3. In stage IIB:
• larger than 2 centimeters but not larger than 5 cm.
small clusters of breast cancer cells (larger than
0.2 millimeter but not larger than 2 millimeters)
are found in the lymph nodes
• larger than 2 centimeters but not larger than 5
centimeters. Cancer has spread to 1 to 3 axillary
lymph nodes or to the lymph nodes near the
breast bone (found during a sentinel lymph node
biopsy); or
• larger than 5 centimeters. Cancer has not spread
to the lymph nodes.
4.
5. Recurrent Breast Cancer
• Recurrent breast cancer is cancer that has
recurred (come back) after it has been
treated. The cancer may come back in the
breast, in the chest wall, or in other parts of
the body.
6. Tamoxifen is beneficial in postmenopausal women
when used alone or in combination with cytotoxic
chemotherapy
Present recommendation: administer tamoxifen for 5
years of continuous therapy after surgical resection.
Postmenopausal women who complete 5 years of
tamoxifen therapy should be placed on an aromatase
inhibitor such as anastrozole for at least 2.5 years
In women who have completed 2–3 years of
tamoxifen therapy, treatment with an aromatase
inhibitor for a total of 5 years of hormonal therapy is
now recommended
7. Metastatic Breast Cancer
Radiation therapy, hormonal therapy, and chemotherapy
have all been used in the treatment of metastatic breast
cancer to palliate the patient and possibly prolong survival.
Palliation is the primary goal of therapy:
the easiest, least toxic treatment that can provide the
best possible response is generally preferred.
• metastasize to virtually any site
• most common sites: bone, lung, pleura, liver, soft tissue,
and the central nervous system.
• The choice of therapy for metastatic disease is based on
the site of disease involvement and the presence or
absence of certain patient characteristics.
9. Radiation
Radiation therapy is primarily used to control
symptomatic disease such as bone metastases,
metastatic brain lesions, and spinal cord
compressions.
10. Hormonal therapy
The goal of hormonal therapy is to reduce the stimulation
of the tumor cells by estrogen.
Tamoxifen, has been the adjuvant hormonal therapy most
commonly used.
most common side effects: hot flashes and vaginal
discharge, but an increased risk of thromboembolic
events and endometrial cancer can also occur.
Fulvestrant, an injectable pure estrogen antagonist, has
also shown activity in patients with hormone-receptorpositive disease progressing on hormonal therapy.
11. Efficacy
Safety
Suitability
Cost
Antiestrogen
Tamoxifen
+++
selective estrogen
receptor
modulator or
SERM
++
Disease flare, hot
flashes;
rare:
thrombophlebitis,
ocular abnormalities,
endometrial cancer
++
premenopausal and
postmenopausal women (and
men) with ER-positive earlystage breast cancer
1,40
0
Aromatase
Inhibitors
3rd gen:
anastrazole
+++
Blocking
aromatase in fat
tissue that is
responsible for
making small
amounts of
estrogen in postmenopausal
women
+++
Hot flashes, nausea,
vomiting, headache,
fatigue;
rare: bone fractures,
musculoskeletal
disorders
+++
+++
initial therapy for metastatic
2750
hormone-sensitive breast
cancer
treat postmenopausal women
with advanced breast cancer
whose disease has worsened
after treatment with
tamoxifen
Pure
Estrogen
Antagonist
Fulvestrant
+++
+++
Hot flashes,
headache, nausea,
vomiting, injection
site reactions
++
postmenopausal women with
metastatic ER-positive breast
cancer after treatment with
other antiestrogens
+++
28,0
00
12. Median duration of response to the first attempt at
hormonal manipulation is usually in the range of 9
to 12 months.
First-line hormonal therapy should be administered
for at least 6 to 8 weeks before disease response is
assessed.
If a patient becomes refractory to hormonal
therapy at any time, chemotherapy should be
given.
13.
