[PHA6115 lec] Endocrine Drugs Flashcards
(158 cards)
1
Q
Composed of several hormone-releasing organs
A
Endocrine System
2
Q
How does the endocrine system maintain body functions and homeostasis?
A
By releasing hormones which are used for several body functions (e.g., growth, reproduction, and defense)
3
Q
Endocrine drugs work like __________?
A
Hormones (Natural, Semi-synthetic or Synthetic)
4
Q
Classification of Endocrine Drugs based on Structure
A
- Peptide (majority)
- Steroidal (adrenal cortex / sex hormones) –> CCPT backbone
5
Q
Classification of Endocrine Drugs based on Function
A
- Releasing hormones
- Stimulating hormones
- Thyroid and pancreatic, adrenal hormones
6
Q
Complex disease characterized by uncontrolled glucose homeostasis associated with several minor and major complications
A
Diabetes
7
Q
3 Cardinal Signs of Diabetes
A
- Polyuria
- Polyphagia
- Polydipsia
8
Q
[Type of DM]
Insulin-dependent, juvenile onset, require insulin therapy for their lifetime
A
DM Type 1
9
Q
[Type of DM]
Insulin-independent, adult onset (commonly), may or may not have insulin therapy
A
DM Type 2
10
Q
[Type of DM]
Glucose intolerance during pregnancy
A
Gestational Diabetes
11
Q
[Type of DM]
Results for non-usual causes or from other diseases present in the patient that may not concern insulin levels
A
Secondary DM
12
Q
[Diabetes]
Therapy is directed at maintaining _________?
A
Euglycemic states (normal blood sugar)
13
Q
It is a 51-amino acid protein with two chains linked by a disulfide bond
A
Insulin
14
Q
Where is insulin produced?
A
Beta cells of pancreas
15
Q
MOA of Insulin
A
Transports glucose into adipose and muscle cells via GLUT 4
16
Q
SAR of Insulin
A
N- and C- terminals of the AA Chain A and B are essential for insulin receptor binding
17
Q
Insulin is produced via __________ of proinsulin
A
Proteolytic modifications
18
Q
Proinsulin is formed by removing what from preproinsulin?
A
24-amino acid
19
Q
[Classification and Pharmacokinetics of Insulin Preparation]
Examples of Rapid-acting
A
Lispro, Aspart, Glulisine (LiAsGlu)
20
Q
[Classification and Pharmacokinetics of Insulin Preparation]
Examples of Short-acting
A
Human Insulin - regular
21
Q
[Classification and Pharmacokinetics of Insulin Preparation]
Examples of Intermediate-acting
A
Lente, NPH insuline (isophane)
> NPH means Neutral Protamine Hagedorn
22
Q
[Classification and Pharmacokinetics of Insulin Preparation]
Examples of Long-acting
A
Ultralente, Glargine, Detemir (UltraDeGlar)
23
Q
Agents that stimulate the release of insulin from the beta cells of the pancreas
A
Insulin secretagogues
24
Q
2 Pharmacophores of Insulin Secretagogues
A
- Sulfonylurea
- Meglitinides
25
MOA of Sulfonylureas
Binds to SUR1 at K-channel and opens the voltage-gated Ca-Channel = Increased intracellular CA and exocytotic release of insulin
26
SAR of Sulfonylureas
1st generation
- small lipophilic at R1
- alkyl/cyclic substituent at R2
- high dose, long plasma half-life, short DOA, high chance for ADR
2nd generation
- large meglitinide group at R1
- high potency, low dose, rapid onset, short plasma half-life, long DOA
27
1st generation Sulfonylureas
Tolbutamide, Chlorpropramide, Acetohexamide (CAT-amide)
28
2nd generation Sulfonylureas
Glyburide or Glibenclamide, Glipizide, Glimepiride ("Gly or gli")
29
MOA of Meglitinides
Similar to sulfonylureas; Repaglinide binds also to SUR1, SUR2A, and SUR2B = Extrapancreatic effects
30
SAR of Meglitinides
Meglitinide is a prototype structure - a benzoic acid derivative of the non-sulfonylurea moiety of Glibenclamide or Glyburide
31
Examples under Meglitinides
Repaglinide
- rapid onset, short DOA
- doesn't cause prolonged hyperinsulinemia
- available in the market
Nateglinde
- rapid onset, longer DOA
32
Anti-diabetic agent that is considered the 1st line treatment with lifestyle change
Biguanides
33
T or F: Biguanides are highly distributed and excreted unchanged in urine
True
34
MOA of Biguanides
- decreases gluconeogenesis
- increases glycogenolysis and glycolysis
- increases insulin sensitivity
35
SAR of Biguanides
2-linked guanidine moiety (Bi + guanidie)
36
Insulin Sensitizers / PPAR Agonists, what does PPAR mean?
