocytopenia Recombinent Human Thrombopoetin: (1) hematopoetic stem cell transplants (accelerate platelet recovery) G-CSF produced in E. coli

(1) Contraindicated: heart failure, pulmonary GM-CSF derived from yeast edema, yeast hypersensitivity

(+) erythroid precursors --> erythropoesis

must have adequate iron intake Formulations: (1) Recombinent fusion protein (thrombopoetin + GM-CSF + IL-3) (2) Recombinant human thrombopoetin

(1) stimulates megakaryocytopoeisis

Drug Polyenes Amphotericin B Nystatin Azoles Imidazoles Ketoconazole Clotimazole Miconazole Triazoles Fluconazole Itraconzaole Voriconazole Others Terbinafine

Mechanism

Therapeutic Uses

Toxicity

Pharmacokinetics

Resistence

Cell Membrane DisruptionDOC for sytemic infections (1) Aspergillus binds to ergosterol forms pores increase spp. (2) Candida spp. (3) Cryptococcus permeability neoformans (4) Dimorphic pathogens binds ergosterol permeability (1) Oral Thrush Less with lipid preperation. (1) Infusion rxns i.e. chills, fever, BP (2) Nephrotoxicity (80% pt's) Normochromic anemia (Epoietin) bitter taste (1) insoluble in water liposomal, bile, coilloidal, lipid complex form. Mutations in ergosterol. (2) Topical, IV or intrathecal Topical. Mutations in ergosterol.

Broad Spectrum: Ketoconzaole: systemic mycoses, Cushing's Itraconazole: dimorphic (-) lanosterol 14--demethylase (P450 systemic nonmeningeal Voriconazole: dependent) ergosterol + 14--methylsterols invasive pulmonary aspergillosis membrane dysfunction Clotimazole: Oral thrush Fluconazole: DOC cocciodial & cryptococcol meningitis prophylaxis in bone marrow transplant pt's

N & V, hepatitis (fluconazole) contraindicated in pregnancy Ketoconazole (4) Endocrine abnormalities (menstral dysfunction & gynocomastia (-) steroid synthesis)

(1) Slowly metabolized by P450. (3) Low pH to dissolve ketoconazole (4) (-) P450 (-) steroid synthesis + drug potentiation (1) Metabolized -P450. (2) Do NOT inhibit human productions. (3) Topcial, IV, PO. (4) Low pH to dissolve except Fluconazole (5) lipid soluble crosss CNS (6) once daily dose w/ less toxicity (1) metabolized by liver (2) inhibits CYP2D6 (antidepressents) (3) accumulate in skin, nails, fats ERG11 mutation nonbindable form of 14--DM

(-) squalene epoxidase ergosterol + squalene dysfunction of cell membrane

(1) DOC=dermatophytes [NailHeadache, GI, Liver enzymes. onychomycoses, skin] (2) Candida albicans Contraindicated in Pregnancy.

None

Cell Wall DisruptionEchinocandins Caspofunginnoncompetitve (-) (1,3)-D-glucan synthase Invasive Aspergillus in pt's failed with amphotericin B or voriconazole. Also used in candida ssp. Rash, pruitis (histamine release) (1) IV (3) metabolized in liver FKS1 gene mutation (subunit of 1,3 -D-GS)

OthersFlucytosine(1) (-) thymidylate synthase = DNA (5FdUMP) (2) RNA synthesis (5-FUTP) used synergistically with amphotericin B (1) Candiasis (2) Cryptococcus (1) taken up by cytosine permease converted to 5-FU (1) (-) uptake into fungal Meylosuppression converted 5FUTP or FdUMP (2) cell esp. if given alone (2) oral administration (3) urinary synthesis of 5-FUMP excretion (4) pentrates CNS (1) distribution to keratinized tissues (2) induces P450 (3) Headache, rash, nausea, vomiting, Long term Tx until new tissue (4) None photosensitivty (hypersensitivity) absorption (+) with fatty meal (5) Fungistatic only (1) topical (Tinactin ) (2) bitter taste

(1) dermatophytes of skin, hair, nails (long Griseofulvin binds microtubules mitotic spindle dysfunction Tx.)

Tolnaftate

believed to inhibit squalene epoxidase

(1) dermaphytic (NOT 1st choice) [Sporothrix schenckii (NOT for Candida) ]

-Never give Ketoconazole + amphotericin B together --> antagonistic actions

AntiprotozoalsDrug Mechanism Killing Activity Uses Adverse Effects

MalariaChloroquine* heme in food vacuole = parasite toxicity Amodiaquinesame as above (-) conversion of free heme into hemozoin (1) Blood schizonts (2) gametocytes Tx: uncomplicated infection + DOC: prophylaxis (except P. falciparum) Pruritis *also used in RA

Tx. of falciparum strains (low cost)

agranulocytosis, aplastic anemia, hepatotoxcity (1) cinchonism (timmitus, headache, nausea, dizziness, flushing, visual) (2) hypotenstion w/ fast infusion (3) hypersensitivity *very long half-life

Quinine* Quinidine* Mefloquine Primaquine* Atovaquone (+proguanil) Pyrimethami ne (+sulfadoxin e) Doxycycline

unknown

(1) DOC: Tx. severe malarial (1) Blood schizonts (2) gametocytes infection (2) Babesiosis (except P. falciparum) (+clindomycin) (1) Blood schizonts (2) gametocytes (except P. falciparum) (1) tissue schizonts (2) hypnozoites (vivax, ovale) (3) gametocytes

unknown

(1) prophylaxis + Tx. chloriquine nausea, dizziness, behavioral resistent falciparum disturbances, GI pain & disturbances Prevention of relapse (1) well tolerated (2) Hemolysis in G6PD pt's

unknown

disruption of plasmodial mitochondrial electron transport chain

(1) alternative prophylaxis (oral only) (2) Pneumocystis carinii (3) Babeisis (1) adjuvant therapy for severe & resistent infections (2) Toxoplasmosis (3) Fansidar (P+S) = prolphylaxis (1) prophylax multidrug resistent spp. (2) adjuvant therapy for severe & chloroquine resistent infections