14. Natural product cancer chemotherapy
drugs: Clinical activity and toxicities
DRUG
MOA
TAXANE
Inhibits mitosis
Paclitaxel
ANTHRACYCLINE
Doxorubicin
Oxygen free
radicals bind to
DNA causing
single- and doublestrand DNA breaks;
inhibits
topoisomerase II;
intercalates into
DNA
CLINICAL APPLICATIONS
ACUTE TOXICITY
Breast cancer, nonsmall cell and small cell
lung cancer, ovarian
cancer,
gastroesophageal
cancer, prostate cancer,
bladder cancer, head
and neck cancer
Nausea,
vomiting,
hypotension,
arrhythmias,
hypersensitivity
Myelosuppression,
peripheral
sensory
neuropathy
Nausea, red
urine (not
hematuria)
Cardiotoxicity
, alopecia,
myelosuppre
ssion,
stomatitis
Breast cancer, Hodgkin’s
and non-Hodgkin’s
lymphoma, soft tissue
sarcoma, ovarian cancer,
non-small cell and small
cell lung cancer, thyroid
cancer, Wilms’ tumor,
neuroblastoma
DELAYED
TOXICITY
15. DRUG
MOA
CLINICAL
APPLICATIONS
ACUTE
TOXICITY
Breast cancer,
non-small cell
lung cancer,
prostate cancer,
gastric cancer,
head and neck
cancer, ovarian
cancer, bladder
cancer
Neurotoxicity,
Hypersensitiv fluid retention,
myelosuppression
ity
with neutropenia
TAXANE
Docetaxel
Inhibits mitosis
Mitomycin
Superficial
Acts as an
bladder cancer,
alkylating agent gastric cancer,
and forms cross- breast cancer,
links with DNA; non-small cell
forma- tion of
lung cancer, head
oxygen free
and neck cancer
radicals, which
(in combination
with
target DNA
radiotherapy)
Nausea and
vomiting
DELAYED TOXICITY
Myelosuppression
, mucositis,
anorexia and
fatigue,
hemolytic-uremic
syndrome
18. The American Society of Clinical Oncology
(ASCO) breast cancer surveillance guidelines:
• Women with a history of breast cancer should
perform monthly BSE and undergo annual
mammography of both the preserved and
contralateral breast.
• The patient should also have a complete
history and physical examination every 3 to 6
months for the first 3 years after diagnosis,
then every 6 to 12 months for 2 years, and
then annually.
20. Basis for Diagnosis
• Chief Complaint: Severe (7 out of 10) hip pain
• Bone scan: multiple metastases to the right
pelvis
• Medications: Ibuprofen 200 to 400 mg PO q4–
6h PRN, calcium carbonate 1,000 mg PO TID
with meals
21. Treatment Objectives
• To decrease the severity of pain
• To minimize adverse reactions or intolerance
to pain management therapies
• To improve the patient’s quality of life and
optimize ability to perform activities of daily
living
22. Bone most common site of secondary breast
cancer
Most common: the spine, skull, pelvis and upper
bones of the arms and legs
http://orthoinfo.aaos.org/figures/A00654F08.jpg
23. • Pain is defined as ‘an unpleasant sensory and
emotional experience associated with actual
or potential tissue damage, or described in
terms of such damage
• most common symptom that provokes people
to seek medical attention
24.
