Exam 3 II Flashcards
(220 cards)
1
Q
Steroid start from which structure?
A
CPPP
2
Q
adrenal cortex
A
produce glucocorticoids and mineralocorticoids
3
Q
testis
A
produce androgens
4
Q
ovaries
A
produce estrogens and progestagens
5
Q
Cortico-steroids
A
- aka Adrenocorticoids
- Glucocorticoids
- Mineralocorticoids
6
Q
anabolic steroids
A
- synthetic
- example of androgen
7
Q
estrane
A
18 carbon steroidal unit
8
Q
androstane
A
19 carbon steroidal unit
9
Q
pregnane
A
21 carbon steroidal unit
10
Q
cholestane
A
27 carbon steroidal unit
11
Q
cholane
A
24 carbon steroidal unit
12
Q
configurational isomers
A
- there are 8 possible variations
13
Q
What are the common configurational isomers?
A
- trans-trans-trans
- cis-trans-trans
- cis-trans-cis
14
Q
What structural feature denotes a steroid as a delta?
A
if there is a double bond between between 4/5 or 5/6
15
Q
What does the statins inhibit and why?
A
- inhibits HMG-CoA reductase
- because it converts HMG-CoA to mevalonic acid which goes on to cholesterol synthesis
16
Q
glucocorticoids and examples
A
- affect intermediary metabolism
- inhibit inflammation
- ex. cortisol, cortisone
17
Q
mineralocorticoids and example
A
- salt retention
- aldosterone
18
Q
pathologic conditions related to adrenal cortex
A
- Cushing’s disease
- Addison’s disease
- Conn’s syndrome
19
Q
What structural feature denotes glucocorticoids?
A
- OH at C17 in the alpha configuration
- OH at C11
- double bond at C4/5
- carbonyl at C3
- beta-Ketol at C17
20
Q
What is the structural difference between glucocorticoids and mineralocorticoids?
A
mineralocorticoids doesn’t contain OH at C17
21
Q
What is important about the C11 OH in mineralocorticoids and glucocorticoids?
A
it is the site of which these compounds attach themselves to the receptors
22
Q
What are problems with natural corticoids?
A
- rare availability of cortisol
- not resistant to first pass metabolism
- side effects
23
Q
What are the products of first pass metabolism of cortisol?
A
- C11 OH -> keto group =O
- C3 =O -> alpha OH
- double bond C4/5 gone
- C17 OH -> keto =O
24
Q
Why does alpha OH at C3 destroys activity?
A
no steroid in body has alpha OH at C3, it’s all beta
25
What are the two categories of adrenocorticoid drugs?
- cortisol
| - prednisolone
26
What are characteristics of cortisol esters?
- more stable
| - slow absorption
27
What are characteristics of cortisol cypionate esters?
- more lipophilic
| - slow absorption in oral administration
28
What are characteristics of cortisol salt forms?
- water soluble
- IV or IM
- fast hydrolysis
29
What is the difference between cortisol and prednisolone?
prednisolone has a double bond at C1/2
30
What are the purpose of modifications of prednisolone?
add substituents to C16 to protect OH and side chains on C17 from being metabolized
31
It is common to see F as a substituent on C9 in prednisolone. Why is this?
- it's small enough to replace H and not change structural feature
- it enhances activity (lec 4-20 @ 4:40)
- helps stabilize OH group at C11
32
What is the advantage of forming an acetonide and tying two -OH groups?
stabilizing compound and giving it a longer half life
33
How does the double bond at C1/2 increase potency?
the chair-conformation is flatter and can sit at the receptor site better
34
Function of adrenocorticoid antagonists
- compete for binding site
| - inhibit biosynthesis of adrenocorticoids
35
ring A in estrogen
benzene
36
aromatase
- gives estrogen compounds their benzene ring
| - rate limiting step
37
metabolism of estrogen
- OH group added to C2 or C4
- COMT methylates that OH group
- activity in lost
- OH on C17 can be glucuronidated
- t1/2 of 20min
38
Why is the distance between two -OH in estrogen important?
it is 8.55 Å and the receptor is 8.55 Å in size
39
What are structural features of estrogen?
