New Medications Presentation

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New Medications Presentation

• Jayne S. Reuben, PhD
• jreuben_at_bcd.tamhsc.edu
• 2008 National Primary Oral Health Care
  Conference
• November 13, 2008

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Objectives

• After review of this material, the dental
  professional should be able to
• Recognize the clinical indications of recent
  drugs approved by the FDA
• Explain the mechanism of actions of the drugs
  discussed in this presentation
• Identify their clinically relevant adverse
  reactions and drug interactions

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Outline

• Diabetes
• CNS
• Cancer
• Pulmonary/CVS
• HIV-1 Infection
• Misc

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New Medications-Diabetes

• DPP4 (Dipeptidyl Peptidase IV ) inhibitors
• sitagliptin phosphate (JANUVIA)
• vildagliptin (not approved)
• sitagliptin and metformin (JANUMET)
• Incretin mimetics
• exenatide (BYETTA)
• Antihyperglycemic analogues
• pramlintide acetate (SYMLIN)

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Incretin Hormones

• GLP-1glucagon-like peptide-1
• GIP glucose-dependent insulinotropic polypeptide
  (aka gastic inhibitory peptide)
• Both promote ?-cell proliferation in pancreas,
  inhibit apoptosis
• GLP-1 also stimulates insulin secretion, inhibits
  gastric emptying, inhibits glucagon secretion,
  promotes satiety
• Release is stimulated by nutrient ingestion and
  degraded by dipeptidyl peptidase-4 (DPP-4).

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GLP-1 and GIP
Cell Metabolism, Volume 3, Issue 3, 2007
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Effects of GLP-1
Cell Metabolism, Volume 3, Issue 3, 2007
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Effects of GLP-1
Cell Metabolism, Volume 3, Issue 3, Pages 153-165
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DPP4 (Dipeptidyl peptidase IV ) inhibitors

• Drugs sitagliptin phosphate (JANUVIA), po
• vildagliptin
• sitagliptin and metformin (JANUMET)
• MOA inhibiting the inactivation of incretin
  hormones- GLP-1 and GIP
• Indication adjunct to treat type 2 diabetes
• Adverse URI, headache
• runny nose, sore throat
• CI type I diabetes, renal dz
• gastroparesis,hypersensitivity
• diabetic ketoacidosis,
• caution in pregnancy

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Incretin Mimetic

• exenatide (BYETTA), sc pen
• Synthetic GLP-1 receptor agonist
• MOA Binding results in ? glucose- dependent
  insulin synthesis and secretion, ? glucagon
  secretion, ? gastric emptying and ? food intake
• Used for type 2 diabetes alone or with other meds
  (not insulin)
• Adverse NV, diarrhea, hypoglycemia, antibodies
• CI hypersensitivity, type 1 or diabetic
  ketoacidosis severe renal impairment

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Antihyperglycemic Analog

• pramlintide acetate (SYMLIN), sc
• Synthetic analog of human amylin-secreted by ?
  cells to control postprandial glucose
• MOA ? glucagon, ? gastric emptying,? satiety
• Indication adjunct with insulin for type 1 and
  2 (with sulfonylureas metformin in type 2)
• Adverse severe hypoglycemia, NV, diarrhea
• CI hypersensitivity, gastroparesis,
  hypoglycemic unawareness
• DI anticholinergics, ?-glucosidase inhibitors,
  oral agents

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(No Transcript)
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Dental Implications

• DI Propoxyphene, NSAIDs enhance hypoglycemia
• Also, ?-blockers and ACE inhibitors
• Morning appointments to minimize stress-related
  hypoglycemia
• Keep glucose on hand -if hypoglycemia becomes
  severe, pt may become unconscious.