25. KEY POINTS
• Oral route is preferred unless contraindicated
• Cancer pain is continuous
• Should be scheduled at regular intervals rather than
prn
• Adjuvant therapy is used to decrease anxiety and
fear with chronic pain (e.g. antidepressants)
26. Opioids
• refers broadly to all compounds related to
opium, a natural product derived from the
poppy
• produce analgesia, affect mood and rewarding
behavior and alter respiratory, cardiovascular,
GI, and neuroendocrine function
31. Side Effects
• Common: Constipation, nausea, vomiting and
somnolence
• Mood changes
• Addiction and physical dependence
• Respiratory complication
32. Drug
Efficacy
Suitability
Side Effects
Safety
Cost
Morphine
++++
++++
+++
++++
• Common: constipation, nausea, vomiting, 60's
(P1345.00/pack)
miosis and somnolence
Hydromorphchanges
++++
++++
+++
++
• Mood
28's
one
(P3640.00/pack)
• Addiction and physical dependence
• Respiratory depression most common
Fentanyl of death of acute overdose
+++
++
+++
+++
cause
5 × 1's
(P2513.00/box)
Methadone
++++
+
+++
+
33. DOC: Morphine Sulphate
- Prototype opioid agonist
- exert major pharmacodynamic effects on mureceptors (strong) and kappa-receptors
- Main indication is for preoperative pain and
chronic malignant pain
34. Plan of Action
Initiate Morphine Sulphate immediate release
15mg PO q3-4hours
If the opiate requirement is determined, switch
to a sustained release formulation
35. Plan of Action
Start with:
- Senna 1 tablet PO BID
- Docusate sodium 100 mg PO BID
- Ibuprofen 800mg q8h with food
- pamidronate 90 mg IV over 2 hours every 4
weeks (Check SCr prior to each dose)
36. Monitor Efficacy and Toxicity
Report any prolonged adverse events, severe
confusion/lightheadedness, or difficulty
breathing
important to take the pain medication around
the clock to prevent the pain from recurring
37. Hypercalcemia of Malignancy
secondary to Bone Metastases
Reported by:
Edward Philip I. Villanueva, MD, FPCP,
FPGS, FPCCP
CHAIRMAN PHARMACOLOGY
DEPARTMENT
38. I. Basis for Diagnosis
• Breast Cancer: commonly associated with
hypercalcemia
• Pain on the right hip
• Decreased appetite
• Increasing fatigue
• Constipation
• More forgetful
• Confusion
• Calcium level: 12.5mg/dl (NV: 9.0-10.8mg/dl)
39. II. Treatment Objectives
• To reduce serum calcium level
• To reverse signs and symptoms of
hypercalcemia
• Avoid exacerbation of hypercalemia
• Reduce gastrointestinal calcium absortion
41. Loop diuretics
• MOA: Enhances urine flow and also inhibits
calcium reabsorption in ascending loop of
Henle
• A/E: ototoxicity, hypovolemia, K wasting,
Hyperuricemia, Hypomagnesemia
• Route: Oral, IV
42. Calcitonin
• MOA: Lowers plasma Ca⁺² and Phosphate
concentrations, blocking bone resorption and
increases urinary calcium excretion by
inhibiting renal calcium reabsorption
• A/E: Nausea, vomiting
• Route: SQ, intranasal, oral
43. Gallium Nitrate
• MOA: Inhibiting bone resorption, reducing
serum calcium in Cancer patient
• A/E: Nephrotoxicity
• Route: Oral
44. Plicamycin
• MOA: Inhibiting bone resorption, reducing
serum calcium in Cancer patient
• A/E: sudden Thromocytopenia, hemorrhage,
hepatic and renal toxicity, hypocalcemia, N/V
45. Phosphate
• MOA: Binds to Calcium ions
• A/E: Hypocalcemia, ectopic calcification, acute
renal failure and hypotension
• Route: Oral, IV
46. Biphosphonates
• MOA: Mimics Pyrophosphate structure. It also
inhibits the activation of enzyme
Farnesyldiphosphate synthase (FPPS) which
utilizes Pyrophosphate
• A/E: Upsets the stomach and inflammation,
erosion of esophagus, flu-like symptoms and
rarely Osteonecrosis of the jaw
• Route: Oral, IV
48. DOC: Pamidronate
• Indication: Osteoclast-mediated bone
resorption, tumor associated osteolysis,
breast and prostate cancer, hypercalcemia
• IV: 60-90mg. Over 4 to 24hrs.
• Onset: 24-48hrs.
• Peak effect: 5-7days
• Half life: 21-35hrs.
