Exam 3 II Flashcards
Steroid start from which structure?
CPPP
adrenal cortex
produce glucocorticoids and mineralocorticoids
testis
produce androgens
ovaries
produce estrogens and progestagens
Cortico-steroids
- aka Adrenocorticoids
- Glucocorticoids
- Mineralocorticoids
anabolic steroids
- synthetic
- example of androgen
estrane
18 carbon steroidal unit
androstane
19 carbon steroidal unit
pregnane
21 carbon steroidal unit
cholestane
27 carbon steroidal unit
cholane
24 carbon steroidal unit
configurational isomers
- there are 8 possible variations
What are the common configurational isomers?
- trans-trans-trans
- cis-trans-trans
- cis-trans-cis
What structural feature denotes a steroid as a delta?
if there is a double bond between between 4/5 or 5/6
What does the statins inhibit and why?
- inhibits HMG-CoA reductase
- because it converts HMG-CoA to mevalonic acid which goes on to cholesterol synthesis
glucocorticoids and examples
- affect intermediary metabolism
- inhibit inflammation
- ex. cortisol, cortisone
mineralocorticoids and example
- salt retention
- aldosterone
pathologic conditions related to adrenal cortex
- Cushing’s disease
- Addison’s disease
- Conn’s syndrome
What structural feature denotes glucocorticoids?
- OH at C17 in the alpha configuration
- OH at C11
- double bond at C4/5
- carbonyl at C3
- beta-Ketol at C17
What is the structural difference between glucocorticoids and mineralocorticoids?
mineralocorticoids doesn’t contain OH at C17
What is important about the C11 OH in mineralocorticoids and glucocorticoids?
it is the site of which these compounds attach themselves to the receptors
What are problems with natural corticoids?
- rare availability of cortisol
- not resistant to first pass metabolism
- side effects
What are the products of first pass metabolism of cortisol?
- C11 OH -> keto group =O
- C3 =O -> alpha OH
- double bond C4/5 gone
- C17 OH -> keto =O
Why does alpha OH at C3 destroys activity?
no steroid in body has alpha OH at C3, it’s all beta
What are the two categories of adrenocorticoid drugs?
- cortisol
- prednisolone
What are characteristics of cortisol esters?
- more stable
- slow absorption
What are characteristics of cortisol cypionate esters?
- more lipophilic
- slow absorption in oral administration
What are characteristics of cortisol salt forms?
- water soluble
- IV or IM
- fast hydrolysis
What is the difference between cortisol and prednisolone?
prednisolone has a double bond at C1/2
What are the purpose of modifications of prednisolone?
add substituents to C16 to protect OH and side chains on C17 from being metabolized
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
What is the advantage of forming an acetonide and tying two -OH groups?
stabilizing compound and giving it a longer half life
How does the double bond at C1/2 increase potency?
the chair-conformation is flatter and can sit at the receptor site better
Function of adrenocorticoid antagonists
- compete for binding site
- inhibit biosynthesis of adrenocorticoids
ring A in estrogen
benzene
aromatase
- gives estrogen compounds their benzene ring
- rate limiting step
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
Why is the distance between two -OH in estrogen important?
it is 8.55 Å and the receptor is 8.55 Å in size
What are structural features of estrogen?
- aromatic A ring
- phenol at C3
- beta OH at C17
- 8.55 Å between -OH groups
Modifications of estrogen to increase half life
- ether at C3
- ester at C3 or C17
- add ethlyne at C17
Function of estrogen antagonists
- compete for binding site
- inhibit biosynthesis of estrogens
ER-alpha
female reproductive tract and mammary gland
ER-beta
- vascular endothelial cells
- CV and bone tissue
What can aromatase inhibitors be used for?
- control reproductive functions
- treatment of estrogen-dependent breast cancers
progesterone
serves as precursor to:
- androgen
- estrogen
- adrenocorticoids
What are structural features of progesterone?
