Term test 1 Flashcards
Propranolol
blocks B1 and B2 adrenergic receptor, antihypertensive and antiarrhythmic
antagonist
Nadolol
B1 and B2 adrenergic receptor, angina prophylactic
longer half life than propranolol
Metoprolol
selective on B1 adrenergic receptor, antiarrhythmic
decrease cardiac output
Carvedilol
B1 and A1 adrenergic receptor, heart failure
non-selective antagonist
decrease cardiac output and vasodilation
Salbutamol
B2 selective agonist
vasodilation in lungs
last 3-6 hours, treats asthma
Salmeterol
B2 selective agonist
lasts 12 hours, treat asthma
BRL37344
B3 adrenergic selective agonist increase lipolysis use in treatment of obesity cardiovascular effect profound hypotension uterine relaxation decrease cardiac contractility
Phenylephrine and methoxamine
A1 adrenergic receptor agonist
vasoconstrictor, treatment for hypotension
decongestant
side effects: induce angina in patients with coronary heart disease
rebound congestion after use
B1 adrenergic receptor
expressed in the heart
increase intracellular Ca level in myocyte
increase force and contractility of heart
increase stroke volume
B2 adrenergic receptor
found in smooth muscle of lungs and blood vessels muscle relaxation decrease intracellular Ca level increase intracellular K level leads to bronchodilation
B3 adrenergic receptor
expressed in adipocytes
increase lipolysis
decrease heart contractility
A1 adrenergic receptor
in smooth muscle, respiratory mucosa and radial muscle of the eye activated by Gq protein vasoconstriction increase in blood pressure increase intracellular Ca level
3 factors affecting the permeability of ion through the selectivity filter
- size of ion
- hydration shell created with aqueous environment
- ability of ion to interact with amino acid in the pore region of channel
3 different subtypes of voltage-gated calcium channels
L-type: long lasting (no inactivation)
P/Q type: Purkinje (mild inactivation)
T-type: transient (rapid opening and closing)
B - scorpion toxins
VGIC enhanced activation leftward shift of dose response curve higher sensitivity Na+ enter cells sooner increase excitability more hyperpolarize less activation energy required to open channel
Tetrodotoxin (TTX), Saxitoxin, u-conotoxin
Pore block
site 1
Na+ ions cannot move down the concentration gradient
no ion movement
Tetrodotoxin (TTX) can inhibit spontaneous action potential
leads to treatment of epilepsy and seizure (hyperactivity of channel)
most neuronal Na channels are sensitive to TTX but some are resistant
7 Na+ channel blockers
Resveratrol (from red wine)
Lidocaine, Procaine (arrhythmia)
Phenytoin, Carbamazepine, Topiramate (headache, pain and migraine)
Quinidine
L-type calcium channel blocker
dihydropyridines (DHP)
verapamil, diltiazem (Non-DHP)
K+ channel blocker
Amiodarone
Resveratrol
French’s paradox
in red wine
effective inhibition of Na+ current by grape extract
C1 = resveratrol derivative
reduce duration of atrial fibrillation
resveratrol and C1 have many targets -> effect unlikely due to one mechanism (can also block late sodium current)
Resveratrol and C1
French’s paradox
in red wine
effective inhibition of Na+ current by grape extract
C1 = resveratrol derivative
reduce duration of atrial fibrillation
resveratrol and C1 have many targets -> effect unlikely due to one mechanism (can also block late sodium current)
M2 muscarinic receptor
decrease heart rate, conduction velocity and contractility
- G protein inhibit T-type calcium channel
- G protein activates K channel move K out
4 nicotinic agonists
- Ach
- Nicotine