Peroxisome Proliferator Activated Receptor
37
MOA of Insulin Sensitizers or PPAR Agonists
- PPAR controls gene expression, increases glucose transporter expression = Increased insulin sensitivity of the body
- Slows down gluconeogenesis and lower systematic fatty acids
38
SAR of Insulin Sensitizers or PPAR Agonist
Thiazolidinedione pharmacophore
39
For agonist activity of the Thiazolidinedione pharmacophore, R must be __________?
Para- substituted phenyl ring attached via methylene bridge
40
Examples of Insulin Sensitizers or PPAR Agonists
Pioglitazone
- only available in the market
Troglitazone
- not used due to severe hepatotoxicity
Rosiglitazone
- limited availability due to increase cardiovascular effects
(TroPioRosi "-glitazone")
41
Enzyme that is made of maltase, sucrase, isomerase, and glucomylase found in the small intestine
Alpha-glucosidase
42
MOA of A-Glucosidase Inhibitors
Inhibits a-glucosidase to inhibit carbohydrate breakdown = Preventing absorption of mono/disaccharides
43
SAR of A-Glucosidase Inhibitors
Mimic the natural substrates of a-glucosidase by having similar structures
44
This group aids in mimicking natural disaccharide substrate
Polyhydroxy groups
45
Examples of A-Glucosidase Inhibitors
Acarbose
- extremely low oral bioavailability
Voglibose
- poolry absorbed
Miglitol
- absorbed orally, not metabolized = excreted unchanged
46
30-31 amino acid peptide produced by prohormone convertase enzymes from proglucagon
GLP-1
47
MOA of GLP-1 Agonist
GLP-1 is released in response to food = Promotes insulin secretion from pancreas
48
SAR of GLP-1 Agonist
GLP-1 Agonist analogs have penultimate amino acid modification to resist metabolism by DPP-IV
49
[GLP-1 Agonist Agents' Modification]
Penultimate Ala --> Gly
Exenatide
50
[GLP-1 Agonist Agents' Modification]
Lys26 has a-glutamoyl-(N-a-hexadaconyl) and Lys34 is replaced by Arg34
Liraglutide
51
[GLP-1 Agonist Agents' Modification]
Fusion of 2 modified GLP-1 to albumin
Albiglutide
52
[GLP-1 Agonist Agents' Modification]
Fusion of 2 modified N-terminal GLP-1 analog to IgG4 Fc domain
Dulaglutide
53
Alternatives to GLP-1 Agonist Analogs
DPP-IV Inhibitors
54
MOA of DPP-IV Inhibitors
Binds to active site in DPP-IV
55
SAR of DPP-IV Inhibitors
3 pharmacophore structure:
a-aminoacylpyrrolidine, xanthine, pyrimidine-2,4-dione
56
Group that binds to the active serine site in DPP-IV
Cyano group
57
T or F: DPP-IV Inhibitors can be taken alone or with metformin or thiazolidinedione
True
58
Examples of DPP-IV Inhibitors
Saxagliptin and Vildagliptin (a-aminoacylpyrrolidine)
Sitagliptin
- piperazine fused pyrazole with a-aminoacyl moiety
Alogliptin
- pyrimidine-2,4-dione pharmacophore
Linagliptin
- xanthine pharmacophore
(VildaSaSiAloLi "-gliptin")
59
37-amino acid hormone released with insulin
Amylin
60
MOA of Amylin Agonist
Suppress glucagon secretion and delay gastric emptying time = Modulation of appetite centers to maintain glucose plasma level