- aromatic A ring
- phenol at C3
- beta OH at C17
- 8.55 Å between -OH groups
40
Modifications of estrogen to increase half life
- ether at C3
- ester at C3 or C17
- add ethlyne at C17
41
Function of estrogen antagonists
- compete for binding site
| - inhibit biosynthesis of estrogens
42
ER-alpha
female reproductive tract and mammary gland
43
ER-beta
- vascular endothelial cells
| - CV and bone tissue
44
What can aromatase inhibitors be used for?
- control reproductive functions
| - treatment of estrogen-dependent breast cancers
45
progesterone
serves as precursor to:
- androgen
- estrogen
- adrenocorticoids
46
What are structural features of progesterone?
- 21 C skeleton
- double bond at C4/5
- ketone at C3
- O functionality a C3 and 20
47
formation of HCG
- lose double bond of progesterone at C4/5
- C3 is glucronidated
=> HCG
48
metabolism of progesterone
- reduction of -OH at C3
- double bond at C4/5 metabolized
- rapid metabolism: t1/2 of 5-10min
49
How can we modify progesterone to increase half life?
- add -OH to C17
- add methyl group to C6
- double bond at C6/7
50
What happens if you block 5alpha-reductase?
stops synthesis of testosterone
51
Side effects of testosterone
it can have both anabolic and androgenic activity
52
Functions of antiandrogens
- block receptors
| - inhibits synthesis of androgens
53
Which enzymes can you inhibit to inhibit production of androgen?
- 17a-hydroxylase/17,20-lyase
| - 5a-reductase
54
Which location in the human body is there presence of prostaglandins?
- reproductive tract
- seminal vesicles
- menstrual fluid
- umbilical cord
- placenta
55
Where else can you find prostaglandins?
Gorgonian Coral / Sea Whip Coral
56
What is the starting material for prostaglandins?
from a 20 carbon fatty acid (arachidonic acid)
57
structural features of prostanoic acid
- 20C fatty acid
- 7C chain attached to C8 in alpha
- 8C chain attached to C12 in beta
58
How are prostaglandins named?
- 3 letters
- PG"X"(subnumber + alpha/beta)
- 3rd letter denotes a functionality group
- subnumber denotes the amount of double bonds in the C8/12 chain
- alpha / beta denotes orientation of -OH at C9 (only for F series)
59
There is a double bond in prostaglandins that is always at the same location. Where is this location?
at C13/14
60
Why is the consequence of C13=C14 in prostaglandins?
- allylic structure
- allylic OH at C15
- weak
- degraded fast
61
eicosanoids
bioactive oxidative metabolites of 20 x carbon fatty acids
62
Eicosanoids are precursors to what?
- prostaglandins
- thromboxane
- leukotriene
63
phospholipase A2
- produce arachidonic acid
| - anti-inflammatory drugs are PLA2 inhibitors
64
COX
- take arachidonic acid to further produce PG
| - target of NSAIDs
65
metabolism of PG
- oxidize C15-OH into =O
- reduction of C13=C14
- beta-oxidation: cutting off 2C from C1 twice
- omega oxidation: C20 from methyl to carboxyl
66
How can you protect the allylic -OH in PG?
add methyl group to C15
67
Why do you get GI side effects from taking non-selective NSADs?
because COX1 is involved in protecting GI mucosa
68
COX1 and COX2 are similar in structure. How do you target COX2?
- active site of COX 2 is much larger
| - have a drug that fits in that pocket but not COX1 pocket
69
salicylic acid
- natural product from willow bark
| - non-selective COX inhibitor
70
function of serotonin
- regulate smooth muscle: CV and GI
| - enhance platelet aggregation
71
What is the precursor to serotonin?
tryptophan
72
What is the rate limiting step in producing serotonin?
- TPH (tryptophan hydroxylase)
| - never saturated
73
With respect to products of trp, how is depression diagnosed?
higher ratio of kynurenine : serotonin
74
VMAT
transports serotonin into vesicle
75
SERT
re-uptakes serotonin back into nerve ending
76
What is the primary site for serotonin synthesis?
