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New Medications Presentation
Jayne S. Reuben, PhD
[email protected]
2008 National Primary Oral Health Care Conference
November 13, 2008
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
Outline
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•
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Diabetes
CNS
Cancer
Pulmonary/CVS
HIV-1 Infection
Misc
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)
Incretin Hormones
• GLP-1:glucagon-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).
GLP-1 and GIP
Cell Metabolism, Volume 3, Issue 3, 2007
Effects of GLP-1
Cell Metabolism, Volume 3, Issue 3, 2007
Effects of GLP-1
Cell Metabolism, Volume 3, Issue 3, Pages 153-165
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
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: N&V, diarrhea, hypoglycemia,
antibodies
• CI: hypersensitivity, type 1 or diabetic
ketoacidosis severe renal impairment
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, N&V, diarrhea
• CI: hypersensitivity, gastroparesis,
hypoglycemic unawareness
• DI: anticholinergics, -glucosidase inhibitors,
oral agents
MEDICATIONS FOR TYPE 2 DIABETES
Classification
Medication
Route
The way it
works
Time and Dose
Sulfonylureas
Glimepiride
(Amaryl)
Glipizide
(Glucotrol)
Glipizide ER
(Glucotrol XL)
Glyburide
Oral
Increases
insulin
production
1 or 2 times a
day
Biguanides
Glucophage
(aka Metformin)
Glucophage XR
Oral
Lowers glucose
from digestion
2-3 times a day,
XR once a day
Take before
each meal
AlphaGlucosidase
Inhibitors
Glyset and
Precose
Oral
Slows
digestion, slows
glucose
production
Thiazolidinedion
es
Actos and
Avandia
Oral
Lowers glucose
production
Once daily with
or without food
Meglitinides
Prandin and
Starlix
Oral
Increases
insulin
production
5-30 minutes
before meals
Oral
Lowers glucose
by blocking an
enzyme
100 mg. once a
day
Injectable
Helps the
pancreas make
insulin, slows
digestion
10 mcg. Inject
within an hour
of AM and PM
meals
Injectable
Controls
postprandial
blood glucose
15 mcg. Inject
before major
meals
DPP-4 Inhibitors
Incretin
Mimetics
Antihyperglycemic
Januvia
Byetta
Symlin
Dental Implications
• DI: Propoxyphene, NSAIDs enhance
hypoglycemia
– Also, -blockers and ACE inhibitors
• Morning appointments to minimize stressrelated hypoglycemia
• Keep glucose on hand -if hypoglycemia
becomes severe, pt may become
unconscious.
CNS
Parkinson’s:
Rotigotine (NEUPRO)- RECALLED
Rasagiline (AZILECT)
ADHD:
Lisdexamfetamine Dimesylate (VYVANSE)
Epilepsy:
Levetiracetam (KEPPRA)
Oxcarbazepine (TRILEPTAL)
Schizophrenia:
Paliperidone (INVEGA)
Parkinson’s 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
Parkinson’s 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
Rotigotine (NEUPRO)
• Transdermal Patch system for early-stage
parkinson’s
• Common side effects: N&V, dizziness, allergy
sleep, disturbances, headache
• Serious Adverse effects:
falling asleep, low BP,
fainting, hallucinations,
compulsive behavior
RECALLED on May 1, 2008
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
Lisdexamfetamine Dimesylate
(VYVANSE)
• 1st prodrug ADHD but not for long term use (>4 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
Antipychotics/Schizophrenia
Typical: block DA
Atypical- block DA & 5-HT
Haloperidol (HALDOL)
clozapine (CLOZARIL,
FASACLO ODT)
Loxapine (LOXITANE)
olanzepine (ZYPREXA)
Molindone (MOBAN)
quetiapine (SEROQUEL)
aripirazole (ABILIFY)
respiridone (RESPERDAL)
paliperidone (INVEGA)*
ziprasidone (GEODON)
Newer Atypicals block DA and 5-HT receptors.
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
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
Mechanisms of AEDs
Phenytoin
Carbamazepine
Valproic acid
Phenobarbital
Benzodiazepine
Valproic acid
Gabapentin?
Ethosuximide
Valproic acid
The Players- AEDs
Old School
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•
•
•
•
•
•
•
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)
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
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
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)
Cancer
Temsirolimus (TORISEL): adv renal cell
sim sirolimus (RAPAMUNE)
tacrolimus (PROGRAF)
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
Cancer Biologics
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:
HIV-1 Infection
• Maraviroc (SELZENTRY)
MOA: CCR5 antagonist
SE: Hepatoxicity, URI, Pyrexia
CCR5-tropic HIV-1 detectable, drugresistant
• Raltegravir Potassium (ISENTRESS)
MOA: HIV-1 integrase strand transfer
inhibitor (HIV-1 INSTI)
Miscellaneous
• Doripenem (DORIBAX): Intra-ab and UTIs
• Methoxypolyethylene glycol-epoetin eta
(MIRCERA)
– Patients w/ chronic renal failure
Drug Classes
which may
cause
Xerostomia
http://www.pharmacytimes.com/is
sues/articles/2007-11_002.asp
References
• Pharmacy Times
http://www.pharmacytimes.com
• Drugs@FDA
http://www.accessdata.fda.gov/scripts/cder/
drugsatfda/index.cfm
• Mosby’s Dental Drug Reference 2008
• NIH Institute websites www.nih.gov