(-) plasmoidial DHFR

(1) tissue schizonts schizonts

(2) blood

Stevens Johnson Syndrome

prevents aa-tRNA A site (-) translation

(1) tissue schizonts (2) blood schizonts

OthersMetronidazol e*Mixed amebicide (1) trophozoites (1) Amebiasis (2) Giardiasis (3) Trichomoniasis

Tinidazole Iodoquinol Paramomyci n Nifurtimox Stiboglucona te Pentamidine Suraminunknown

(1) trophozoites

Luminal amebicide

(1) given with above drugs

Paramomycin should be avoided in pt's with renal disease & GI ulcerations

(1) DOC American trypanosomiasis (T. cruzi) (1) Leishmania (1) Pneumocystis carinii (2nd choice) (3) alternative for African sleeping (1) African trypanosomiasis (especially T. gambiense)

NOTE: (1) All anti-malaria drugs can be taken orally (2) all can upset the GI (3) chloroquine, primaquine, quinine cause hemolysis in G6PD deficient patients (4) Chloroquine, quinine, quinidine,sulfadoxine/pyrimethamine safe in pregnancy

AntihelminthsDrug Benzimidazoles Mebendazole Abendazole Mechanism(-) microtubule polymerization (glucose transport, glycogen, Oxphos)

Uses

Adverse Effects(1) diarrhea (heavy worm burden) (2) allergic rxns to death products (3) do NOT use in pregnancy (PP instead)

Pharmacology

see bottom

oral

Pyrantel Pamoate paralysis) (Ach release + (-) AchE = Ach atNMJ )

depolarizing NMJ blocker (parastic

see bottom

(1) GI, headache, weakness (1) Mazotti-like rxn - pruritis, fever, arthralgia (from dying microfilariae) (2) NOT used when BBB impaired (Trypanosomiasis or menigitis) (1) Mazotti rxn (from dying microfilariae) dizzieness, drowsiness, N&V, skin rash, hea "feeling", sialorrhea

(1) oral (2) CAN be used for pregnancy

Ivermectin

GABA-mediated neurotransmission (parasitic paralysis)

see bottom

(1) oral (2) P-gp keeps it out of CNS

Diethylcarbamazin not well understood (arachodonic acid path?) but kills microfilariae in skin but NOT in e nodules that contain female adult worm Praziquantelmembrane Ca++ permeability muscle activity followed by paralysis (tetani)

see bottom

oral (1) oral (2) must be stored < 30C (3) bitter taste (1) oral (2) DO NOT give w/ pyrantel pamoate (counteracting effects) oral

see bottom

Piperazine Oxamniquine

activation of GABAerigic receptors (hyperpolarization paralysis)

see bottom

unknown

see bottom

Protein Synthesis InhibitorsDrug MOA Spectrum Therapeutic Uses Adverse Effects Kinetics

TetracyclinesTetracylcine Doxycycline Minocycline Demeclocycline Tigecycline (glycycline)Treatment: Facial acne, Borrelia & Leptospira, Treponema pallidum (2nd behind penicillin), Contraindicated in pregnancy, children. SIADH, Calymatobacterium granulomatis, Bones & teeth growth problems. Vestibular amoebas, cholera, Brucella, Atypicals toxicity. Superinfections - Candida, C. (Chlamydia, Mycoplasma, Rickettsia), difficile. Phototoxicity - psuedotumor malaria, Helicobacter pylori, Post-exposure cerebri. Renal & hepatic toxicity. prophylaxis: Yersina, Tularemia (doxycycline) MDR G+, anaerobes, MRSA, VRE Similar to other tetracyclines. Drug-Drug: Increased plasma [Warfarin] Renal excretion (except: doxycyclin).Bacteriostatic. 50% oral bioavailability (except: doxycycline & minocycline= 100%) . Main resistence via efflux pump. Niesseria have tetM to displace tetracyclines from target. Crosses BBB & placenta. Bacteriostatic. Resistence - Proteus & psuedomonas.

binds 30S subunit --> blocks binding of aminoacyl-tRNA = inhibits protein synthesis

Broad

Broad

AminoglycosidesStreptomycin Gentamicin Amikacin Tobramycin Neomycin Spectinomycinbinds 30S subunit: (1) Aerobic blocks translocation, (2) G- & blocks initiation complex, Enterococc (3) causes misreading of . mRNA 2nd line in tuberculosis (amikacin, streptomycin), Brucellosis (gentamicin) , Yersinia pestis - Plague (gentamicin, streptomicin), Tularemia, Pseucdomonas (tobramycin), Enterococci Neomycin ONLY given topically. Bactericidal, PAE, concetration dependant killing. Parenteral ONLY. Does NOT cross BBB. Kidney - excretion. Resistence via acetylation, adenylation, phosphorylation.