Enterochromaffin cells
77
What is the fate of serotonin after its reuptake into nerve endings?
- stored via VMAT
| - degraded by MAO
78
What can be used as marker for serotonin-producing tumor?
5HIAA levels which is a break down product of serotonin
79
serotonin receptors
- 5HT1: Gi
- 5HT2: Gq
- 5HT3: ligand-gated ion channel
- 5HT4-7: Gs, Gi
80
What stimulates release of serotonin?
- mechanical stretching
- glucose
- efferent vagal stimulation
81
serotonin effects on GI
- stimulate peristalsis
- enhance peristalsis effects
- N/V/D
82
serotonin role in clot formation
enhance aggregation response
83
serotonin role in immune system
- bind to serotonin receptors on immune cells
| - induce release of cytokines
84
serotonin role in CV system
- induce vasoconstriction
- amplify vasoconstriction effects of other NT
- vagus nerve activation (opposite of previous, this causes hypotension)
85
What are the autacoids?
- histamine
- bradykinin
- kallidin
86
What are autocoids?
- molecule that our body secretes that has local and short action
- synthesized in same tissue that they act upon
87
storage of histamine
- granules of mast cells
- bound to heparin in mast cells
- basophils in blood
88
Where is histamine synthesized?
- granules in skin
- gastric mucosa
- hematopoietic cells
- neurons
89
How is histamine metabolized?
- MAO
| - oxidative deamination
90
role of histamine
- mediate inflammation
- increase gastric acid secretion
- NT in nervous system
91
What happens to antibodies (IgE) after they are released by plasma cells?
- they bind to FceRI receptor on mast cells
| - this primes the mast cells
92
How does crosslinking trigger release of histamine?
crosslinking -> conformational change -> increase intracellular Ca -> release of histamine
93
What is the role of histamine in CNS?
- sleep-wake cycle
- appetite
- immunity
- learning and memory
94
What does histamine cause in the periphery?
- epidermis: itch
| - dermis: pain & itching
95
What is another way histamine can be released other than in the allergic reaction?
histamine displaced from its bound form
96
What are symptoms of "red-man syndrome"?
- pruritus
- erythema
- hypotension
- flushing in face, neck, upper body
97
Histamine receptor are what kind of receptors?
GPCRs
98
What are the different types of histamine receptors?
H1, H2, H3, H4
99
H1 role and examples of drugs that target them
- acute allergic reaction
| - cetirizine
100
H2 role and examples of drugs that target them
- gastric acid secretion
- cimetidine
- rantidine
101
H3 role and examples of drugs that target them
- NT modulation
- thioperamide
- clobenpropit
- tiprolisant
102
H4 role and examples of drugs that target them
- immune modulator
| - thioperamide
103
Where are H1 located?
- smooth muscle
- endothelium
- brain
104
Where are H2 located?
- gastric mucosa
- cardiac muscle
- mast cells
- brain
105
Where are H3 located?
- presynaptic auto / hetero receptors
- brain
- myenteric plexus
106
Where are H4 located?
- eosinophils
- neutrophils
- CD4 t cells
107
H1 G protein mechanism
- coupled to Gaq
- phosphlipase C -> IP3 and DAG
- increase Ca
108
H2 G protein mechanism
- couples to Gas
| - increase cAMP
109
H3 G protein mechanism
- coupled to Gai
| - decrease cAMP
110
H4 G protein mechanism
- couple to Gai
- decrease cAMP
- increase Ca
111
What are the effects of H1 histamine receptor?
- ↑ Ca -> eNOS -> NO -> vascular smooth muscle -> ↑cGMP -> ↓ Ca -> relax smooth muscle
- ↑ Ca -> endothelial cells contract -> exudate
- ↑ attention & vigilance
- ↓ appetite
112
What are the effects of H2 histamine receptor?
- increases gastric acid secretion via parietal cell
- increase working memory
- ↑ cAMP -> activate protein kinase -> ↓ Ca -> relax smooth muscle
113
What are the effects of H3 histamine receptor?