• Excretion: Kidneys
49. Non Pharmacologic
• Hold calcium supplement
• Patient education:
– Confusion, decreased appetite, constipation are
due to high levels of calcium
– Nausea and vomiting are side effects of
Pamidronate
– Eat small frequent meals to help with the Nausea
and vomiting
51. Basis for diagnosis
• Type 2 diabetes mellitus for 7 years
• 20 packs per year tobacco history
• Overweight
52. Treatment Objectives
• Continue control of blood sugar by
maintaining normal or near-normal ranges
– KeepHbA1C of <7
• Prevent disease and drug related
complications
53. Pharmacologic Intervention
• Insulin Therapy
• Oral Antidiabetic Regimen
– Patients with Type II diabetes are frequently
treated with combinations of these drugs and are
therefore utilizing multiple strategies
54. Drug Class
Action
SULFONYLUREA AND
MEGLITINIDES
Insulin secretagogue
BIGUANIDES
Insulin Sensitizer
THIAZOLIDINEDIONES
Insulin Sensitizer
Effects
•
•
Decreased endogenous
glucose production
Reduces insulin resistance
•
ALPHA-GLUCDIDASE
INHIBITOR
Competitive inhibitors of
the intestinal
α-glucosidases
•
•
GLP-1 AGONISTS
reduce circulating glucose
increase glycogen,fat, and
protein formation
Glucagon-like peptide-1 •
(GLP-1) receptor agonist •
Reduce conversion of starch
and disaccharides to
monosaccharides
reduce postprandial
hyperglycemia
enhances glucose-dependent
insulin secretion
inhibits glucagon secretion
delays gastric emptying, and
decreases appetite
Clinical
Application
DM type 2
DM type 2
DM type 2
DM type 2
DM type 2
55. Insulin Sensitizers
THIAZOLIDINEDIONES (TZDs)
• increases insulin sensitivity in adipose tissue,
liver, and muscle
– do not increase insulin levels and therefore do
not induce hypoglycemia
– Ex; Rosiglitazone, Pioglitazone
• Toxicities:
– Fluid retention
– edema, anemia
56. Insulin Sensitizers
BIGUANIDES
• block breakdown of fatty acids and to inhibit hepatic
gluconeogenesis and glycogenolysis
• increases insulin receptor activity and metabolic
responsiveness in liver and skeletal muscle
• Does not induce hypoglycemia, Lowers serum lipids and
decreases weight
• Adverse effect: GI distress, lactic acidosis
• Ex; Metformin
57. GLP-1 AGONISTS AND MIMETICS
• Exenatide- Glucagon-like peptide-1 (GLP-1)
receptor agonist
–
–
–
–
enhances glucose-dependent insulin secretion
inhibits glucagon secretion
delays gastric emptying, and decreases appetite
not orally available and must be injected
• Sitagliptin- dipeptidyl peptidase-IV (DPP-IV)
inhibitor that slows the proteolytic inactivation of
GLP-1 and other incretin hormones
– Dose adjustment – Kidney disease
59. Drug Class of Choice
• Biguanides and
Glucagon-like peptide1 mimetics
– Metformin + Sitagliptin
60. Pharmacologic Intervention
• Continue Metformin
• Discontinue Rosiglitazone, shift to Sitagliptin
• Efficacy monitoring: blood glucose, HbA1C in 3
months
• If patient requires hospitalization for worsening
dehydration or if renal function declines further
– hold metformin
62. Non pharmacologic Intervention
• Counsel KF to;
– continue diabetes medications and selfmonitoring.
– Remind her of the importance of diet/exercise in
the treatment of diabetes.
– Remind her to maintain all follow-up
appointments for diabetes.
– Report any shortness of breath or swelling in the
legs to the physician.
64. Basis for diagnosis
• Present in patients medical history
• Use of paroxetine (controlled
under current regiment)
• Decreased appetite over the past
few weeks and increasing fatigue.
• Slightly confused
67. SELECTIVE SEROTONIN REUPTAKE
INHIBITORS (SSRIs)
• Selectively inhibit reuptake of
serotonin
– increase synaptic serotonin levels
– also cause increased 5HT receptor
activation and enhanced postsynaptic
responses.
– At present, SSRIs are the most
commonly prescribed first-line agents
in the treatment of both MDD and
anxiety disorders. Their popularity
comes from their ease of use,
tolerability, and safety in overdose.
