INDIRECT-ACTING SYMPATHOMIMETICS ?NET>DAT>SERT ? Amphetamines oMOA: they have a similar structure fo monoamines and are recognized by the Norep transporter (NET) and will be taken up and stored into the vesicles by VMATS? WILL CAUSE A PHYSICAL DISPLACEMENT OF THE vesicular NORepi. oDRUGS: ?
Adderall (Amphetamine Salts) ?Dexedrine (dextroamphetamine) ?Desoxyn (methamphetamine) ?Vyvanse (Lisdexamfetamine) ? Methylphenidates oMOA: inhibits NET so NORepi will remain in the synapse longer oDRUGs: ?Ritalin ?Concerta ?Focalin (dexmethylphenidate) ?USES: treatment of ADHD, Narcolepsy (person falls asleep at any moment) ?ADR:
OPERIPHERAL? VASOCONSTRICTION/REFLEX BRADYCARDIA, increased BP, urinary retention, constriction of GIT causing spasm OCENTRAL?
DECREASED APPEITITE (SHORT LIVED), aggression, paranoia, hallucinations, delusions, euphoric effect, insomnia, overdose can cause cerebral hemorrhage OANTIDOTE? NONE. TREAT SYMPTOMS, GIVE AN antihypertensive like prazosin MISCELLANEOUS INDIRECT-ACTING SYMPATHOMIMENTICS ?DRUGS: oBenzphetamine (Didrex) oDiethylpropion oPhendimetrazine OPROVIGIL (MODAFINIL)? FOR NARCOLEPSY, ALSO WORKS TO increase histamine in the brain and can promote wakefulness ONUVIGIL (ARMODAFINIL)?
FOR NARCOLEPSY, ALSO WORKS to increase histamine in the brain and can promote wakefulness oStrattera (Atomoxitene) ?For ADHD, inhibits only NET so no euphoria or abuse potential, 2nd line treatment not as effective. ?Reversible liver damage, BBW for increase in suicide ?CYP2D6? POOR METABOLIZERS WILL REQUIRE LOWER dose oEphedrine ?Mixed acting havinf indirect and direct agonist effects. ?Used in cough and cold treatment ?Linked to cardiovascular deaths ?Indirect action in brain causes euphoria/wakefulness TRICYCLIC ANTIDEPRESSANTS Pharmacology II Review ?
MOA: work by inhibiting SERT and NET; allows serotonin and NORep to remain in the synapse to interact with postsynaptic receptors ?NONSELECTIVE? CAN BLOCK ALPHA- 1(VASODILATION? LIGHTHEADEDNESS, ORTHOSTATIC hypotension), histamine (sedation) and muscarinic receptors (dry mouth, constipation, urinary problems, blurred vision) ?QUINIDINE TYPE EFFECT? WIDENING OF THE QRS complex due to reduced cardiac conduction ?
Increased weight gain ?OVERDOSE? CAN BE FATAL “LOADED GUN” ?USES: depression, OCD, neuropatic pain (inhibit the reuptake of Norep and 5-HT in the spinal cord to allow the NTs to remain in the synapse longer and reduce release of substance P and glutamate), nocturnal enuresis ?DRUGS: oImipramine ?Desipramine ?
Clomipramine oAmitriptyline (Elavil) ?Nortriptyline oDoxepin oProtriptyline oTrimipramine oMaprotiline oAmoxapine SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs) ?DRUGS oFluovoxamine oSertraline (Zoloft) oCitalopram (Celexa) oParoxetine (Paxil) oEscitalopram (Lexapro) oFluoxetine (Prozac) ?MOA: selectively block SERT and are much safer than TCAs ?ADR: activation of 5-HT2A centrally causes agitation, insomnia, anorexia, sexual dysfunction. Activation of 5-HT3 in GIT can cause vomiting, diarrhea ?DDIS: PAXIL/PROZAC/FLUVOXAMINE? GOOD CYP2D6 inhibitors SEROTONIN-NOREPI REUPTAKE INHIBITORS (SNRIs) ?DRUGS: Pharmacology II Review OVENLAFAXINE (EFFEXOR)?