- regulates release of its own and other's receptors
| - ↓ cAMP -> ↓ Ca2 -> ↓ NT
114
What are the effects of H4 histamine receptor?
- induce chemotaxis
- secrete cytokines
- regulate neuropathic pain and pruritus
115
What would histamine agonists be used for?
- provocative tests for bronchial hyper-reactivity
| - positive control for triple response
116
triple response
- localized red spot
- flare
- wheal
117
examples of first generation antihistamines
- diphenhydramine
- chlorpheniramine
- hydroxyzine
- doxylamine
118
What is the target of first generation antihistamines?
H1 receptor
119
side effects of first generation antihistamines
- dry mouth / nose
- dilated pupils
- decreased motility
- sedation
120
What are the antihistamines used to treat motion sickness and how does it work?
- promethazine
- dimenhydrinate
- has anti-muscarinic activity -> decrease motility
121
examples of second generation antihistamine
- loratadine
- cetirizine
- fexofenadine
122
characteristics of second generation antihistamine
- they are metabolites of first generation
- longer duration
- less sedating
123
examples of third generation antihistamine
- desloratadine
| - levocetirizine
124
characteristics of third generation antihistamine
- long acting
| - not associated with sedation or cardiotoxicity
125
H3 inverse agonist
- Pitolisant
| - reduce sleep cycles in patients with narcolepsy
126
types of kinin
- bradyknin
| - kallidin
127
properties of kinin
- potent vasodilator
| - released when there is some sort of tissue damage, infection, inflammation
128
bradykinin
- predominant kinin in plasma
- made from HMW kininogen
- bind to bradykinin B2 receptor
- metabolite bind to B1 receptor
129
kallidin
- predominant kinin in tissue
- made from LMW kininogen
- can be a precursor to bradykinin
- bind to bradykinin B2 receptor
- metabolite bind to B1 receptor
130
B2 receptor
- vasodilation
| - acute pain
131
B1 receptor
- vasodilation
| - chronic pain
132
ACE
aka kininase II that breaks down bradykinin to inactive metabolites
133
C1-INH
inhibit proteases of kallikrein-kinin
134
C1-INH deficiency
- increases amount of bradykinin
- leads to vasodilation
- angioedema
135
HAE
hereditary angioedema
136
What are mechanisms of drugs used to treat HAE?
- selective B2 receptor antagonist
- C1 esterase inhibitor
- kallikrein inhibitor
137
example of selective B2 receptor antagonist
Icabitant (HOE-140/Firazyr – FDA–approved in 2011)
138
example of C1 esterase inhibitor
- Cinryze (FDA-approved 2008)
| - Berinert (FDA-approved 2009)
139
example of kallikrein inhibitor
Ecallantide (Kalbitor – FDA–approved 2009)
140
Which PG are the most biologically important?
- PGE
- PGF
- PGI
- thromboxane
141
What are the types of PG receptors?
- EP
- FP
- IP
- DP
- TP
142
What kind of receptors are PG receptors?
GPCRs
143
What are the fates of arachidonic acid?
- leukotriene
| - PG
144
Why are there GI side effects when taking NSAIDs?
- NSAIDs prevent production of PG
| - PG has a cytoprotextive effect on GI
145
corticosteroid mechanism of action
inhibit phospholipase A
146
PG effect on CV system
- dilation of arterioles, pre-cap, sphincters, post-cap venules
- increase CO
- increase HR
147
PG effect on ductus arteriousus
maintaining opening of duct. art.
148
PG effect on blood platelets
inhibit platelet aggregation
149
PG effect on smooth muscle
- bronchial relax
- uterine: during pregnancy, body becomes more sensitive to PG
- intestinal contract
150
PG effect on gastric secretions
- inhibit gastric secretion and pepsin content
- increase mucus secretion
- cytoprotective effect on GI
151
PG effect on peripheral nervous system
- cause pain / irritation
| - sensitize nerve endings
152
PG effect on inflammatory / immune response
potentiate pain-producing effects of other autocoids
153
PG effect on reproductive system
amniotic fluid elevated during labor
154
What can happen if NSAIDs are taken during pregnancy?
it may prolong pregnancy and labor
155
therapeutic applications of PG
- induce abortion
- labor inducion
- dysmenorrhea (painful uterine bleeding)
- impotence
- platelet aggregation
- open angel glaucoma
- GI ulcers
- pulm. HTN
- patent duct. art.