Contraindicated in pregnancy. "A mean guy" nephrotoxicity, ototoxicity, neuromuscualr blockade (inhibits Ach release)

binds 30S but does NOT cause misreading

Narrow

Penicillin resistent/allergic Gonnorrhea

Bactistatic

MacrolidesErythromycin Azithromycin ClarithromycinToxoplasma, Atypicals - (Mycoplasma, Broad: MAC, Chlamydia). Legionellosis G+, G-, (azithromycin), Respiratory infections anaerobes, (diphtheria, bordetella, haemophilus). H. pylori. atypicals Staph & strep. Cat Scratch (Bartonella). GI upset (motilin receptors), prolonged Q-T interval. Clarithromycin & erythromycin esolate contraindicated in pregnancy P450 metabolism (except: azithromycin)Erythromycin is acid labile so must be coated. . Bacteriostatic. Safe for pregnancy. Resitence: (1) decreased affinity for 50S, (2) erythromycin esterase, (3) increased efflux/no penetration

binds 50S subunit --> inhibits translocation

New AgentsLinezolidbinds 50S --> blocks initiation complex Resistent strains - MRSA, VRE, VRSA Meylosupression, peripheral and optic neuropathy. Drug-Drug: Inhibits MAO (hypertensisve crisis). Arthralgia, venous irritation, hyperbilirubinemia Bactiostatic. Inhibits MOA Inhibits P450. Bactericidal. PAE. Risistence: methylation (quinupristine) Acetylation & efflux (Dalfoprostine)

Quinupristin/dalfopri bind to separate sites on the 50S subunit stin (streptogramin)

VRE

OthersChloramphenicolbinds 50S subunit --> inhibits peptidyltransferase binds 50S preventing translocation Broad ALTERNATIVE: Because of toxicity only used for bacterial meningitis in infants with allergies to beta-lactams & Rickettsial infections in children & pregnant women where tetracyclines contraindicated anaerobes - Bacteroides, toxoplasma Gray Baby Syndrome. Bone marrow suppression. bacteriostatic. Inhibits P450

Clindamycin

Pseudomembranous colitis

Bacteriostatic

Nucleic Acid Synthesis InhibitorsDrug MOA SpectrumExtended: G-

Therapeutic Uses

Adverse Effects

Kinetics

QuinolonesFirst Generation Nalidixic Acid Second Generation Ciprofloxacin Ofloxacin Norfloxacin Third Generation Levofloxacin GemifloxacinUTI's hemolysis in G6PD pt's

Extended: G-, G+, Atypical inhibits DNA gyrase (topisomerase II) & topoisomerase IV.

Anthrax, psuedomonas, 2nd line TB, legionella, brucellosis, typhoid fever, UTI's. Atypicals (Mycoplasma, Chlamydia) Typhoid fever (ciprofloxacin)

Extended: G-,more G+, Atypical

S. pneumoniae (CAP), atypicals, MAC, Typhoid fever (Levofloxacin)

cartilage & tendon damage, CNS, Q-T prolongation, GI upset, phototoxicity. Inhibits P450 - Increases concentrations of warfarin & theophylline. Seizures when taken with NSAIDs- enhanced GABA displacement. Contraindicated in children & preganancy.

Bactericidal, concentration dependent killing, PAE. Renal excretion (except: moxifloxacin). High tissue penetration. Resistence - altered target & decreased permability, increased efflux.

(topisomerase II) & topoisomerase IV.

Fourth Generation Moxifloxacin

SulfonamidesSulfamethoxazole (Cotrimoxazole) Mafenide Silver sulfadizine Sulfapyridine + 5aminosalicylic acid (Sulfasalzine) Sulfadoxine Sulfadiazine Otherstakes e-'s from enzymes leading to (1) reduced cytoxic intermediates (2) binding to DNA & proteins --> cell death Decomposes in acidic urine (5.5 or bleeding.

Susceptible to Beta-lactamases. See bottom for combinations.

"HNPEK"

Bacteroides fragilis (Cefoxitin, Cefotetan). Haemaphilus Influeznae (Cefuroxime, cefaclor), Neisseria meningitis. Proteus, Klebsiella, Escherichia. Disulfiram-like rxns and decreased pletelets (Cefoperazone, cefamndole, cefotetan). Hypersensitivtiy. Nephrotoxicity. Pseudomembranous Colitis. NOT active against: Listeria, Atypicals, MRSA, & Enterococci.

See above.

Third Generation: Cefotaxime Ceftriaxone Ceftazidime Cefoperazone Cefixime Fourth Generation: Cefepime Cefpirome Carbapenems Imipenem Meropenem Monobactams Aztreonam

See above. Psuedomonas (Ceftazidime). Gonorrhea (Cetriaxone, Cefixime) Meningitis (Cetriaxone, Cefotaxime) Typhoid Fever (Ceftriaxone) Acute Otitis Media (Ceftriaxone) Enterobacteriaceae.

Disulfiram-like rxns and decreased pletelets (Cefoperazone, cefamndole, cefotetan). Hypersensitivtiy. Nephrotoxicity. Pseudomembranous Colitis.

NOT active against: Listeria, Atypicals, MRSA, & Enterococci.

Cefepime: Pseudomonas

See above.

Broad:

Enterobacter. Bacteroides.

Nephrotoxic: dehydropeptidase-1 on epithelial cells of kidney convert to toxic substrate (give cilastatin to prevent). Meropenem similar but without nephrotoxicity.

NOT active against: enteroccocus, MRSA, clostridium

See above.

Narrow: G-

H. Influeznae, Pseudomonas in pt's allergic to penicillin "Red Man/ Red Neck" syndrome (hypotension after rapid IV injection). Nephrotoxicity. Ototoxicity.

Tolerated by penicillin allergies.

NON-Beta LactamsVancomycin Fosfamycin Bacitracin Cycloserineinhibits glycosylation reaction of PBP's. phosphoenoylpyruvate analog inhits synthesis of UDP-NAM (early cell synthesis stage) mixture of polypeptides prevents D-alanine addition pentapeptide. Narrow: G+ Enterococci(endocarditis), MRSA, Clostridium difficile. Bactericidal.