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CNS

• Parkinsons
• Rotigotine (NEUPRO)- RECALLED
• Rasagiline (AZILECT)
• ADHD
• Lisdexamfetamine Dimesylate (VYVANSE)
• Epilepsy
• Levetiracetam (KEPPRA)
• Oxcarbazepine (TRILEPTAL)
• Schizophrenia
• Paliperidone (INVEGA)

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Parkinsons Disease Agents that Increase
Dopamine functions

• Replacing the synthesis of dopamine - L-Dopa
• Combination Pills
• L-dopa carbidopa (SINEMET)
• Inhibiting the catabolism of dopamine
• selegiline (ELDERPRYL) rasagiline (AZILECT)
• entacapone (COMTAN) tolcapone (TASMAR)

SE Orthostatic Hypotention
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Parkinsons Disease Agents that Increase
Dopamine functions

• Stimulating the dopamine receptor sites directly
  
• bromocriptine (PARLODEL)
• pramipexole (MIRAPEX)
• ropinrole (REQUIP, REQUIP XL
• rotigotine (NEUPRO)-RECALLED
• Blocks uptake and enhances dopamine release
  amantadine (SYMMETREL)
• Stimulating the release of dopamine - amphetamine

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Rotigotine (NEUPRO)

• Transdermal Patch system for early-stage
  parkinsons
• Common side effects NV, dizziness, allergy
  sleep, disturbances, headache
• Serious Adverse effects
• falling asleep, low BP,
• fainting, hallucinations,
• compulsive behavior
• RECALLED on May 1, 2008

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Agents that decrease Acetylcholine function

• Blocking Acetylcholine receptors
• Atropine
• benztropine (COGENTIN)
• biperiden (AKINETON)
• procyclidine (KEMADRIN)
• Inhibit Acetylcholine production
• trihexyphenidyl (formally ARTANE)
• Side effects from blocking Acetylcholine
• Dry mouth, Urinary retention, Blurred vision,
  Constipation

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Lisdexamfetamine Dimesylate (VYVANSE)

• 1st prodrug ADHD but not for long term use (gt4
  wk)
• High potential for abuse
• Some dry mouth
• growth suppression, pyrexia sudden death, stroke,
  MI,
• The effects of tricyclic antidepressants,
  meperidine, phenobarbital and phenytoin may be
  potentiated by amphetamines.
• CI hypertension, hyperthyroidism, glaucoma
  history of drug abuse, MAOIs w/in 14d

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Antipychotics/Schizophrenia

• Typical block DA
• Haloperidol (HALDOL)
• Loxapine (LOXITANE)
• Molindone (MOBAN)

• Atypical- block DA 5-HT
• clozapine (CLOZARIL, FASACLO ODT)
• olanzepine (ZYPREXA)
• quetiapine (SEROQUEL)
• aripirazole (ABILIFY)
• respiridone (RESPERDAL)
• paliperidone (INVEGA)
• ziprasidone (GEODON)

Newer Atypicals block DA and 5-HT receptors.
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TYPICAL vs ATYPICAL

• Typical
• Extrapyramidal effects
• Hyperprolactinemia
• Sedation
• Orthostatic hypotension
• Neuroleptic Malignant syndrome
• Moderate Weight Gain
• Dry Mouth

• Atypical
• Extrapyramidal effects?
• Diabetes Mellitus
• Hyperprolactinemia
• Orthostatic hypotension
• Hypercholesterolemia
• Sedation ?
• Weight Gain
• Seizures
• Prolonged QT, Vent Arrhythmias
• Agranulocytosis
• Dry Mouth

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Paliperidone (INVEGA)

• New Atypical for Schizophrenia but NOT approved
  for dementia-related psychosis
• Metabolite of resperidone
• Hypersensitivity reactions, including
  anaphylactic reactions and angioedema, have been
  observed in patients treated with risperidone and
  paliperidone.
• Minimal anti-cholinergic effects

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Mechanisms of AEDs
Phenobarbital Benzodiazepine Valproic
acid Gabapentin?
Phenytoin Carbamazepine Valproic acid
Ethosuximide Valproic acid
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The Players- AEDs