- 21 C skeleton
- double bond at C4/5
- ketone at C3
- O functionality a C3 and 20
formation of HCG
- lose double bond of progesterone at C4/5
- C3 is glucronidated
=> HCG
metabolism of progesterone
- reduction of -OH at C3
- double bond at C4/5 metabolized
- rapid metabolism: t1/2 of 5-10min
How can we modify progesterone to increase half life?
- add -OH to C17
- add methyl group to C6
- double bond at C6/7
What happens if you block 5alpha-reductase?
stops synthesis of testosterone
Side effects of testosterone
it can have both anabolic and androgenic activity
Functions of antiandrogens
- block receptors
- inhibits synthesis of androgens
Which enzymes can you inhibit to inhibit production of androgen?
- 17a-hydroxylase/17,20-lyase
- 5a-reductase
Which location in the human body is there presence of prostaglandins?
- reproductive tract
- seminal vesicles
- menstrual fluid
- umbilical cord
- placenta
Where else can you find prostaglandins?
Gorgonian Coral / Sea Whip Coral
What is the starting material for prostaglandins?
from a 20 carbon fatty acid (arachidonic acid)
structural features of prostanoic acid
- 20C fatty acid
- 7C chain attached to C8 in alpha
- 8C chain attached to C12 in beta
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)
There is a double bond in prostaglandins that is always at the same location. Where is this location?
at C13/14
Why is the consequence of C13=C14 in prostaglandins?
- allylic structure
- allylic OH at C15
- weak
- degraded fast
eicosanoids
bioactive oxidative metabolites of 20 x carbon fatty acids
Eicosanoids are precursors to what?
- prostaglandins
- thromboxane
- leukotriene
phospholipase A2
- produce arachidonic acid
- anti-inflammatory drugs are PLA2 inhibitors
COX
- take arachidonic acid to further produce PG
- target of NSAIDs
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
How can you protect the allylic -OH in PG?
add methyl group to C15
Why do you get GI side effects from taking non-selective NSADs?
because COX1 is involved in protecting GI mucosa
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
salicylic acid
- natural product from willow bark
- non-selective COX inhibitor
function of serotonin
- regulate smooth muscle: CV and GI
- enhance platelet aggregation
What is the precursor to serotonin?
tryptophan
What is the rate limiting step in producing serotonin?
- TPH (tryptophan hydroxylase)
- never saturated
With respect to products of trp, how is depression diagnosed?
higher ratio of kynurenine : serotonin
VMAT
transports serotonin into vesicle
SERT
re-uptakes serotonin back into nerve ending
What is the primary site for serotonin synthesis?
Enterochromaffin cells
What is the fate of serotonin after its reuptake into nerve endings?
- stored via VMAT
- degraded by MAO
What can be used as marker for serotonin-producing tumor?
5HIAA levels which is a break down product of serotonin
serotonin receptors
- 5HT1: Gi
- 5HT2: Gq
- 5HT3: ligand-gated ion channel
- 5HT4-7: Gs, Gi
What stimulates release of serotonin?
- mechanical stretching
- glucose
- efferent vagal stimulation
serotonin effects on GI
- stimulate peristalsis
- enhance peristalsis effects
- N/V/D
serotonin role in clot formation
enhance aggregation response
serotonin role in immune system
- bind to serotonin receptors on immune cells
- induce release of cytokines
serotonin role in CV system
- induce vasoconstriction
- amplify vasoconstriction effects of other NT
- vagus nerve activation (opposite of previous, this causes hypotension)
What are the autacoids?
- histamine
- bradykinin
- kallidin
What are autocoids?
- molecule that our body secretes that has local and short action
- synthesized in same tissue that they act upon
storage of histamine
- granules of mast cells
- bound to heparin in mast cells
- basophils in blood
Where is histamine synthesized?
- granules in skin
- gastric mucosa
- hematopoietic cells
- neurons
How is histamine metabolized?
- MAO
- oxidative deamination
role of histamine
- mediate inflammation
- increase gastric acid secretion
- NT in nervous system
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
How does crosslinking trigger release of histamine?
crosslinking -> conformational change -> increase intracellular Ca -> release of histamine
What is the role of histamine in CNS?