61
SAR of Amylin Agonist
Pramlintide
- more water soluble
- reduced aggregation
62
Aids in reabsorption of glucose from renal proximal tubules
SGLT2
63
MOA of SGLT2 Inhibitor
Inhibit SGLT2 = Decreased renal threshold for glucose = Increased urinary glucose excretion
64
SAR of SGLT2 Inhibitor
Phlorizin pharmacophore and a glucose moiety that bind to Thr156 and Lys 157 moiety of transporter
65
T or F: SGLT2 Inhibitor is recommended from patients with DM Type 1 and patients with renal impairment
False, not recommended
66
Examples of SGLT 2 Inhibitors
Phlorizin
- pharmacophore with glucose
Dapagliflozin, Empagliflozin, Canagliflozin
(Phlorizin + CanaDapaEmpa "-gliflozin")
67
Only mammalian organ that can incorporate iodine into organic molecule
Thyroid gland
68
Source of throxine (T4) and triiodothyronine (T3)
Thyroid gland
69
Medications for disorders associated to thyroid gland
HRT and/or anti-thyroid drugs
70
Major regulatory step in Thyroid Glands
TSH release
71
Stimulates thyroid gland to create thyroid hormon
TSH
72
T3 or T4: Which one is the precursor?
T4 - thyroxine
73
T3 or T4: Which is the active form and is a negative feedback molecule for the anterior pituitary?
T3 - triiodothyronine
74
3 Types of Thyroid Replacement Hormones
1. Hypothalamic - TRH
2. Pituitary - TSH
3. Organ - T4 and T3
75
Examples of Anti-thyroid Drugs
Thioamides, Anions, Radioactive I2, Propranolol
76
MOA of T4 and T3
T4 is transported into the cells and is converted into T3
T3 then enters the nucleus, interacts with DNA = Stimulation/Inhibition of gene transcription
77
SAR of T4 and T3
2 phenyl rings linked with X group
78
[SAR of T4 and T3]
X is
Oxygen
79
[SAR of T4 and T3]
R1 and R4'
R1 - alanine group
R4' - OH group
80
[SAR of T4 and T3]
R3, R5, R3'
Iodine (T3)
81
[SAR of T4 and T3]
R5'
Iodine (T4)
82
[SAR of T4 and T3]
Potency between L and D-isomers
L-isomer is more potent than D-isomer
83
Slower-acting than iodides
Thioamides
84
MOA of Thioamides
Potent inhibitors of thyroperoxidase (TPO)
85
SAR of Thioamides
Thiouracil C2 keto/enol and unsubstituted N1 - essential for activity
Thiouracil C4 keto and C5/C6 alkyl substitution - increased activity
N1 methyl of MMI = Removes inhibition of peripheral deiodination
86
Examples of Thioamides
Propylthiouracil (PTU) and Methimazole (MMI)
87
MOA of Anions
Competitively blocks iodide transporter = Blocks iodine uptake
88
Examples of Anions
Pertechnetate, Perchlorate, Thiocyanate
89
MOA of Radioactive I2
Destroys thyroid gland cells = Lowers hormone levels
90
MOA of Propranolol
Inhibits deiodination of T4 to T3
91
Unsaturated steroid alcohol derived from terpenoid squalene
Sterols
92
What backbone does sterols possess?
CPPP
93
Where are sterols derived?
Natural sources such as;
Cholesterol (animals)
Phytosterol (plants)
Ergosterol (fungi)
94
What are the functions of sterols?