CAN RAISE BP oDesvenlafaxine (Pristiq) ODULOXETINE (CYMBALTA)? ISSUE OF HEPATOXICITY OMILNACIPRAN (SAVELLA)? *FIBROMYALGIA PAIN ?MOA: selective for only SERT & NET ?ADR: similar to SSRI, insomnia, agitation ?USES: depression, pain, OCD, NOT nocturnal enuresis MONOAMINE OXIDASE INHIBITORS (MAOIs) ?DRUGS: OPHENELZINE (NARDIL) ?
IRRERVERSIBLY INHIBITS MAO- A and MAO-B OTRANYLCYPROMINE? IRRERVERSIBLY INHIBITS MAO-A and MAO-B OSELEGELINE (EMSAM)? SELECTIVE FOR MAOB AND IS reversible. Used as a transdermal patch. ?MAO-Type A: metabolizes most monoamines, type B metabolizes primarily dopamine and NE. ?By inhibiting MAO, you are allowing higher concentrations of the MAO to remain in the synapse to activate the neuron. ?
Interactions: interaction with “tyramine” containing FOODS? CHEESES, RED WINE, PICKLED ITEMS, ETC. COMBO w/sympathomimetic amines can lead to increases in BP, cranial bleeding. oTyramine is a type of indirect acting sympathymimetic that can be taken up into the neuron and displace Norepi which can lead to activation of alpha-1 receptors and a large increase IN BLOOD PRESSURE? HTN CRISIS ?Treatment of serotonin syndrome: supportive care AND CYPROHEPTIDINE **?
A 5-HT2A RECEPTOR Antagonist ?High levels o monomaines in different areas of the brain can increase the production of a substance called brain derived neurotropic factor (BDNF) which can help nerves grow. ATYPICAL ANTIDEPRESSANTS ?DRUG: Bupropion (Wellbutrin) Pharmacology II Review oAntidepressant and smoking cessation agent oCan cause insomnia, weight loss, no sexual dysfunction ?DRUG: Nefazodone oConcern of hepatotoxicity oPotent histamine blocker producing a sedative effect ?DRUG: Trazadone oAlpha1 blocking effects oPotent HI blockers producing a sedative effect ?
DRUG: Vilazadone (Viibryd) oInhibitor of SERT and partial agonist of 5-HT1A claiming to have a faster onset of action than other antidepressants ?DRUG: Mirtazepine oAn antagonist at alpha-, H-1, 5-HT2, and 5-HT3 receptors oWhen we block the alpha-2 receptors we get an increase in the efflux of norepri from the neuron bc alpha-2 is found on serotonergic neurons. ?DRUG: Lithium oPrimiarly used for mania, thought to control the manic portion of bipolar disorder oMOA: no clearly understoof but thought to reduce the effects of monoamines, shown to inhibit the release of norepi from the presynaptic neuron. oNarrow therapeutic index, dehydration puts you at risk for toxicity which can cause muscle tremors, rashes.
TRADITIONAL ANTIPSYCHOTICS ?LIMBIC SYSTEM? AREA OF BRAIN THE CONTROLS OUR emotion, contains D1, D2, D3, and D4 receptors. Activation of these receptors results in agitation, hallucination, hypervigilance ?SCHIZOPHRENIA? POSITIVE SYMPTOMS OF HALLUCINATIONS, paranoia, delusions, aggression. Negative symptoms of being socially withdrawn, lacking cognitive skills. ?Strong evidence that shows psychosis could be due to excessive dopaminergic activity. ?DRUGS: oChlorpromazine (Thorazine) oThioridazine (Mellaril) oFluphenzine (Prolixin) oPerphenazine (Trilafon) oTrifluoperazine oThiothixene (Navane) oHaloperidol (Haldol) oMolindone oLoxapine OPIMOZIDE (ORAP)?