- Carbachol
- Succinylcholine
2 nicotinic antagonists
- d-tubocurarine at NMJ
2. a-bungarotoxin (irreversible antagonist)
3 positive allosteric modulators of Nicotinic cholinergic receptor
- Galantamine
- Physostigmine/Neostigmine
- a7 PAM (positive allosteric modulator) (inhibit breakdown of acetylcholine, increase ACh concentration at synaptic cleft)
3 phosphorylation of nicotinic cholinergic receptor
- PKA
- PKC
- TK (tyrosine kinase)
a-bungarotoxin
irreversibly binds to and block the nicotinic receptor
NMJ blockade at skeletal muscle
paralysis
death by respiratory depression
b-bungarotoxin
prevents release of ACh from motor nerve endings
not enough release of ACh to stimulate muscle movement
paralysis
D-Tubocurarine
non-depolarizing NMJ blocking drug antagonist compete with agonist prevent binding of ACh on receptor zero efficacy
Neostigmine
ACh esterase inhibitor
prevent breakdown of ACh leads to increase ACh concentration
overcome non-depolarizing NMJ blockade (d-tubocurarine)
Succinylcholine
depolarizing blockade
2 molecules of ACh binding together
binds to nicotinic receptor and leads to activation
not metabolized by ACh esterase
longer activation leads to desensitization of receptor
leads to flaccid paralysis
GABAa receptor
allow Cl- to enter cell fast activation and inactivation pentamer M2 region leads to hyperpolarization
Benzodiazepine (diazepam)
increase frequency of GABA channel opening and affinity/potency for GABA for receptor
shift dose response curve left
leads to sedative, muscle relaxation, anticonvulsant, coma
GABAa receptors inverse agonist (NAM)
negative allosteric modulators
reduce influx of Cl- into cells
accompanied by anxiety (anxiogenic)
Where is the high affinity binding site for benzodiazepine (diazepam)?
between a1 and y2 (histidine 101)
insensitive to a4 and a6 containing receptor
TP003
plus maze experiment selective for a2/a3 containing GABA receptor anxiolytic effect (reduce anxiety)
a1 GABA receptor subtype
mediates sedation
Zolpidem acts at BZD site
a2 and a3 GABA receptor subtype
anxiolytic effect
if inverse agonist at a3 = anxiogenic
no selective drug on market currently
3 types of Glutamate receptor
modulate Na, Ca and K 1. NMDA (most permeable to calcium) 2.AMPA 3. Kainate (KA) 3 TM region, 2nd region is a hairpin loop within the membrane
PCP and Ketamine
acts on glutamate receptor
hallucinogen, dissociative anesthetic
How does NMDA (memantine) antagonist improve Alzheimer disease?
reduce calcium toxicity, reduce loss of neurons, protect neuronal function
Furosemide and Toreasemide
inhibit NKCC2 at TAL
block Na/Cl reabsorption at H2O impermeable segment
impairs H2O clearance
increase K secretion
inhibit Ca and Mg reabsorption and increase their secretion
Adverse effect of furosemide and torasemide
intravascular volume depletion
reduced GFR
hypokalemia (metabolic alkalosis due to hydrogen loss)
hyperuricemia (increase uric acid in plasma, crystal forming leads to gout)
acute rapid infusion may lead to transient deafness (NKCC1 in inner ear)
but generally tolerated really well
Gitelman’s Syndrome
reduce expression of NCC at distal convoluted tubule reduce reabsorption of Na increase H2O excretion low blood pressure salt wasting hypokalemia and metabolic alkalosis
Chlorothiazide and hydrochlorothizide
blocks NCC
increase K secretion
decrease Ca excretion (stimulate Ca reabsorption in DCT)
treat hypertension, edema
adverse effect: hypokalemia, hyponatremia, hypercalcemia
Dopamine Transporter
12 TM regions
use Na gradient
regulates dopamine level in synaptic cleft