• Old School
• phenobarbital (1912)
• phenytoin (1938)
• carbamazepine (1952)
• ethosuximide (1958)
• valproic acid (1963)
• benzodiazepines (1965)

• Newbies
• felbamate (1993)
• gabapentin (1994)
• lamotrigine (1994)
• tiagabine (1997)
• topiramate (1998)
• levetiracetam (1999)
• zonisamide (2000)
• oxcarbazepine (2003)
• vigabitrin (not approved)

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levetiracetam (KEPPRA)

• Inhibits synchronous neuronal firing by an
  unknown mechanism
• T1/2 6-8, clinical effect longer ? bid
• Approved add-on but increasingly 1st line for
  CPS, GTC
• Psychiatric (may be alleviated with B6),
  sedation, ataxia
• Renally cleared, no hepatic metabolism
• No known drug interactions

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oxcarbazepine (TRILEPTAL)

• Blocks Na channels
• T1/2 10, bid
• 1st line or add-on for CPS
• Fewer side-effects than CBZ since no epoxide
  metabolite
• Hyponatremia, rash, ataxia, sedation
• Induces UGT, CYP3A4. Inhibits 2C19.
• Some drug interactions, esp decr OCPs

aprepitant, aripiprazole, barbiturates,
bortezomib, bosentan, buprenorphine, BZDs, all,
CCBs, dihydropyridines, contraceptives, oral,
contraceptives, other, disopyramide, docetaxel,
efavirenz, eplerenone, ethanol, gefitinib,
itraconazole, ketoconazole, lamotrigine,
paclitaxel, phenytoins, repaglinide, risperidone,
sildenafil, sodium oxybate, tadalafil, tricyclic
antidepressants, verapamil, voriconazole
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Cancer

• Granisetron Transdermal System (SANCUSO)
• similar to Ondansetron (ZOFRAN)
• (5-HT3) receptor antagonist N V
• Nilotinib HCl Monohydrate (TASIGNA) CML
• Bcr-Abl kinase inhibitor
• see also imatinib (GLEEVEC)

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Cancer

• Temsirolimus (TORISEL) adv renal cell
• sim sirolimus (RAPAMUNE)
• tacrolimus (PROGRAF)

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Metastatic/advanced breast Cancer

• Lapatinib Ditosylate (TYKERB) adv breast
• MOA EGFR tyrosine kinase inhibitor
• SE stomatitis
• Admin w/ capecitabine (XELODA)
• Ixabepilone (IXEMPRA)
• MOA microtubule inhibitor
• SE sensory neuropathies, stomatitis,
  mucositis

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Cancer Biologics
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Pulmonary/CVS

• Aliskiren (TEKTURNA)-hypertension
• MOA renin inhibitor
• SE
• Nebivolol (BYSTOLIC) hypertension
• MOA ?1-selective antagonist
• SE
• Ambrisentan (LETAIRIS)- PAH
• MOA endothelin receptor antagonist SE

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HIV-1 Infection

• Maraviroc (SELZENTRY)
• MOA CCR5 antagonist
• SE Hepatoxicity, URI, Pyrexia
• CCR5-tropic HIV-1 detectable, drug- resistant
• Raltegravir Potassium (ISENTRESS)
• MOA HIV-1 integrase strand transfer
  inhibitor (HIV-1 INSTI)

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Miscellaneous

• Doripenem (DORIBAX) Intra-ab and UTIs
• Methoxypolyethylene glycol-epoetin ?eta
• (MIRCERA)
• Patients w/ chronic renal failure

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Drug Classes which may cause Xerostomia
http//www.pharmacytimes.com/issues/articles/2007-
11_002.asp
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References

• Pharmacy Times http//www.pharmacytimes.com
• Drugs_at_FDA http//www.accessdata.fda.gov/scripts/c
  der/drugsatfda/index.cfm
• Mosbys Dental Drug Reference 2008
• NIH Institute websites www.nih.gov