INDICATED FOR *TOURETTE’S Syndrome ?ADR: increase in prolactin, amenorrhea, neuroleptic malignant syndrome (intense muscle tremow/rigidity), tardive dyskinesia (irrerverible movement disorder), arrhythmias, photosensitivity, dermatitis, retinopathies, “extrapyramidal effects” (dystonia, pseudoparkinsonism, muscle rigidity, akathisia) oExtrapyramidal effects typically reversed with the use of anticholinergics such as Benxtropine, trihexyphenidyl. Pharmacology II Review ATYPICAL ANTIPSYCHOTICS ?DRUGS: OARIPIPRAZOLE (ABILIFY)? PARTIAL AGONIST AT D2 OCLOZAPINE (CLOZARIL)? NO RISK FOR TARDIVE dyskinesia ?First of the atypical?
Advantage: lower risk of tardive and movement disorders. Only drug indicated for reducing suicidal thoughts and actions ?ADR: seizures, myocardities, *agranulocytosis ?Pt may exhibit more aggression and agitation oOlanzapine (Zyprexa) oQuetiapine (Seroquel) ORISPERIDONE (RISPERDAL)? METABOLITE OF haloperidol oZiprasidone (Geodon) oPaliperidone (Invega) oLurasidone (Latuda) oAsenapine (Saphris) oIloperidone (Fanapt) oOlanzapine + Fluoxetine (Symbyax) ?As a class have less risk of movement disorders. Bind D2 but with lesser affinity and do not block other receptors as much reducing ADRs ?MORE AFFINITY FOR 5-HT2A RECEPTORS? BENEFIT NOT shown yet ?
These drugs treat both positive and negative symptoms of psychosis** so can improve patients interactions with society and cognitive skills ?ADR: increase in weight, lipids, glucose levels. Arrhythmias. oClozapine and olanzapine worse in increasing these levels oAbilify and Geodon have least effect. Geodone has a black box warning on causing fetal ventricular arrhythmias by blocking the delayed rectifier current. PARKINSON’S DISEASE ?Primiarly due to the loss of dopaminergic neurons in the basal ganglia with symptoms arising with loss of 80% of neurons. Focus on D2 Receptors* ?Gold standard? drugs that are neuroprotective?
AAAD INHIBITORS? AROMATIC AMINO ACID decarboyxalse or dopa decarboxylase inhibitor oDRUG: Carbidopa ?Sinemet= Levodopa+ Carbidopa ?Reduces the amount of peripheral dopamine so less ADR ? COMT Inhibitor oDRUG: Talcapone ?Can cross BBB and inhibit COMT, longer duration of action, significant hepatoxicity* oDRUG: Entacapone (Comtan) ?Cannot cross the BBB, relatively short duration of action but preferred bc no hepatoxicity ?Stalevo= Levodopa+carbidopa+entacapone ?DRUG: Levodopa oPrecursor to dopamine OADR: PERIPHERAL? VASODILATION, ORTHOSTATIC hypotension, reflex tachycardia, melanin (brown SALIVA); CENTRAL?
POTEN EMETIC SO PRONOUNCED nausea and vomiting OSHORT ? LIFE? GET FLUCTUATIONS OF DOPAMINE BLOOD levels ?When too high: dyskinesia and hallucinations ?When too low: bradykinesia, muscle rigidity, and muscle tremors o“wearing off” a type of tolerance that occurs with the dying off of the neurons o“free radicals” can be produced and be neurotoxic and can accerlate neuronal degeneration ? DOPAMINE RECEPTOR AGONISTS OERGOT DERIVATIVES? ACTIVATE DOPAMINERGIC receptors but used today to control *hyperprolactinemia* ?DRUGS: ?Bromocriptine ?Pergolide Pharmacology II Review oTaken off market let to proliferation of mitral valves in heart leading to pulmonary HTN.