G+, GNarrow: G+ Narrow:

Uncomplicated UTI's Nephrotoxicity. 2nd line for TB Dose-limiting neurotoxicity. Topical Use Only

Beta-Lactamase Inhibitors

Drug

MOA

Spectrum

Therapeutic Uses

Adverse Effects

KineticsOral bioavailability (F) better for Valacyclovir. Acyclovir used IV or topically. Oral bioavailability better for Famciclovir. Penciclovir used topically Oral bioavailability better for Valgancyclovir. Gancyclovir used IV, intraocular, oral. Topical only (all cells can Pi it)!!

Herpesvirdae InfectionsAcyclovir / Valacyclovirguanine analogs --> inhibits viral DNA polymerase (NOTE: must be phosphorylated by viral thymidine kinase then by cellular kinases) HSV-1/2, VZV, EBV HSV infections, VZV if > 12y/o Headache, N & V, rashes, diarrhea Neurotoxicity (headache), N & V, nephrotoxic

Penciclovir / Famciclovir

Gancyclovir / Valgancyclovirpyrimidine (thymidine) analog (ONLY cellular phos. needed) cytosine analog (NO phos.)

CMV, HSV-1/2, VZV, EBV

CMV retinitis, CMV prophylaxis

Bone marrow suppression (neutropenia) Even host cells can phosphorylated it so only used topically Nephrotoxcity (NOTE: co-administration with probenicid which blocks secretion of cidofovir into tubules can alleviate nephrotoxicity) electrolyte abnormalities hypocalcemia & hypomagnesemia (chelation), neurotoxicity, nephrotoxicity irritation of eyes

Trifluridine

HSV-1/2, VZV

Ocular HSV infections

Cidofovir

CMV retinitis

IV, intravitreal, topical

Foscarnet

pyrophosphate analog (NO phos.) --> inhibits viral DNA polymerase & reverse transcriptase antisense oligonucleotide (binds mRNA---> (-) protein synthesis)

HSV-1/2, VZV, CMV, HIV

Alternative to HSV & CMV infections

IV

Fomivirsen

CMV retinitis in pt's who don't respond to 1st lines

intravitreal

Respiratory VirusesAmantadine Rimantadine Oseltamovir Zanamivir Ribavirin Palivizumab(-) viral uncoating by inhibiting M2 protein --> raises pH in endosome prevent release by inhibiting neuroamidase Influenzae Type A Tx & prophylaxis for Influenzae A, Parkinsons (amantadine) Nervousness, insomnia Nausea, GI bronchospasm Teratogenic (contraindicated in pregnancy) conjuntival irritation, rash, anemia, jaundice SC crosses BBB, oral does NOT cross BBB, oral Oral intranasal

Influenzae Type A & B

Tx & prophylaxis for Influenzae A & B

Influenzae, inhibits mRNA capping & RNA Parainfluezna, measles, polymerase Lassa fever, RSV, HepC Ab against F-glycoprotein on RSV bind to receptors on host and affect transcription, translation, protein processing, viral maturation cytosine analog adenosine analog guanosine analog RSV

RSV bronchitis, Lassa fever, alternative for Influenzae, parainfluenzae, measles, Hep C Prophylaxis for RSV in high risk children

Hepatic VirusesInterferonsINF-alpha: HBV, HCV, HPV INF-alpha: chonic Hep B, Hep C (INF-alpha + ribavirin) HZV, Hairy cell Luekemia (INFalpha + zidovudine), Kaposi sarcoma, refractory condylomat acuminata (genital warts) Chronic HBV, HIV Lamivudine resistent HBV Lamivudine resistent HBV nephrotoxicity flu-like symptoms, bone marrow supression, neurotoxicity, cardiotoxicity, hypersensitivity comes in pegylated forms which provide for a longer half-life

Lamivudine Adefovir Entecavir

HBV, HIV

RetroviralsNRTI'smyelosupression, neuropathy, myopathy, N & V, headache, insomnia, drug-drug interaction: tylenol, stavudine, azoles, amphoteracin B, gancyclovir contraindicated IV to mother, syrup to baby, acetaminophen enhances AZT toxicity. Stavudine has antagonistic effect on AZT. Azoles inhibit AZT metabolism. Greater myelosuppression with Amphoteracin B & gancylcolivr

Zidovudine (AZT)Thymidine analog HIV 1/2

used in pregnancy to prevent vertical transmission

Stavudine (d4T) Didanosine (ddI)deoxyadenosine analog HIV

lipoatrophy, hyperlipidemia, mitochondrial toxicity pancreatitis, peripheral neuropathy, N & V, rash

Lamivudine (3TC)cytosine analog HIV, HBV

well tolerated, may be some N & V, headache well tolerated, may be some N & V, headache, hyperpigmentation Hypersensitivity ( if rechallenged can be fatal), headache, N & V, diarrhea well tolerated, headache, N & V

Emtricitabine (FTC) Abacavir (ABC) Tenofovir** (TDF) NNRTI's Nevirapine Efanvirenz Delavirdine Protease Inhibitors Saquinavir Ritonavir Lopinavir Indinavir Atazanavir Integrase Inhitiors Zintevir Fusion Inhibitors Enfuvirtide (T-20)prevents HIV from infecting new cells by inhibiting integrase binds Gp41 --> inhibits fusion of the viral and cellular membrane HIV-1 ONLY inhibits post-translational processing (maturation) by inhibiting protease HIV-1/2 HIV Often used with other PI's b/c of potent P450 inhibition it can act as a "fall guy" to reduce first pass effect of the other PI's non-competitive inhibition of RT HIV 1 ONLY HIV-1 guanosine analog AMP analog HIV HIV, HBV

Rashes (Stevens-Johnson), hepatotoxicity Rashes, CNS effects Nausea, GI, Rashes Nevirapine: best oral bioavailability (95%), all 3 metabolized by CYP450