156
dinoprostone
- brand name Cervidil
- PGE2
- used for therapeutic abortion
157
alprostadil
- brand name Caverject
- used for ED
- used to prevent platelet aggregation -> improve harvest and storage of blood platelets
- used to maintain duct. art.
158
epoprostenol
- brand name: Flolan
| - used for pulmonary HTN
159
misoprostol
- brand name: Cytotec
| - used as cytoprotective agent
160
latanoprost
- brand name: Xalatan
| - used for open angle glaucoma
161
glucocorticoid effect on carbohydrate and protein
- catabolize protein from muscle and bone
- decreased growth
- osteoporosis
- elevated levels of glucose
162
glucocorticoid effect on calcium
- decrease Ca absorption from intestine
| - destroy protein matrix of bone
163
glucocorticoid effect on lipid
fat redistribution
164
glucocorticoid effect on immunological activity
- decrease eosinophils, lympocytes, neutrophils, basophils
- decreased function of lymphocytes and macrophages
- atrophy of lymphoid tissue
165
glucocorticoid effect on inflammatory activities
- inhibit PLA2
| - decrease PG, leukotrienes, thromboxanes
166
glucocorticoid effect on CNS system
- depression
- irritability
- psychotic episodes
- altered EEG
167
What happens to adrenal gland when on chronic glucocorticoid?
- decreased ACTH
| - leads to atrophy of adrenal gland
168
How do you combat against adrenal atrophy (due to glucocorticoid)?
- taper off glucocorticoid
- administer ACTH
- alternate day therapy
169
effect of mineralcorticoid
- Na and water retention
- K and H loss
- act on distal tubules and collecting ducts
170
examples of mineralcorticoid
- aldosterone
- fludrocortisone
- DOC (Desoxycorticostirone)
171
protein binding of glucocorticoids
- bound to CBG (corticosteroid binding globulin)
| - aka transcortin
172
How can you explain dexamethasone's increased potency?
- because CBG has low affinity for synthetic compounds
| - more in the free / active form
173
symptoms of drug induced Cushing's syndrome
- elevated glucose
- depress immune system
- peptic ulver
- myopathy
- psychosis
- osteoporosis / fractures
174
therapeutic uses of adrenal steroids
- adrenal insufficiency (Addison's)
- Congenital Adrenal Hyperplasia
- arthritis
- allergic reactions
- ocular inflammation
175
What is one thing to note before treating ocular inflammation with adrenal steroids?
- make sure that it's not associated with infection
- if it is infected and treated with a. steroids, pain will go away but infection will stay
- a. steroids will enhance infection
176
Contraindications and precautions for adrenal steroids
- agitation
- ulcer
- diabetes
- osteoporosis
- HTN
- infections
177
adrenal steroid inhibitors
- aminoglutethimide
| - spironolactone
178
aminoglutethimide
- brand name: Cytadren
- inhibits synthesis of glucocorticoid steroid
- treat Cushing's
- prevent production of estrogen in breast cancer pt
179
spironolactone
- brand name: Aldactone
- mineralocorticoid receptor antagonist
- structurally similar to aldosterone and sits on the receptor and prevent activity
- used as diuretic
- similar structure to testosterone; inhibits test. synthesis
- treat hirsuitism
180
Where does spermatogenesis occur?
- Seminiferous Tubule
| - Sertoli Cells
181
Where is testosterone produced?
Leydig cells
182
Which hormone stimulates anterior pituitary?
- GnRH
| - puberty stimulates hypothalamus to release GnRH
183
5a-reductase
testosterone -> dihydrotestosterone (a more active metabolite)
184
What are the androgenic effects of puberty?
- growth of genital glands
- voice change
- body hair
- skin thickness
185
What are the anabolic effects of puberty?