69. Pharmacologic Intervention
• Monitoring parameters: signs and symptoms
of depression; depression may worsen with
new diagnosis and prognosis
• adverse events of paroxetine:
– Nausea
– vomiting
– constipation/diarrhea
– sexual dysfunction
70. Non-Pharmacologic Intervention
• Counsel KF to continue depression medication
unless otherwise directed by her physician.
• She should seek a psychologist to discuss her
new diagnosis. She should report any
new/worsened depression symptoms to her
physician.
Notas del editor
Breast cancer was the first neoplasm shown to be responsive to hormonal manipulation. Women with node-positive disease have a high risk of both local and systemic recurrence. Thus, lymph node status directly indicates the risk of occult distant micrometastasis. In this situation, postop- erative use of systemic adjuvant chemotherapy with six cycles of cyclophosphamide, methotrexate, and fluorouracil (CMF proto- col) or of fluorouracil, doxorubicin, and cyclophosphamide (FAC) has been shown to significantly reduce the relapse rate and prolong survival. Alternative regimens with equivalent clinical benefit include four cycles of doxorubicin and cyclophosphamide and six cycles of fluorouracil, epirubicin, and cyclophosphamide (FEC). Each of these chemotherapy regimens has benefited women with stage II breast cancer with one to three involved lymph nodes. Women with four or more involved nodes have had limited benefit thus far from adjuvant chemotherapy. Long-term analysis has clearly shown improved survival rates in node-positive premeno- pausal women who have been treated aggressively with multiagent combination chemotherapy. The results from three randomized clinical trials clearly show that the addition of trastuzumab, a monoclonal antibody directed against the HER-2/neureceptor, to anthracycline- and taxane-containing adjuvant chemotherapy ben- efits women with HER-2-overexpressing breast cancer with respect to disease-free and overall survival. Longer durations of tamoxifen therapy do not appear to add additional clinical benefit.
goal of hormonal therapy is to reduce the stimulation of the tumor cells by estrogen. Adjuvant hormonal therapy should be offered to any pa- tient whose tumor overexpresses hormone receptors [either ER or progesterone (PgR)], regardless of patient age, nodal status, or menopausal status. Tamoxifen, a selective estro- gen-receptor modulator (SERM), has been the adjuvant hor- monal therapy most commonly used. In the meta-analysis performed by the EBCTCG of all randomized trials started before 1990, tamoxifen therapy showed a significant reduc- tion in the annual odds of breast cancer recurrence and mor- tality.53 Data from the meta-analysis showed that 5 years of tamoxifen was superior to 1 to 2 years of tamoxifen. A subsequent study (NSABP B-14) showed that 10 years of tamoxifen was inferior to 5 years, so it is recommended that tamoxifen be discontinued after 5 years.54 However, the benefits of tamoxifen must be weighed against the side ef- fects of treatment, particularly when the drug is being used in the adjuvant setting. The most common side effects of tamoxifen include hot flashes and vaginal discharge, but an increased risk of thromboembolic events and endometrial cancer can also occur. third-generation aromatase inhibitors have been extensively studied as first and second-line therapy for metastatic breast cancer. Fulvestrant, an injectable pure estrogen antagonist, has also shown activity in patients with hormone-receptor- positive disease progressing on hormonal therapy. The choice of hormonal therapy is patient-specific and may be influenced by prior therapy in the adjuvant setting, toxicity profiles, cost, and ease of administration. Historically, the antiestrogentamoxifen was the backbone of hormonal therapy. However, the partial agonist activity of tamoxifen, resulting in an in- creased incidence of thromboembolic disease and endome- trial cancer, as well as the development of drug resistance has prompted the development of alternative agents. romatase inhibitors (letrozole, anastrazole, and ex- emestane), which interfere with the final step of estrogen biosynthesis, are another class of compounds used as hor- monal therapy in patients with metastatic breast cancer. Re- cent data suggest that these agents are also effective in the adjuvant setting. The ATAC (Arimidex, Tamoxifen Alone or in Combination) Trialists’ Group found superior disease- free survival for anastrozole as adjuvant therapy in post- menopausal women with hormone-sensitive disease when compared to tamoxifen or the combination of tamoxifen and anastrozole.53 As a result, anastrozole was granted acceler- ated approval as adjuvant therapy for breast cancer.