N/V/D N/V/D, parasthesis, liver toxicity, increased plasma concentrations of other PI's, lipodystrophy syndrome(Cushing like) indirect hyperbilirubinemia, juandice, hepatitis, renal stones, lipodystrophy syndrome (Cushing like) Prolonged Q-T, hyperbilirubenemia, NOTE: there is NO lipodystrophy syndrome

Saquinavir: poor oral (F). All are CYP450 inibitors but Ritonavir is MOST POTENT. All are biliary excreted

HIV

HIV

DOES NOT effect already infected cells only parenteral antiretroviral drug

HIV

hypersensitivity, arthrus reactions

- lipodystrophy syndrome: hyperglycemia, hyperTAG's, fat redistribution (Cushing-like) HAART: 2NRTI's + 1NNRTI 2NRTI's + 1protease Inhibitor NRTI's : "LEAD STAte" NNRTI's: "non-friendly NED" Protease: "RAILS" Respiratory: "POR RAZpiratory viruses" Hepatic: "I knew that pale-ALE would cause hepatitis"

Drug 1st Line TB Rifampin Isoniazid Pyrazinamide Ethambutol Streptomycin 2nd Line TB Amikacin Ethionamide Capreomycin Cycloserine Para-aminosalicylic acid Ciprofloxacin Ofloxacin Rifapentin Rifabutin MAC Drugs Ethambutol Rifabutin Clarithromycin Azithromycin Drug for Leprosy Dapsone Rifampin Clofazimine

MOAbinds beta subunit to inhibit RNA polymerase inhibits mycoloic acid synthesis activation by catalase peroxidase (KatG) --> inhibits 2 enzymes from genes KasA & InhA converted to pyrazinic acid --> lowers pH = inhibiting growth inhibits arabinosyl transferase --> inhibitng arabinogalactan synthesis for cell wall aminoglycoside

UseTherapeutic - TB, Staphlococcal endocarditis, Leprosy. Prophylaxis TB, meningicoccus, Haemophilus influeanzae TB (therapeutic & prophylaxis)

Adverse Effects

Kinetics

Hepatitis, red-orange discoloration, flu-like Hepatitis, anemia, thrombocytopenia, peripheral neuropathy (depletes B6) Hepatitis, gout Optic Neuritis, Gout, hepatitis. NMJ blockade, nephrotoxicity, ototoxicity

Bactericidal, induces P450 (OC's, antiepileptics) Bactericidal, Metabolism - acetylated (genetic variation) Resistence - mutations in KatG & overexpression of InhA. Bactericidal Bactirostatic Bactericidal

TB - given to shorten therapy time TB & MAC - given to delay resistent strains Used when resistence known or suspected

aminoglycoside INH analogue peptide protein synthesis inhibitor prevents incorperation of D-ala to growing monomer --> inhibits cell wall synthesis PABA analog Fluroguinolones Rifamycins Rifapentin = long half-life. Psychosis, peripheral neuropathy. (depletes B6) Hepatitis, intense gastric irritation, peripheral neuropathy. Postural hypotension.

Elsewhere in spreadsheet. NOTE: use neumonic "MAC"-- Treatment: Rifabutin, Ethambutol, Azithromycin, Clarithromycin, Ciprofloxacin. Prophylaxis: Rifabutin, Azithromycin, Clarithromycin.

inhibits folate synthesis

hemolysis in G6PD pt's. Peripheral neuropathy, nephrotic syndrome, exfoliative dermatitis. Optic neuritis. See above. Anti-inflammatoy for erythemia nodosum leprosum (Thalidomide = DOC) Skin pigmentation.

Bacteriostatic. Metabolized - acetylation.

Bacteriostatic

Multibacillary (lepromatous) Leprosy = Dapsone + rifampin + clofazimine Pausibacillary (tuberculoid) Leprosy = Dapsone + rifampin - cortecosteroid use acceptable to create better access for drugs when TB becomes disseminated to meningitis & pericarditis - Initial Phase = 4 drugs for 2 months -Continuous Phase = 2 drugs for 4 months (Isoniazid + Rifampin) -Second line drugs when resistence develops to Isoniazid & Rifampin. -Second lines also have MUCH longer administration period (2 years !!) -NOTE: 1st line TB drugs could cause hepatitis - MAC disease presents itself as pulmonary disease, lymphadenitis, bacteremia - Erythema Nodosum = antigen-antibody response to

-Continuous Phase = 2 drugs for 4 months (Isoniazid + Rifampin) -Second line drugs when resistence develops to Isoniazid & Rifampin. -Second lines also have MUCH longer administration period (2 years !!) -NOTE: 1st line TB drugs could cause hepatitis - MAC disease presents itself as pulmonary disease, lymphadenitis, bacteremia - Erythema Nodosum = antigen-antibody response to mycobacterial antigens

NeurolepticsDrug MOA Typcial Neuroleptics Chlorpromazine Trifluoperazine Thioridazine Fluphenazine Halperidol Atypical Neuroleptics Clozapine Risperidone Olanzapine QuetiapineD4, 5-HT2, H1, M, -1 antagonist (little D2) D2 (main) & 5HT2A, 2/1 antagonist. Antipsychotic agranulocytosis, seizures, paradoxical hypersalivation , ANS toxicity, wieght gain intermediate weight gain risk low potency, minimal EPS, minimal effect on prolactin levels , metabolized by CYP1A2, CYP2D6 low potency. metabolized CYP2D6. NOTE: Risperidone has NO effects on muscarnic receptors low potency Ant- D2, H1, M, -1 Ant- D2,H1, M, -1 Ant- D2, H1, M, -1 Ant- D2, -1 Ant- D2, -1