- sleep-wake cycle
- appetite
- immunity
- learning and memory
What does histamine cause in the periphery?
- epidermis: itch
- dermis: pain & itching
What is another way histamine can be released other than in the allergic reaction?
histamine displaced from its bound form
What are symptoms of “red-man syndrome”?
- pruritus
- erythema
- hypotension
- flushing in face, neck, upper body
Histamine receptor are what kind of receptors?
GPCRs
What are the different types of histamine receptors?
H1, H2, H3, H4
H1 role and examples of drugs that target them
- acute allergic reaction
- cetirizine
H2 role and examples of drugs that target them
- gastric acid secretion
- cimetidine
- rantidine
H3 role and examples of drugs that target them
- NT modulation
- thioperamide
- clobenpropit
- tiprolisant
H4 role and examples of drugs that target them
- immune modulator
- thioperamide
Where are H1 located?
- smooth muscle
- endothelium
- brain
Where are H2 located?
- gastric mucosa
- cardiac muscle
- mast cells
- brain
Where are H3 located?
- presynaptic auto / hetero receptors
- brain
- myenteric plexus
Where are H4 located?
- eosinophils
- neutrophils
- CD4 t cells
H1 G protein mechanism
- coupled to Gaq
- phosphlipase C -> IP3 and DAG
- increase Ca
H2 G protein mechanism
- couples to Gas
- increase cAMP
H3 G protein mechanism
- coupled to Gai
- decrease cAMP
H4 G protein mechanism
- couple to Gai
- decrease cAMP
- increase Ca
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
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
What are the effects of H3 histamine receptor?
- regulates release of its own and other’s receptors
- ↓ cAMP -> ↓ Ca2 -> ↓ NT
What are the effects of H4 histamine receptor?
- induce chemotaxis
- secrete cytokines
- regulate neuropathic pain and pruritus
What would histamine agonists be used for?
- provocative tests for bronchial hyper-reactivity
- positive control for triple response
triple response
- localized red spot
- flare
- wheal
examples of first generation antihistamines
- diphenhydramine
- chlorpheniramine
- hydroxyzine
- doxylamine
What is the target of first generation antihistamines?
H1 receptor
side effects of first generation antihistamines
- dry mouth / nose
- dilated pupils
- decreased motility
- sedation
What are the antihistamines used to treat motion sickness and how does it work?
- promethazine
- dimenhydrinate
- has anti-muscarinic activity -> decrease motility
examples of second generation antihistamine
- loratadine
- cetirizine
- fexofenadine
characteristics of second generation antihistamine
- they are metabolites of first generation
- longer duration
- less sedating
examples of third generation antihistamine
- desloratadine
- levocetirizine
characteristics of third generation antihistamine
- long acting
- not associated with sedation or cardiotoxicity
H3 inverse agonist
- Pitolisant
- reduce sleep cycles in patients with narcolepsy
types of kinin
- bradyknin
- kallidin
properties of kinin
- potent vasodilator
- released when there is some sort of tissue damage, infection, inflammation
bradykinin
- predominant kinin in plasma
- made from HMW kininogen
- bind to bradykinin B2 receptor
- metabolite bind to B1 receptor
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
B2 receptor
- vasodilation
- acute pain
B1 receptor
- vasodilation
- chronic pain
ACE
aka kininase II that breaks down bradykinin to inactive metabolites
C1-INH
inhibit proteases of kallikrein-kinin
C1-INH deficiency
- increases amount of bradykinin
- leads to vasodilation
- angioedema
HAE
hereditary angioedema
What are mechanisms of drugs used to treat HAE?
- selective B2 receptor antagonist
- C1 esterase inhibitor
- kallikrein inhibitor
example of selective B2 receptor antagonist
Icabitant (HOE-140/Firazyr – FDA–approved in 2011)
example of C1 esterase inhibitor
- Cinryze (FDA-approved 2008)
- Berinert (FDA-approved 2009)
example of kallikrein inhibitor
Ecallantide (Kalbitor – FDA–approved 2009)
Which PG are the most biologically important?