?Cabergoline oDRUG: Ropinirole (Requip) ?For *restless leg syndrome* oDRUG: Pramipexole oDRUG: Apomorphine ?Rescue medication when somebody is in the ‘off phenomenon’. Also a potent emetic oThese drugs have longer ? lives so no wearing off phenomenon and no on/off phenomenon. No free radical production oADR: N/V, hallucinations, dyskinesia, pronounced somnolence, “impulse control disorder” ?MOA-B Inhibitors oDRUGS: ?Seligiline (Eldepryl) ?Rasagiline (Azilect) oCan be used for initial and adjunt therapy oADR: stimulant effects because these drugs have amphetamine like metabolites causing insomnia ? Muscarinic Receptor Antagonists.
oDRUGS ?Trihexphenidyl ?Benztropine oTrying to balance the ACh and DA levels. oThese two drug use to treat the extrapyramidial side effects, especially good for tremor. ?DRUG: Amantadine oAn antiviral drug shown to increase dopamine release from neurons as well as blocking muscarinic receptors as well oAdjunt therapy oHelps with akinesia and muscle rigidity ALZHEIMER’S DISEASE ?Neurodegenerative disease where there is destruction of cholinergic neurons mainly in hippocampus and cortex. Want to raise central ACh levels. ?SIMILAR TO MYASTHENIA GRAVIS? WHERE NICOTINIC receptors destroyed at NM junction ? CHOLIESTERASE INHIBITORS.
oDRUG: ?Tacrine (Cognex) ?Donepezil (Aricept) ?Rivastigmine (Exelon) ?Galantamine (Razadyne) oADR: diarrhea, vomiting, headache. ? NMDA RECEPTOR ANTAGONISTS oDRUG: ?Riluzole (Rilutek) ?Memantine (Namenda) oMOA: blocks NMDA receptors; too much GLUTAMATE BINDING TO ITS RECEPTORS? INCREASE INFLUC OF CA2+ INTO THE NEURONS? TOO MUCH CA2+ CAN BE toxic to neurons oHave modest ability to increase cognitive skills Pharmacology II Review AMYOTROPHIC LATERAL SCLEROSIS (ALS) ?Fetal neurodegenerative disease with death in 5yrs (90%) ?Death of the upper motor neurons which goes from the brain down to the lateral column of the spinal CORD?
DEAD NEURONS INFILTRATED BY VARIOUS IMMUNE CELLS? HARDENING OR SCLEROSIS? SPINAL NEURONS DIE? muscle no longer gets stimulation ?DRUG: Riluzole (Rilutek) oMOA: NMDA antagonists ?Decrease glutamate stimulation and removal of glutamate from the synapse ?DRUG: Ceftriaxone o3rd generation cephalosporin that increases the EXPRESSION OF GLT-2 TRANSPORTERS? WILL REMOVE GLUTAMATE FROM THE SYNAPSE? LESS NMDA excitation and neuronal death Pharmacology II Review MULTIPLE SCLEROSIS (MS) ?Disorder where immune system begins to attack the myelin sheath. ?“RELAPSING REMITTING MS”? WHERE OLIGODENDROCYTES remyelinate the nerves and symptoms subside.
As disease progresses the relapse lasts longer than the remission ?DRUG: Interferon Beta oAvonex oRebif oBetaseron oMOA: has ability to suppress the immune system. IV admin OBENEFITS? REDUCED ABILITY FOR T-CELLS TO MOVE OUT OF CIRCULATION INTO CNS, LESS CYTOKINE PRODUCTION? decreased relapses ODISADVANTAGE? PTS DEVELOP NEUTRALIZING AB TO interferon so wearing off over time oADR: flu like symptoms, injection site rxn (lipodystrophy), lower WBC, increase in seizure, increase in heart failure, increase in depression ?DRUG: Copaxone (Glatiramer Acetate) oMOA: immune modulatory agent admin IV to reduce the movement of T-cells into CNS.
oADR: after 15 min, get *transient chest pain, feels like MI ?DRUG: Tysabri (Natalizumab) oMOA: monoclonal AB against a4b1 integrin on T -cells, infusion once a month. oBlocking on this integrin prevent T-cell from interacting with VAM-1 and will not move across the BBB into CNS. OAT RISK FOR *PML? PROGRESSIVE MULTIFOCAL Leukoencephalopathy, a very severe infection of the brain. ?DRUG: Ampyra (Dalfampridine) oMOA: K+ channel blocker to inhibit neuronal conduction so less K+ efflux to improve muscle strength. Taken by mouth. oWhen immune cells attack neuron get DEMYELIENATED NEURON? K+ CHANNEL EXPOSED? K+ LEVELS?