Tamoxifen – acts like an anti-estrogen in breast cells, it acts like an estrogen in other tissues, like the uterus and the bones - stop the growth and even shrink tumors in women with metastatic breast cancer. It can also be used to reduce the risk of developing breast cancer in women at high riskAromatase inhibitors: cannot stop the ovaries from making estrogen, so they are only effective in women whose ovaries aren’t working (like after menopause)Fulvestrant - first blocks the estrogen receptor and then also eliminates it temporarily; acts like an anti-estrogen throughout the body
median duration of response to the first attempt at hormonal manipulation is usually in the range of 9 to 12 months, and the duration of any subsequent responses is generally shorter. First-line hormonal therapy should be administered for at least 6 to 8 weeks before disease response is assessed. After initiation of therapy, some patients may experience a flare (or worsen- ing) of their disease that may or may not be accompanied by hypercalcemia. If a patient becomes refractory to hormonal therapy at any time, chemotherapy should be given.
Adjuvant therapy should be tailored to the individual characteristics of the patient, and the benefits must be weighed against the risks of treatment, recognizing that the threshold for derived benefit of therapy varies be- tween individual patients. The American Society of Clinical Oncology (ASCO) has issued recommended breast cancer surveillance guidelines.63 Generally, women with a history of breast cancer should perform monthly BSE and undergo annual mammography of both the preserved and contralat- eral breast. The patient should also have a complete history and physical examination every 3 to 6 months for the first 3 years after diagnosis, then every 6 to 12 months for 2 years, and then annually.
combining an insulin sensitizer (e.g., a TZD or metformin) with insulin or an insulin secretagogue (e.g., a sulfonylurea) can both improve glycemic control in a poorly controlled Type II diabetic patient and lower the dose of each drug required to achieve a therapeutic effect
Sulfonylureas and meglitinides inhibit the ß cell K+/ATP channel at the SUR1 subunit, thereby stimulating insulin release from pancreatic ß cells and increasing circulating insulin to levels sufficient to overcome insulin resistanceBIGUANIDES:Mechanism—Activates AMP-dependent protein kinase (AMPPK) to block breakdown of fatty acids and to inhibit hepatic gluconeogenesis and glycogenolysis; increases insulin receptor activity and metabolic responsiveness in liver and skeletal muscleTHIAZOLIDINEDIONES (TZDs):Mechanism—Bind and stimulate the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPARγ), thereby increasing insulin sensitivity in adipose tissue, liver, and musclea-GLUCOSIDASE INHIBITORSMechanism—Carbohydrate analogues that bind avidly to intestinal brush border a-glucosidase enzymes, slowing breakdown and absorption of dietary carbohydrates such as starch, dextrin, and disaccharides. Flatulence, bloating, abdominal discomfort, and diarrhea are common adverse effects, all of which result from gas released by bacteria acting on undigested carbohydrates that reach the large intestine.GLP-1 (Glucagon-like peptide-1) mimetics are the newest class of drugs developed for the treatment of diabetes. On the basis of these trials, sitagliptin was approved in 2006 as an adjunct to diet and exercise to improve glucose control in Type II diabetes. It can be used as monotherapy or in combination with a TZD or metforminThe known physiological functions of GLP-1 include:increases insulin secretion from the pancreas in a glucose-dependent manner.decreases glucagon secretion from the pancreas by engagement of a specific G protein-coupled receptor.increases insulin-sensitivity in both alpha cells and beta cellsincreases beta cells mass and insulin gene expression, post-translational processing and incretion.inhibits acid secretion and gastric emptying in the stomach.decreases food intake by increasing satiety in brain.promotes insulin sensitivity.