DAT deletion leads to hyperactivity, motor and cognitive deficits
increase depression
Serotonin receptors (SERT) and Selective serotonin reuptake inhibitors (SSRIs)
12 TM regions
transport of Na, Cl and 5HT into presynaptic cells
associated with mood, anxiety, sleep, appetite, gastrointestinal cortical areas…
hyperactivity - anxiety
hypoactivity - depression
Fluoxetine (Prozac) and Sertraline (Zoloft)
antidepressant
treat anxiety, OCD, eating disorder
delayed efficacy
long half-lives (7-15 days)
unwanted effects: sexual dysfunction, weight gain, headache nausea, suicidal ideation, akathisia (movement disorder, hard to stay still)
Aspirin and celecoxib
anti-inflammatory
celecoxib more selective for COX2 than aspirin, less side effect
3 structural features of GPCRs
7 TM domains
EC N terminus and 3 loops
IC C terminus and 3 loops
2 types of Class A GPCRs
dopamine receptor (d1 and d2) and B-adrenergic receptor
1 type of class B GPCRs
secretin receptors
2 types of Class C GPCRS and its features
Glutamate receptor and GABA-B receptors
contains VFT (Venus flytrap) domain and CRD (cysteine rich domain)
form obligate dimer, either homodimers or heterodimers
RGS protein
promote GTP hydrolysis and turn off G alpha protein signal
RGS protein acting as effector in GPCR signalling
bind to RhoGEF (p115-RhoGEF)
activates GEF activity
RhoA-GDP -> RhoA-GTP
leads to cytoskeleton rearrangement and transcriptional upregulation
Structure of adenylyl cyclase
2 groups of 6 TM domains
linked by C1 domain and C2 domain at C-terminus
Structure of voltage gated ion channels (VGIC)
4 domains each with 6 TM regions
a-subunit
2 Monoclonal antibodies for ErbB therapeutics
Herceptin (ErbB2 breast and gastric cancer)
Cetuximab (ErbB1 colorectal cancer)
ErbB1 inhibitors and ErbB1 + ErbB2 inhibitors
ErbB1 only:
- Gefitinib
- Erlotinib
ErbB1 + ErbB2
- Lapatinib
- CI-1033
- EKB-569
(approved for non-small-cell lung cancer treatment)
Trastuzumab (Herceptin) and cetuximab
Herceptin binds to ErbB2 breast and gastric cancer treatment in combination of paclitaxel
cetuximab binds to ErbB1 for colorectal cancer
4 effects after insulin stimulation
- increased glucose synthesis
- increased glycogen synthesis in liver and muscle
- increased fatty acid synthesis
- increased uptake of amino acids (and protein synthesis)
IGF-1 excess leads to?
gigantism, acromegaly (excess insulin growth factor after puberty)
IGF-2
single peptide
fetal growth factor
binds to mannose 6 phosphate receptor
growth effects through IGF-1 receptors (similar effect)
Which dopamine receptor is important for treating schizophrenia (antipsychotics)?
D2 dopamine receptors
chlorpromazine
Signal transduction pathway of ErbB (start from PI3K)
PI3K -> PIP2 -> PIP3 -> PDK -> PKB/AKT -> mTOR -> protein synthesis
PKB/AKT —> Ras/MAPK PIP2 -> IP3 + DAG -> PKC
ErbB1
forms homo/hetero dimer
1,2,3,4
recruits Grb2/Shc/Sos -> Ras -> MAPK
ErbB2
no specific ligand can dimerize without ligand hetero with 1,3,4 potent stimulators of cell proliferation and internalize slowly high expression in tumor
ErbB3
ligand: heregulin, neuregulin have an inactive kinase domain has six different PI3K binding domains knockout has atrioventricular defects hetero with 1,2
ErbB4
binds neuregulin and other ligands forms homo and hetero dimers with 1,2,4 recruits Grb2/Shc/Sos -> Ras -> MAPK knockout has heart developmental defects may play a role in schizophrenia
Psoriasis
lesions caused by rapid production of keratinocytes with inflammation
hyperactive response to growth factors amphiregulin and ErbB1-3 expression