1. Regulates cell membrane fluidity
2. Precursor for bile acids
95
T or F: Sterols are also precursors for steroid hormones
True
Glucocorticoids, Mineralocorticoids, Sex hormones
96
General Steroid MOA
Bind to steroid receptors which are kept inactive by HSP
97
General Steroid MOA
Bind to steroid receptors which are kept inactive by HSP
Steroid-receptor enters nucleus several process occurs with Co-A and HRE of DNA
Steroid effects are seen in transcription of mRNA and translation of proteins
98
[Adrenal Glands and Different Zones]
Outermost
Glomerulosa - mineralocorticoids - Na and fluid reabsorption, K excretion
99
[Adrenal Glands and Different Zones]
Middle
Fasciculata - glucocorticoids - Intermediary metabolism, CV function, growth, immunity
100
[Adrenal Glands and Different Zones]
Innermost
Reticularis - gonadal hormones - primary and secondary sex characteristics, reproduction
101
Examples of Steroidal Drugs
Aldosterone (mineralcorticoid)
Cortisol (glucocorticoid)
Estradiol
- primary estrogen
- 2ndary female characteristics
Testosterone
- primary androgen
- 2ndary male characteristics
Progesterone
- primary progestin
- prepares uterus for pregnancy
102
T or F: Steroid structures will always contain CPPP backbone, like a modified cholesterol molecule
True
103
11-hydroxylated steroid hormone
Glucocorticoids
104
17-hydroxylated steroid hormone
Sex hormones
105
Only aldehyde-containing steroid hormone
Aldosterone
106
Only aromatic steroid hormone
Estrogen
107
SAR of Steroidal Drugs
C20 thiofluoromethyl = Increases GC receptor affinity
21-OH required for MC activity
21-Cl increases GC receptor affinity
107
SAR of Steroidal Drugs
C20 thiofluoromethyl = Increases GC receptor affinity
21-OH required for MC activity
21-Cl increases GC receptor affinity
X16 (a/b-methyl) substitution = Decreases MC activity but increases GC activity
6a/9a halogenation (F/Cl) = Enhances activity for both GC and MC
3-keto and delta-4,5 = Essential for activity of both GC and MC
11-b = Essential for GC activity
Delta-1,2 = Increases GC activity
108
Mainly used for their anti-inflammatory activity but can also be used for non-inflammatory uses
Glucocorticoids
109
MOA of Glucocorticoids
Promotes histone deacetylase activity = Reverse action of histone acetyltransferase = Inhibition of gene expression for inflammation
110
Uses of Glucocorticoids
Gout, arthritis, SLE, colitis, asthma, hypoglycemia, Addison's disease
111
Availability of Glucocorticoids
Systemic and Topical corticosteroids
112
Examples of Glucocorticoids
Hydrocortisone
- aka cortisol
Prednisolone
113
[Non-inflammatory Effects of Glucocorticoids]
CNS
Profound behavioral changes when given in large doses
114
[Non-inflammatory Effects of Glucocorticoids]
Excretory
Normal renal excretion (MC effect)
115
[Non-inflammatory Effects of Glucocorticoids]
Gastric
Stimulation of gastric acid secretion, which can lead to
development of peptic ulcer
116
[Non-inflammatory Effects of Glucocorticoids]
Bone
Antagonism of the effect of vitamin D on calcium absorption
117
[Non-inflammatory Effects of Glucocorticoids]
Blood
Increase of platelets and RBC
118
[Non-inflammatory Effects of Glucocorticoids]
Respiratory
Development of fetal lung
119
Uses of Mineralocorticoids
Addison's disease, diagnosis of Conn's syndrome
120
Examples of Mineralocorticoids
Aldosterone
- regulation of salt and water in the body
- not commercially available
Fludrocortisone
- used to raise cortisol and for detecting Conn's syndrome through the fludrocortisone suppression test
121
AKA male sex hormones produced by the Leydig cells of testis, adrenal, and ovary
Androgens
122
Major androgen in males that is synthesized from progesterone or dehydroepiandrosterone (DHEA)
Testosterone
123
Testosterone is activated by ___________ into dihydrotestosterone (DHT) that occurs usually in the prostate organ of the body
5a-reductase
124
Effects of Androgen
Normal development of male during infancy to puberty
Development of facial, pubic, and auxiliary hair; darkening of skin
Anabolic action
Increased muscle size and strength