inhibit the ß cell K+/ATP channel at the SUR1 subunit, thereby stimulating insulin release from pancreatic ß cells and increasing circulating insulin to levels sufficient to overcome insulin resistance1st gen- therefore, should be used cautiously in patients who are unable to recognize or respond to hypoglycemia2nd gen- better suited for nonobese patients
TZD- Bind and stimulate the nuclear hormone receptor peroxisome proliferator activated receptor-γ (PPARγ), Less hepatotoxicRosiglitazone shares the common Tzd adverse effects but appears to carry more cardiovascular risk than pioglitazone. Concurrent administration of nitrates and insulin putatively enhances the risk of myocardial infarction and is contraindicated; renin-angiotensin system blockers may have a similar risk but are not specifically prohibited.BIG- Activates AMP-dependent protein kinase (AMPPK) toGI distress associated with metformin use is usually transient and can be minimized by slow titration of the dose
BIG- Activates AMP-dependent protein kinase (AMPPK) toGI distress associated with metformin use is usually transient and can be minimized by slow titration of the dose
Exe-Typically used in combination with metformin or a sulfonylurea to improve glucose controlDigoxin levels should be monitored in patients receiving digoxin and sitagliptinGLP-1 (Glucagon-like peptide-1) mimetics are the newest class of drugs developed for the treatment of diabetes. On the basis of these trials, sitagliptin was approved in 2006 as an adjunct to diet and exercise to improve glucose control in Type II diabetes. It can be used as monotherapy or in combination with a TZD or metforminThe known physiological functions of GLP-1 include:increases insulin secretion from the pancreas in a glucose-dependent manner.decreases glucagon secretion from the pancreas by engagement of a specific G protein-coupled receptor.increases insulin-sensitivity in both alpha cells and beta cellsincreases beta cells mass and insulin gene expression, post-translational processing and incretion.inhibits acid secretion and gastric emptying in the stomach.decreases food intake by increasing satiety in brain.promotes insulin sensitivity.
Pioglitazone - metabolized by CYP2C8 and CYP3A4 to active metabolites. Thebioavailability of numerous other drugs also degraded by theseenzymes may be affected by pioglitazone therapy (affects OCPs). Bladder cancerRosiglitazone- rapidly absorbed and highly protein-bound.It is metabolized in the liver to minimally active metabolites. carry more cardiovascular riskAn adverse effect common to both Tzds is fluid retention, which presents as a mild anemia and peripheral edema, especially when the drugs are used in combination with insulin or insulin secretagogues. Both drugs increase the risk of heart failure.Biguanides- insulin-sparing agent and does not increase body weight or provoke hypoglycemia, it offers obvious advantages over insulin or sulfonylureas in treating hyperglycemia. common toxic effects of metformin are gastrointestinal (anorexia, nausea, vomiting, abdominal discomfort, and diarrhea), contraindicated in patients with renal disease, alcoholism, hepatic disease, or conditions predisposing to tissue anoxia (eg, chronic cardiopulmonary dysfunction) because of the increased risk of lactic acidosis induced by these drugs.Sitagliptin- Common adverse effects include nasopharyngitis, upper respiratory infections, headaches, and hypoglycemia when the drug is combined with insulin secretagogues or insulin.PriceMetformin- Ansures ER tab 500 mg56's (P392.00/pack) Dimet- P3.85/film-coated tabTHIAZOLIDINEDIONES- Actos, Pioglitazone HCl (P2230.03/pack) to(P3579.68/pack). Pioglitazone Tab 5mg (PIOGLON) 3.50php/tabSulfonylureas- Aforglim (P597.44/box) to (P690.63/box) 1-50php/tabA-glucosidase inhibitors- Xelevia film-coated tab(Sitagliptin)- (P1503.80/box) to (P1503.80/box) Januvia (P1460.00/pack)