CONSTANTLY HYPERPOLARIZED oADR: increased risk of seizures, increased risk of UTI ?DRUG: Gilenya (Fingolimod) oMOA: prodrug structurally related to sphingosine which will act as an agonist at sphingosine phosphate 1 (S1P1) oS1P1 is found on T-cells to help them migrate out of the thymus and out of the lymph node. When drug binds the receptor becomes internalized and immune cells cannot get into circulation oADR: infections, damage to macular in eyes (eye exams*), lung toxicity, liver toxicity, bradycardia (1st dose phenomenon*) ?DRUG: Novantrone (Mitoxantrone) OFOR SEVERE CASES OF MS? SECONDARY OR PROGRESSIVE.
MS, used for various types of lymphomas because it suppresses B and T cells. oADR: *Severe cardiomyopathy Pharmacology II Review CORTICOSTEROIDS ?Substances help to maintain body’s homeostasis ?HPA Axis? “Diurnal rhythm; substances released at certain times of the day. Undergoes feedback inhibition ?Glucorticoid and Mineralocorticoid Receptor ?GLYCYRRHIZIC ACID? FOUND IN BLACK LICORICE, A SUBSTANCE THAT inhibits 11B-HSD that can induce HTN. It prevents cortisol from being converted to cortisone so high levels of cortisol accumulate? more MR activation? more Na+ channel production, Na+ retention, K+ loss, edema, etc? HTN ? CORTICOSTERIODS.
oMineralocorticoid Agonist ?Fludrocortisone (Florinef) oGlucocorticoid Receptor Agonist ?Cortisol/hydrocortisone ?Prednisone ?Prenisolone ?Cortisone ?Methylprednisolone ?Triamcinoline ?Betamethasone ?Dexamethasone oCRF: Achthrel ?Used to indicate if secondary adrenal insufficiency (defect in hypothalamus) oACTH: Cosyntropin ?Used to determine is patient has primary adrenal insufficiency (Defect in adrenal cortex) ?
Uses of Corticosteroids OREPLACEMENT THERAPY? PATIENTS WITH ADRENAL insufficiency (Addison’s Disease, Confenital Adrenal Hyperplasia) oImmunosuppressants oAnti-Inflammatory Drugs ?IKB chaperone proteins release complex of NFKB which will go into the nucleus to increase transcription of inflammatory genes (cyclooxygenase 2, cytokines, and cell adhesion molecules) ?Use glucocorticoids as anti-inflammatory drugs BECAUSE? INCREASE TRANSCRIPTION OF IKB (NO NFKB release) and Annexin-1 (inhibits PLA2 so less PGE2).
Directly interacts with NFKB to inhibit production of pro-inflammatory genes ?ADR: Hyperglycemia, loss of muscle mass, thinning of skin, lipolysis (*buffalo hump), cataracts, reduced bone mineral density (reduce activity of osteoblasts), immunosuppression, increase in stomach acids, HTN, insomnia, psychosis, depression ?Negative feedback will shut down endogenous production of corticosteroids. It will take a few days for enzymes to be turned back on so TAPER patient off slowly. ? CORTISOL SYNTHESIS INHIBITORS oDRUG ?
Trilostane ?Aminoglutethimide ?Metryapone ?Ketoconazole oMOA: inhibit enzymes in liver responsible for cortisol synthesis oUSES: Cushing’s diease Pharmacology II Review IMMUNOSUPPRESSANTS ? L OOKING AT T CELLS? MAJOR ROLE IS TO PROLIFERATE WHEN presented with antigens by antigen presenting cells. ?Summary: Dendritic cells or antigen presenting cells bind to T cell receptors? activates PLC? generation of IP3? increases intracellular levels of Ca2+? activates Calcineurin?desphorylate NFAT?