Therapuetic Usesintractable hiccups, intractable pain, initial tx of mania to hold pt over. vomiting, intractable pain aggressive behavior in children & elderly, intractable pain intractable pain, used in noncompliant pt's, aggressive behavior Tourettes, Hypomania, Stuttering, Aggressive behavior, intractable pain

Adverse Affectscholestatic jaundice (rare)

Drug-Drug Interactions

Pharmacokineticslow potency high potency

highest cardiotoxcity (arrythmias), blindness

low potency, medorizadine (active metabolite). NO antiemitic effect. high potency, IM depot preparations very high potency, IM depot preparations

Antipsychotic

D2 (main) & 5HT2A Antipsychotic, aggressive behavior antagonist. Also blocks weight gain (5-HT2c). Somnolence. NMS (tranquillization) Bipolar I. M, H1, alpha-1, 5HT2C D2, 5HT2A, alpha-1 antagonist psychtoic pt's with PD intermediate weight gain risk

Other Notes on Neuroleptics - blockade is instant (EPS & NMS can manifest) but effects take at least 2-4 weeks (imrovement on psychosis) - must beware of drug-drug interactions with atypicals - all neuroleptic s lower threshold for convulsions --> seizures (most incidence = clozapine) - possibility of neuroleptic malignant syndrome (treatment = dantrolene, bromocriptine, pergolide) -atypicals have less EPS & weight gain - note there are two main adverse effects: (1) Neuroletpic malignant syndrome (2) EPS - all of the phenothizines can prolong QT - deconoate preparations for NON-compliant pt's (injection every couple of weeks) -Weight gain & Q-T interval longation is a problem with atypical neuroleptics & some typical - neuroleptics can disrupt thermoregulatory centers --> dimished ability of body to respond to hot OR cold temps - Traditionals metabolized by P450

Therapeutic Uses of Neuroleptics - Acute Psychosis - Agitation (in mentally retarded & dementias) - Schizophrenia, schizoaffective - Tourette's - Huntington's - Alcoholic hallucinosis - Nausea & Vomiting (phenothiazines) - Preoperative sedation - Pruritis (promethazine) - Intractable Hiccups - Intractable Pain

Drug

MOA

Duration of Action

Therapeutic UsesTonic clonic seizures, muscle relaxant, analgesia, alcohol withdrawl (particularly seizures) Insomnia

Adverse Effects

Kinetics

BenzodiazapinesDiazepam Flurazepam Temazepam Clonazepam Lorazepam Alprazolam Oxazepam Chlordiazepoxide Triazolambinds BDZ receptor at alphagamma interface --> increasing affinity of GABA-A receptor for GABA --> increasing the frequency of Cl- channel opening long long (40-100hrs) medium (8-9hrs) medium medium (10-20hrs) medium (12-15) medium (6-9hrs) Long short (1-1.5hrs)

Contraindicated with the use of SSRI's (inhibit P450), other CNS depressants & in pregnancy. Hangover effects. Temazepam,Lorazepam, oxazepam = Inactive Absence seizures, Panic Disorder Physical & psychological dependence. metabolite - used in elderly . CytP450 Reduced hand-eye coordination. metabolism. Clonazepam is acetylated. Sleep maintance. Status elipticus Decreased REM sleep. Anterograde Avoid diazepam & triazolam (frequent dosings) amnnesia. Tolerance. Reduction in to avoid daytime sedation. Panic disorder, agoraphobia, sensitivity of medulla to PCO2. stress-related anxiety. Paradoxical aggression. Elderly Transient insomnia, initial insomnia, sleep maintaince. Alcohol withdrawl Initial insomnia, transient insomnia GAD Initial insomnia sedation of children & elderly in institutions minimal side effects NOTE: does NOT potentiate other CNS depressents

Non-BenzodiazepinesBuspirone Zolpidem Zaleplon Chloral Hydrate5HT1A autoreceptors???? omega-1 BDZ (only hypnotic) omega-1 BDZ (only hypnotic) short (2-11hrs) short (2hrs) very short (.5hrs) terrible taste

- Flunitrazepam = "roofie" or date rape drug - all benzodiazepines have WIDE THERAPEUTIC INDEX - beta-carboline = BDZ inverse agonist - flumezonil = BDZ antagonist

Therapeutic Uses of Benzo's - Anxiety disorders - Sleep Disorders - Seizure Disorders - Muscle spasms - Spasticity - Induction of 'concious sedation' and amnesia - Induction of General Anesthesia - Ethenol (or barbituate) detoxification

Drug Tricyclics Imipramine (Desipramine) Clomipramine Amitriptyline (Nortriptyline) Others - HC's Trazodone Bupropion Mirtazapine SSRI's Fluoxetine Paroxetine Escitalopram Sertraline Fluvoxamine Venlafaxine* MAOI's Tranylcypromine Phenelzine Bipolar Drugs

MOA

Therapeutic Uses

Adverse Effects

Pharmacology

Blocks re-uptake of 5-HT & NE. Also blockade of -1, M, H1 receptors. {Imipramine > NE, Amitriptyline > 5HT}

Depression, enuresis, panic disorder {imipramine}, neuropathic pain, OCD{clomipramine}

sedation (esp. amitriptyline), sexual dysfunction, weight gain (H1 blockade) , prolong Q-T narrow therapeutic index, P450 metabolism which interval (especially: imipramine & could inhibit metabolism of drugs like anticoagulants. amitriptyline) , anticholinergic effects which may Should not be taken with other CNS depressants. NOTE: alter GI transit time for Li+, digoxin, tylenol, etc. that SSRI's are more potent P450 inhibitors. Orthostatic hypotension, contraindicated in Desipramine is LESS sedating, so use in pt's that pregnancy, decrease seizure threshold, require awakefullness. tachycardia, dry mouth, contraindicated in benign prostatic hypertrophy & glaucoma