- PGE
- PGF
- PGI
- thromboxane
What are the types of PG receptors?
- EP
- FP
- IP
- DP
- TP
What kind of receptors are PG receptors?
GPCRs
What are the fates of arachidonic acid?
- leukotriene
- PG
Why are there GI side effects when taking NSAIDs?
- NSAIDs prevent production of PG
- PG has a cytoprotextive effect on GI
corticosteroid mechanism of action
inhibit phospholipase A
PG effect on CV system
- dilation of arterioles, pre-cap, sphincters, post-cap venules
- increase CO
- increase HR
PG effect on ductus arteriousus
maintaining opening of duct. art.
PG effect on blood platelets
inhibit platelet aggregation
PG effect on smooth muscle
- bronchial relax
- uterine: during pregnancy, body becomes more sensitive to PG
- intestinal contract
PG effect on gastric secretions
- inhibit gastric secretion and pepsin content
- increase mucus secretion
- cytoprotective effect on GI
PG effect on peripheral nervous system
- cause pain / irritation
- sensitize nerve endings
PG effect on inflammatory / immune response
potentiate pain-producing effects of other autocoids
PG effect on reproductive system
amniotic fluid elevated during labor
What can happen if NSAIDs are taken during pregnancy?
it may prolong pregnancy and labor
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.
dinoprostone
- brand name Cervidil
- PGE2
- used for therapeutic abortion
alprostadil
- brand name Caverject
- used for ED
- used to prevent platelet aggregation -> improve harvest and storage of blood platelets
- used to maintain duct. art.
epoprostenol
- brand name: Flolan
- used for pulmonary HTN
misoprostol
- brand name: Cytotec
- used as cytoprotective agent
latanoprost
- brand name: Xalatan
- used for open angle glaucoma
glucocorticoid effect on carbohydrate and protein
- catabolize protein from muscle and bone
- decreased growth
- osteoporosis
- elevated levels of glucose
glucocorticoid effect on calcium
- decrease Ca absorption from intestine
- destroy protein matrix of bone
glucocorticoid effect on lipid
fat redistribution
glucocorticoid effect on immunological activity
- decrease eosinophils, lympocytes, neutrophils, basophils
- decreased function of lymphocytes and macrophages
- atrophy of lymphoid tissue
glucocorticoid effect on inflammatory activities
- inhibit PLA2
- decrease PG, leukotrienes, thromboxanes
glucocorticoid effect on CNS system
- depression
- irritability
- psychotic episodes
- altered EEG
What happens to adrenal gland when on chronic glucocorticoid?
- decreased ACTH
- leads to atrophy of adrenal gland
How do you combat against adrenal atrophy (due to glucocorticoid)?
- taper off glucocorticoid
- administer ACTH
- alternate day therapy
effect of mineralcorticoid
- Na and water retention
- K and H loss
- act on distal tubules and collecting ducts
examples of mineralcorticoid
- aldosterone
- fludrocortisone
- DOC (Desoxycorticostirone)
protein binding of glucocorticoids
- bound to CBG (corticosteroid binding globulin)
- aka transcortin
How can you explain dexamethasone’s increased potency?
- because CBG has low affinity for synthetic compounds
- more in the free / active form
symptoms of drug induced Cushing’s syndrome
- elevated glucose
- depress immune system
- peptic ulver
- myopathy
- psychosis
- osteoporosis / fractures
therapeutic uses of adrenal steroids
- adrenal insufficiency (Addison’s)
- Congenital Adrenal Hyperplasia
- arthritis
- allergic reactions
- ocular inflammation
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
Contraindications and precautions for adrenal steroids
- agitation
- ulcer
- diabetes
- osteoporosis
- HTN
- infections
adrenal steroid inhibitors
- aminoglutethimide
- spironolactone
aminoglutethimide
- brand name: Cytadren
- inhibits synthesis of glucocorticoid steroid
- treat Cushing’s
- prevent production of estrogen in breast cancer pt
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
Where does spermatogenesis occur?