NFAT enters the nucleus and act as a transcription factor? enhances the transcription of IL-2? IL-2 protein will leave a cell and activate IL-2 receptors on T-cells? activates CDK? rapid proliferation of more T-cells ?For prevention of organ rejection post transplantation ?DRUG: Cyclosporine oMOA: derived from fungus; it binds to cyclophillin to form a complex that inhibits calcineurin so less dephosphorylation of NFAT less IL-2 gene transcription and less proliferation of T-cells oADR: nephrotoxicity*, HTN, neurotoxicity/seizures, muscle tremors, hirsutism. Narrow therapeutic index ?DRUG: Tacrolimus (Prograf).
oMOA: Binds to FKBP12 (another immunophillin) to form a complex to inhibit calcineurin oADR: tremors, seizures, hirsutism, **less HTN and hyperlipidemia OPROBLEM? TENDS TO DESTROY BETA CELLS OF PANCREAS? hyperglycemia, an induced diabetic state ?DRUG: Pimecrolimus (Elidel) oSimilar to tacrolimus oTopical preparation for psoriasis ?DRUG: Sirolimus (Rapamune) oSometimes referred to as rapamycin oMOA: binds FKBP12 to inhibit protein called mTOR which will work to further inhibit CDK2 which is essential for cell cycle oADR: increases is triglycerides and fatty acids, reductions in blood cells oBe consistant when taking with or without food to avoid drug fluctuations. ?
DRUG: Everolimus oMOA: binds to FKBP to inhibit CDK ?DRUG:Azathiopurine (Imuran) oMOA: work by inhibiting nucleotide synthesis. Drug is metabolized to 6-mercaptopurine than 6- thioguanine and when incorporated into DNA strand in place of guainine will halt DNA replication. o6-mercaptopyrine metabolized by xanthine oxidase (lower dose if pt on allopurinol) and thiopurine methyltransferase (TPMT; a polymorphic enzyme, if pt has low levels can cause fatal anemia) oADR: decrease in WBS, RBC, platelets ?DRUG: mycophenolate Mofetil (Cellcept, Myfortic).
oMOA: prodrug metabolized into MPA to inhibit inosine dehydrogenase which is important for the synthesis of purines and will thus make it more difficult for cells to replication and proliferate oADR: decrease WBC, RBS, platelets ?DRUG: Daclizumab oMOA: monoclonal AB against CD25 used in ‘induction phase’ of transplant to suppress immune system. ?DRUG: Basiliximab oMOA: monoclonal AB against CD25 used in ‘induction phase’ of transplant to suppress immune system. ?DRUG: Muromonab-CD3 oMOA: Monoclonal AB against CD3 which will produce a rapid internalization of Tcell receptor and rapid depletion of Tcells from blood stream oUSE: in ACUTE rejection of organ, not for infuction of maintance.
oADR: cytokine release syndrome which can lead to muscle aches, joint aches, fever, cardiovascular COLLAPSE? PRETREAT WITH GLUCOCORTICOIDS TO PREVENT this. RETINOIDS ?MOA:binds to either two receptors in nucleus ORAR? PRIMARILY IN SKIN TO REDUCE INFLAMMATION and promote epithelial differenation ORXR? PRIMARILY INVOLVED IN APOPTOSIS IN CELLS Pharmacology II Review ?Are nuclear hormone receptors and function as heterdimers acting as transcription factors to bind to promoter region that has retinoic response element ?1st generation DRUGS: oTretinoin (Retin-A) ?ADR: photosensitive (apply at bedtime), broken down by benzoyl peroxide.
oIsotretinoin (Accutane) ?2nd Generation DRUGS: oAcitretin (Soriatane) ?Very long half life, patient has to wait a long time before trying to get pregnant ?3rd Generation DRUGS: oTazarotene oBexarotene ?Binds RXR and is used orally for types of cancers (T cell lymphomas) oAdapalene (Differin) oCalcipotrene(Dovonex) ?Binds vitamin D receptors but similar effects as retinoids ?USES: treatment of ACNE & PSORIASIS ?These drugs reduce production of sebum and increase the turnover for epithelial cells ?ADR: drying out of skin, increases if cholesterol/lipids, hepatoxicity, depression/suicidal thoughts, reduces nightvision, teratogenicity. O.