MCPP (metabolite) = 5-HT agonist. Trazadone = 5-HT antagonist. Can also block H1 & alpha-1 receptors unclear (DA increase??) blockade of alpha-2 presynaptic receptors on 5HT & NE neurons . Also blocks H1

Depression in pt's with insomnia or agitation (seditive effect). Also can be used in pt's with cardiac problems (less toxic) 2nd choic antidepressant, nicotine withdrawl 2nd choice antidepressant esp in insomnia & agitation (seditive effect). Some anxietlytic & Panic disorders

priapism, orthostatic hypotension, xerostomia, exacerbate ventricular arrythmias Seizures (bulemics). Weight loss. Tremor. agitation, insomnia Weight gain. Sedation. Constipation Contraindicated in pregnancy.

inhibit re-uptake of 5-HT (venlafaxime: also inhibits NE reuptake)

Depression, OCD (fluvoxamine), bulemia, anxiety, panic disorder, phobia, GAD (Venlafaxime)

nausea, anxiety , GI, sexual dysfunction, hypokalemic seizures (bulemics), appetite supression, serotonin syndrome, discontinuation syndromes (suicidal ideation, depression) . Fluvaxime (sedation)

inhibit P450 - CYP2D6 & CYP3A4. Elimination takes at least 1-2 months after disuse (makes withdrawl unlikely & must wait a while before going on MOAI's)

inhibit MAO-A & MAO-B

2nd choice antidepressants, phobic disorders, panic disorders, atypical depression

drug-drug interactions (meperidine, SSRIs, barbiturates, alcohol, pseudoephedrines), catecholamine crisis when eat certain tyramine containing foods

When switching therapy to MAOI's must give at least 6 weeks before administering MAOI's. Phenylzine inactivated via acetylation which shows genetic variation.

Lithium

unknown but several hypothesis: (1) modulation of 2ndry messengers --> inhibition of IP3/DAG & adenylate cylcase. (2) Electrolyte disturbance Li+ mimics role of Na+ (displaces it inside cell) but cannot get pumped out via Na+/K+

Bipolar, adjuvant for depression, schizophrinia

intention tremor, weight gain, diabetes insipidus (polyuria & polydypsia), hypothyroidism narrow TI, drug-drug interactions (1) NSAID's & (goiter), nausea & vomiting, worsening of skin diuretics reduce excretion, (2) ACE inhibitors increases problems, contraindicated in pregnancy, Li+ concentration, (3) cough medicines depress T4 reversible leukocytosis. At chronic high doses production ataxia, cardiac arrythmias, hypotesion, convulsions.

Valproate Carbamazepine

Rapid cyclers

*Default to SSRI as has fewer overall side effects *venlofaxime- SSNRI Serotonin Syndrome = MAOI + SSRI, TC's, HC's Hypertensive Crisis = MAOI + sympathomemetics, tyramine Death Syndrome = MAOI + meperidine - note that they may have various acute mechanisms but the long term mechanisms are the same - act in limbic system and prefrontal cortex - Long Term Mechanism =the increased monoamines in synaptic left causes a down regulation of postsynaptic receptors in CNS (adrenergic & serotonergic) - long term mechanism takes about 2-6 weeks which corresponds to therapeutic response of these drugs - Fluoxetine is the only approved treatment for depression in children - Treatment of serotonin syndrome = dantrolene or cyproheptadine - Wash out periods before starting MAOI: SSRI = 6 weeks HC's & TC's = 2 weeks -Atypical Depression = depression with phobia or psychotic features

Weight gain except SSRI's and brubrion

Therapeutic Uses of Antidepressents - Depression - Panic disorder (tricyclics, SSRI's) - Obsessive-Compulsive Disorder (SSRI's, clomipramine) - Chronic Pain, neuropathic pain - Eating Disorders (bulemia nervosa) - Social Phobia (SSRI's) - Generalizaed Anxiety Disorder (SSRI's) - ADHD (buproprion, imipramine)

Drug

MOA

Effects

Toxicity/Overdose

Withdrawl

Treatment

CommentsTheophylline can be used for reversible airway obstruction e.g. Asthma. Can cross placenta and breast milk so contraindicated in pregnancy and lactation. Because of respiratory stimulation can be used in apnea in neonates, cheyne stokes breathing, opiod respiratory depression.

CNS Stimulantsdecreased appitite, increased peristalsis, tachycardia. blocks adenosine Respiratory stimulation . receptors in CNS. Higher Stimulates reticular formation. doses can inhibit Stimulates medullary response to phosphodiesterase CO2. Increased HR, contractility, causing increased cAMP diuresis, relaxation of bronchial smooth muscle.

Caffeine Theophylline

Insomnia, agitation.

headache, fatigue, drowsiness. Irritability, restlessness, decreased HR & BP

Stop having it

Nicotine

activate (block if high decreased appitite, stimulates dose) nicotinic receptors reticular formation, respiratory in adrenal medulla, CNS, centers, CRTZ, vasomotor center. NMJ, ANS ganglia. Increased BP, HR, vasoconstriction. causes release of catecholamines & indolamines Decreased appitite & weight loss , stereotyped behavior (automatisms)

Central repiratory paralysis from meduallary disruption, PANS blockade causing GI paralysis, decreased in BP. Psychotic state. Convulsions. Anorexia, palpitations, angina, arrythmias.

irritability, restlessness, insomnia, fatigue, constipation, increased appitite & weight gain, anxiou, bradycardia, palpatations, gastric disorders.

Quit

Patch - smoking cessation. Secreted into milk and crosses placenta.