Increased RBC production
Helps maintain normal bone density
124
Effects of Androgen
Normal development of male during infancy to puberty
Development of facial, pubic, and auxiliary hair; darkening of skin
Anabolic action
Increased muscle size and strength
Increased RBC production
Helps maintain normal bone density
125
[Anti-androgen agents]
Androgen-receptor blockers
Spironolactone
126
[Anti-androgen agents]
Examples of Spironolactone
Flutamide, Nilutamide, Trifluorophenyl derivatives
127
[Anti-androgen agents]
Agents for BPH or Prostate Cancer
Finasteride and Dutasteride
- steroid amide as 5a-reductase inhibitor
Quinazolines
- alpha-1 blockers
Abiraterone
- steroidal agent that blocks enzymes responsible for the synthesis of androgens
Serenoa repens
- Saw palmetto
128
C-18 steroid with aromatic ring
Estrogen
129
Estrogen exists in 3 forms
Estradiol (most potent)
Estrone
Estriol
130
C21 with 3-keto-4-ene, C20 keto)
Progestins
131
Progestins naturally occur as _______
Progesterone (most potent)
132
Uses of Estrogen and Progestins
Hypogonadism in young females, contraception, and HRT
133
Aside from sex characteristics, Estrogen contributes to ________
Bone integrity - prevents bone resorption
134
MOA of Estrogens
Binds to ER(a/b) = Dimerization - migrates to the cell nucleus and binds to specific estrogen-response elements (ERE) = DNA transcription
135
ADRs of Estrogen
Increased risk for breast and endometrial cancer, breast tenderness
Nausea, increased risk for migraine
HTN
Thromboembolic events
136
Progestins added to estrogen during HRT to reduce unwanted effects
Modified Progestins
137
SAR of Modified Progestins
Androstane or pregnane steroid nuclei = Essential for progestic activity
Etc
138
MOA of Anti-Progestins
Competes with progesterone at receptor sites
139
SAR of Anti-Progestins
Contain C11-phenyl group that aids in competitive receptor blockade
140
Examples of Anti-Progestins
Ulipristal
- for emergency contraception
Mifepristone
- for abortion
141
[Anti-Estrogen for Cancer Therapy]
Used for estrogen-related cancer
Aromatase Inhibitor
Ex. Anastrozole, Exemestane
142
[Anti-Estrogen for Cancer Therapy]
Used for breast CA, but may cause endometrial CA
Selective Estrogen Receptor Modulators (SERMs)
Ex. Ospemifene - dyspareunia
Raloxifene - osteoporosis
Clomifine - infertility
143
3 Primary Hormones involved in managing Ca levels in the Body
Calcitonin (CT), Parathyroid hormone (PTH), and Vitamin D
144
Promotes urinary secretion of Ca and prevents intestinal absorption during hyperglycemia
Calcitonin
145
Promotes inhibits renal secretion of Ca and promotes bone resorption during hyperglycemia
PTH
146
MOA of 2nd Generation SERMs
Agonist activity on estrogen receptors in osteoblast and osteoclast but in the breast and uterus
147
SAR of 2nd Generation SERMs
Triarlyethylene derivatives of Tamoxifen
Phenol/Phenoxy ring system = Essential to mimic A-ring of estrogen for receptor binding
Propeller orientation of 3 rings = Essential for receptor binding and activity
148
Examples of 2nd Generation SERMs
Lasofoxifene, Ospemifene, Bazedoxifene, Toremifene
149
MOA of Bisphophonates
Binds to the hydroxyapatite of the bone = Prevents osteoclast activity = Reduces osteoclast proliferation and life span
150
SAR of Bisphophonates
Analogs of pyrophsphates
R1-OH = Maximizes affinity for hydroxyapatite = Improved antiresorptive activity
R2 substitution can vary
Amino alkyl with 3-atom chain with the N atom in a heterocyclic ring = Optimal activity
151
Examples of Bisphophonates
Etidronate, Risedronate, Alendronate, Pamidronate
(RiEtiAlePami "-dronate")
152
[Other agents]
Decrease bone resorption by osteoclast
Calcitonin
153
[Other agents]
PTH analog, increases number of osteoblast
Teriparatide
154
[Other agents]
Calcimimetic, increase Ca sensitivty = Lower PTH secretion = Lower serum Ca levels
Cinacalcet
155
[Other agents]
Increases mineralization of hydroxyapatite = Stronger bones/teeth
Sodium fluoride
156
[Other agents]
Increase bone formation and decrease bone resorption
Strontium ranelate