Sitagliptin is a selective inhibitor of the enzyme dipeptidyl peptidase-4 (DPP-4). This enzyme rapidly metabolizes the endogenous incretins, namely glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP).1 Metformin acts by reducing hepatic glucose production, mainly due to inhibition of gluconeogenesis. It also increases non-oxidative skeletal muscle glucose disposal and, because of consequently less ‘glucotoxicity’, it can improve residual pancreatic beta-cell funcBecause this effect is independent of DPP-4 activity, it is of potential relevance to its combination with sitagliptin. A further reason for combining these two drugs relates to the fact that, unlike insulin itself and secretagogues such as sulfonylureas, neither sitagliptin nor metformin is associated with hypoglycaemia or weight gain. In response to the presence of food, GLP-1 is released from the endocrine L cells of the lower small intestine/ colon and GIP from K cells in the upper small intestine. Both hormones increase insulin secretion when plasma glucose concentrations are above the normal fasting range. They have an additive effect, but GLP-1 inhibits gastrointestinal motility and gastric emptying, and reduces appetite and food intake to a greater extent than GIP, and also attenuates glucagon secretion. DPP-4 inhibition increases plasma concentrations of GLP-1 and GIP, which are reduced in patients with type 2 diabetes, and therefore has a variety of beneficial effects on glycaemia.Sitagliptin and metformin combination therapy is contraindicated in patients:10with renal disease or renal dysfunction, usually a serum creatinine level of 133 µmol/L or above in males or 124 µmol/L or above in females, or an estimated creatinine clearance of less than 60 mL/min/1.73 m2. This is because sitagliptin is primarily excreted unchanged in the urine through active tubular secretion, and metformin can also accumulate in patients with renal failure. Sitagliptin and metformin combination therapy should also be temporarily discontinued in patients undergoing radiological studies involving intravascular administration of iodinated contrast materials that may impair renal function.with known hypersensitivity to sitagliptin or metformin.with acute or chronic metabolic acidosis, including diabetic ketoacidosis, with or without coma. This relates to the reported association between metformin and lactic acidosis, the occurrence of which remains rare.11who are pregnant or lactating.
Metformin- cannot use if impaired renal/hepatic function • congestive heart failure (CHF), hypoxic/acidotic states, alcoholism
As initial therapy in type 2 DM when diet & exercise do not provide adequate glycemic control. As adjunct to diet & exercise to improve glycemic control in type 2 DM inadequately controlled on metformin or sitagliptin alone, or combination sitagliptin & metformin, or triple combination sitagliptin, metformin or a sulfonylurea, or max tolerated dose of metformin & a PPARγ agonist, or insulin & metformin alone.Individualized dosage. Initially 50 mg/500 mg bd. Max daily dose: Sitagliptin 100 mg/metformin 2 g.Janumet pack= 28s
SSRI- Highly selective blockade of serotonin transporter (SERT) • little effect on norepinephrine transporter (NET)Toxicity:Well tolerated but cause sexual dysfunction• risk of serotonin syndrome with MAOIs (characterized by hyperthermia, muscle rigidity, myoclonus, and rapid fluctuations in mental status and vital signs); • Interactions: Some CYP inhibition (fluoxetine 2D6,3A4; fluvoxamine 1A2; paroxetine 2D6)SSRIs lack significant cardiotoxicity, and do not bind as avidly to muscarinic (cholinergic), histamine, adrenergic, or dopamine receptors. As a consequence, SSRIs are generally better tolerated than TCAs. sertraline is more often associated with diarrhea, and paroxetine is associated with constipationSNRI-Moderately selective blockade of NET and SERTToxicity: Anticholinergic, sedation, hypertension (venlafaxine) • Interactions: Some CYP2D6 inhibition (duloxetine, desvenlafaxine)TCA- Mixed and variable blockade of NET and SERTLong half-lives • CYP substrates • active metabolites • Toxicity: Anticholinergic, α-blocking effects, sedation, weight gain, arrhythmias, and seizures in overdose • Interactions: CYP inducers and inhibitorsMAOI’s- Blockade of MAO-A and MAO-B (phenelzine, nonselective) • MAO-B irreversible selective MAO-B inhibition (lowdose selegiline)Very slow elimination • Toxicity: Hypotension, insomnia • Interactions: Hypertensive crisis with tyramine, other indirect sympathomimetics • serotonin syndrome with serotonergic agents, meperidine
SELECTIVE SEROTONIN REUPTAKE INHIBITORS (SSRIs)Mechanism—Selectively inhibit reuptake of serotonin and thereby increase synaptic serotonin levels; also cause increased 5HT receptor activation and enhanced postsynaptic responses. At high doses, also bind NE transporter.