- positive N balance
- protein synthesis
- body growth (weight, muscle, bone, etc)
- closure of epihysis
186
characteristics of testosterone
- metabolized in liver
- ester forms have better efficacy
- 98% is bound to SHBG (mainly) and albumin
187
Explain the signal transduction of testosterone
- in target tissue, testosterone is converted to active metabolite by 5a-reductase
- goes into nucleus to bind to receptor
- transcription -> biological activity
188
Target tissues convert testosterone into its active metabolite. All but which tissues do not do this?
- hypothalamus
| - pituitary
189
testosterone propionate
- brand name: Testex
| - natural androgen
190
methyltestosterone
- brand name: Virilron
| - orally active androgen
191
How can you modify testosterone to reduce metabolism?
alkylate -OH at C17
192
oxandrolone
- brand name: Oxandrin
- anabolic steroid
- ratio of anabolic : androgenic = about 10:1
193
What are approved uses for anabolic steroids?
- burn
- chronic illness
- atrophy due to chemotherapy
194
Adverse effects of androgens
- jaundice
- edema
- testicular atrophy
- prostate hypertrophy -> prostate cancer
- feminizing effects for males
195
Mechanism of action of anti-androgens
- inhibit synthesis (GnRH)
- inhibit formation into active metabolite
- androgen-receptor antagonist
196
GnRH inhibitor
Leuprolide
197
5α- reductase Inhibitor
finasteride
198
flutamide
- brand name: Eulexin
- non-steroidal receptor inhibitor
- inhibits androgen to receptor in nucleus
- used in prostate cancer
- most effective when used in combination with Leuprolide
199
What are other functions of estrogen?
protective effect in bone and CV system
200
progesterone
- needed for complete sexual development
| - menstrual regulation
201
conjugated estrogen
- brand name: Premarin
- sulfated esters of estrone
- can be taken orally
202
ethinyl estradiol
- brand name: Estinyl
| - has a C17 substituent that protects itself from FPM
203
diethylstilbesterol
- brand name: Stilphostrol
- orally active and not destroyed b y FPM
- not steroid in structure; has similar -OH ends like steroid though
204
side effects of ovarian steroids
- nausea
- fluid retention
- stroke
- thromboembolism
- chloasma
- breast cancer
205
teamoxifen
- brand name: Nolvadex
- similar to estrogen in structure - alters transcription
- low dose: estrogenic activity
- high dose: anti-estrogenic activity
206
raloxifene
- brand name: Evista
- selective ER-beta
- treat / prevent PM osteoporosis
207
anastrozole
- brand name: Arimidex
- inhibit aromatase
- used in advanced breast cancer
208
progesterone acetate
- brand name: Cyclin
- natural
- poor GI absorption
209
norethindrone
- brand name: Norlutin
- good oral activity
- substituents to prevent being metabolized
210
RU-486
- brand name: Mifefpristone
- competitive antagonist of progesterone
- used for medical abortion
211
How can we control membrane penetration of histamine?
- ionize it
| - mast cells have pH of 5.6 and keeps histamine in its cation form
212
What are the mechanisms by which histamine is metabolized?
- N-methylation
| - oxidation
213
structure of 1st generation anti-histamine
- two aromatic groups
| - tertiary aliphatic amine
214
characteristics of 1st generation histamine
- highly lipophilic
- sedative
- anti-musc, anti-a-adrenergic, anti-serotonin
215
What are the classifications of first generation anti-histamines?
- Ethylenediamines
- Ethanolamine Ethers
- Alkyl Amines
- Piperazines
- Tricyclic H1 Antihistamines
216
Ethylenediamines
early version of anti-histamines
217
Ethanolamine Ethers
- Diphenylhydramine
- Dramamine (motion sickness)
- Doxylamine (sleep)
- anti-cholinergic effects
218
Alkyl Amines
- longer duration
| - decreased sedative effects
219
Piperazines
- teratogenic effects is rodents
| - cetirizine
220
characteristics of second generation antihistamines
- increased H1 selectivity
- limited CNS entry
- long-acting