Amphetamines

Cocaine

blocks reuptake of DA (main) , 5HT, NE.

Stereotyped behavior, decreased Seizures, arrythmias, increased appitite, paranoia, hallucinations, BP,mydrasis, perforated nasal agitation.Vasocontrictive to nasal septum, psychosis, hallucinations, mucosa, increased HR, BP, agitation, respiratory depression, alertness. hyperthermia.

Overdose: Acidification of ravenous hunger, fatigue, Can be used for narcolepsy urine. Chlorpromazine can be increased REM sleep. Similar to & ADHD. Effects last longer helpful in controlling ANS & cocaine. than cocaine. psychosis. Can be used as local Overdose: beta- & alphaCrash phase: dysphoria, anesthetic in the eye. blockers. Withdrawl: no tx depresssion, sleepiness, fatiue, Metabolite necessary. Maintainance: bradycardia. Craving phase: benzoylecgonine used in desipramine, want more cocaine urine screening. Half-life avg. fluphenthixol. = 1 hr.

HallucinigensLSD5-HT1A agonist at presynaptic autoreceptors in Raphe nucleus --> 5HT release block glutamanergic NMDA receptors synthesia, SANS & PANS stimulation Horizontal & verticle nystagmus, dissociation experiences, NO feeling of pain, hallucinations, flushing, sweating, combative CNS effects are combination amphetamine & hallucinogen. Tightening of jaw, altered water dynamics, alertness, euphoria. none Most potent hallucinogen. Dependence and tolerance do NOT occur

Phencyclidine (PCP)

"bad trips", ecstasy pt's often present dehydrated from raves, schizophrenic episodes, "flashbacks", agitation

none

In case of bad trip chlorpramazine, diazepam, haloperidol Amphetamine & hallucinogen combo.

MDMA (Ecstasy) Atropine Scopalamine

not clear - may involve 5HT cotransporter reduction

CannabinoidsMarijuanaCannibinoid receptors increased HR, vasodilation, increased BP, bronchodilation conjunctival reddening, euphoria, reduction in intraoccular pressure, muscle relaxant. N/C in pupil size. Increased appitite Horizontal nystagmus None Horizontal nystagmus Used in glaucoma, spasticity releif in MS, and antiemitic for cancer pt's as well as helping with anorexia.

Dronabinol Nabilone

OpiodsHeroinPhysical dependence: Opiate receptors on presynaptic terminals decrease release of NE in locus cereulus which causes upregulation of NE receptors on postsynaptic nuerons. When Opiates withdrawn NE is resumed but with supersensitivity from the increased receptors Primary phase: increased ANS activity (mydriasis, raised Overdose: Naloxone. BP, HR, temp.). Protracted Withdrawl: (1) Methadone (2) phase: reduced ANS activity. Clonidine (3) Clonidine"flu-like"- anxious, Naltrexone. Maintainance: apprehensive, restless, insomnia, buprenorphine, naltrexone. flushes, sweating chills, goosebumps, miosis

loss of conciousness, decreased respiration, cyanosis, decreased BP, constricted pupils

Methadone

CNS Depressents

Ethanol

Overdose: ventilation, Metabolisim: (1) Alcohol sedatives, antipsychotics, dehydrogenase-75% (2) Slurred speech, nystagmus, Decreased BP, Euphoria, Coarse tremor, anxiety, elevated glucose & electrolytes, Microsomal oxidizing works through GABA disinhibited behavior, disinhibition, slurred speech, BP, hallucinations (primarily thiamine. Withdrawl: system-25%. With chronic receptors to enhance incoordination, memory reduced visual acuity, relaxation of visual), delerium tremons Chlordiazipoxide, oxazepam, use men can get cirrohsis of GABA-mediated synaptic impairment, coma, stupor. vascular and uterine smooth (overactive ANS). Gran Mal paraldehyde {nuerotoxic}, liver causing increase transmission. Peripheral vasodilation with volume muscle. seizures. carbamazepine, gabapentin, estrogens leading to loss. SSRI, thiamine. Maintainance: gyenocomastia and testicular disulfiram. atrophy. When given at higher doses will Cause amnesia (used in rape). Can be used for narcolepsy & cateplexy, daytime sleepiness, alcohol withdrawl. Also sold as body-building supplement. Synthesized from GABA breakdown.

Bind GHB receptors and cause massive desensitizaiton Tolerance demonstrated. Can wake act as inhibitory NT's in of GHB receptors resulting in someone from comatose state and the brain inhibiting release of DA, GABA, opiates in hydroxybutyrate cause hyperexcitability, aggressive release of GABA, DA, the brain. Increases secretion of (GHB) behavior. Can cause respiratory opiates. growth hormone --> anabolic effect on protein synthesis. arrest and death.

Yes

Barbiturates

Increases duration of CLchannel of GABA-A receptors

Overdose: gastric lavage & supportive {DO NOT give Weakness, tremor, anxiety, CNS stimulants}. CNS depression, CVS & respiratory orthostatic hypotension, nausea, Withdrawl: Pentobarbitol, problems, sedation, coma. abdominal cramps, agitation. secobarbital, dephenylhydantion (if sezure history present) Overdose: flumazenil Withdrawl: flurazepam.

BZD's

Steroids

- Nicotine, cocaine, amphetamine, ethanol, opiods ---> increase DA levels in nucleus accumbens - increased DA in NA responsible for euphoric effects - recent studies show that naltrexone can reduce alcoholic cravings - LSD, mescaline, ecstacy all involve reducing serotonin effects -Alcohol dehydrogenase rate limited b/c it uses NAD as cofactor which is limited in our body -Microsomal metabolizing system found in liver increases with chronic alcoholism which may accout for tolerance.