- Seminiferous Tubule
- Sertoli Cells
Where is testosterone produced?
Leydig cells
Which hormone stimulates anterior pituitary?
- GnRH
- puberty stimulates hypothalamus to release GnRH
5a-reductase
testosterone -> dihydrotestosterone (a more active metabolite)
What are the androgenic effects of puberty?
- growth of genital glands
- voice change
- body hair
- skin thickness
What are the anabolic effects of puberty?
- positive N balance
- protein synthesis
- body growth (weight, muscle, bone, etc)
- closure of epihysis
characteristics of testosterone
- metabolized in liver
- ester forms have better efficacy
- 98% is bound to SHBG (mainly) and albumin
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
Target tissues convert testosterone into its active metabolite. All but which tissues do not do this?
- hypothalamus
- pituitary
testosterone propionate
- brand name: Testex
- natural androgen
methyltestosterone
- brand name: Virilron
- orally active androgen
How can you modify testosterone to reduce metabolism?
alkylate -OH at C17
oxandrolone
- brand name: Oxandrin
- anabolic steroid
- ratio of anabolic : androgenic = about 10:1
What are approved uses for anabolic steroids?
- burn
- chronic illness
- atrophy due to chemotherapy
Adverse effects of androgens
- jaundice
- edema
- testicular atrophy
- prostate hypertrophy -> prostate cancer
- feminizing effects for males
Mechanism of action of anti-androgens
- inhibit synthesis (GnRH)
- inhibit formation into active metabolite
- androgen-receptor antagonist
GnRH inhibitor
Leuprolide
5α- reductase Inhibitor
finasteride
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
What are other functions of estrogen?
protective effect in bone and CV system
progesterone
- needed for complete sexual development
- menstrual regulation
conjugated estrogen
- brand name: Premarin
- sulfated esters of estrone
- can be taken orally
ethinyl estradiol
- brand name: Estinyl
- has a C17 substituent that protects itself from FPM
diethylstilbesterol
- brand name: Stilphostrol
- orally active and not destroyed b y FPM
- not steroid in structure; has similar -OH ends like steroid though
side effects of ovarian steroids
- nausea
- fluid retention
- stroke
- thromboembolism
- chloasma
- breast cancer
teamoxifen
- brand name: Nolvadex
- similar to estrogen in structure - alters transcription
- low dose: estrogenic activity
- high dose: anti-estrogenic activity
raloxifene
- brand name: Evista
- selective ER-beta
- treat / prevent PM osteoporosis
anastrozole
- brand name: Arimidex
- inhibit aromatase
- used in advanced breast cancer
progesterone acetate
- brand name: Cyclin
- natural
- poor GI absorption
norethindrone
- brand name: Norlutin
- good oral activity
- substituents to prevent being metabolized
RU-486
- brand name: Mifefpristone
- competitive antagonist of progesterone
- used for medical abortion
How can we control membrane penetration of histamine?
- ionize it
- mast cells have pH of 5.6 and keeps histamine in its cation form
What are the mechanisms by which histamine is metabolized?
- N-methylation
- oxidation
structure of 1st generation anti-histamine
- two aromatic groups
- tertiary aliphatic amine
characteristics of 1st generation histamine
- highly lipophilic
- sedative
- anti-musc, anti-a-adrenergic, anti-serotonin
What are the classifications of first generation anti-histamines?
- Ethylenediamines
- Ethanolamine Ethers
- Alkyl Amines
- Piperazines
- Tricyclic H1 Antihistamines
Ethylenediamines
early version of anti-histamines
Ethanolamine Ethers
- Diphenylhydramine
- Dramamine (motion sickness)
- Doxylamine (sleep)
- anti-cholinergic effects
Alkyl Amines
- longer duration
- decreased sedative effects
Piperazines
- teratogenic effects is rodents
- cetirizine
characteristics of second generation antihistamines
- increased H1 selectivity
- limited CNS entry
- long-acting
