drugs of biochem Flashcards
Ouabain (Strophantine – cardiac glycosides)
potent inhibitor of na k pump.
secondary transporter is slowed down (na/ca antiport)
ca levels increase in heart, leading to positive ionotropic effect.
t n p and a domains of p atapse
T domain – transport
N domain – ATP/ADP binding
P domain – phosphorylation
A domain – phosphatase activity
serca 1,2,3 ?
SERCA 1 striatal muscle
SERCA 2 smooth muscle, striatal muscle, heart muscle
– phospholambane
SERCA 3 platelets, endothelial cells and other non- muscle cells
pmca 1,2,3,4,5???
PMCA 1 general
PMCA 2 neuronal - higher affinity for cAMP phosphorylation
than PMCA 4
PMCA 3 striatal muscle, brain
PMCA 4 general
PMCA 5
alpha 1,2,3,4 in na k atpase
α1 - all tissues (heart also), kidney outer medulla only α1
α2 - striatal muscle, smooth muscle, heart (T-tubules)
brain (astrocytes)
adipocytes
α3 - brain (neurons)
heart (small amount)
ovary
leukocytes
α4 - testis
alpha 2»_space;»» alpha 3»» alpha 1»> senetivity to oubain
fxyd subunit
Tissue-specific regulator in the heart, kidney, pancreas, foetal liver
- 7.2 KDa (58 amino acids) – one transmembrane domain
- not an integral part of the enzyme
- different izoforms
Heart (FXYD1, phospholemman)
-when dephosphorylated it decreases the Na+ affinity of the α-subunit
-adrenergic β1 receptor stimulation → PKA stimulation →
phosphorylation of phospholemman → [Na+]i [Ca2+]i ↓ -prevention of
arrythmia
Kidney (FXYD2)
-increases the affinity of the enzyme for ATP
Kidney medulla is nearly anoxic under physiological conditions
- Some reabsorptions are under the control of the Na+-pump
- Moderate increase in the affinity for ATP → increased pump activity
(Fine tuning! Large affinity increase would cause further ATP ↓ !)
phosphorylation of C terminal loop on Na/K atpase
for some god damn reason Camp dependent phosphorylation inhibits it and PKC phosphorylation causes endocytosis of it. Way to get teaching dumb physiology.
aldosterone receptors alpha 1,2,3
long-term upregulation – isoform-specific
α1 – vascular smooth muscle
α2 – heart
α3 – brain
D1 and D2 receptors; phosphorylation by both PKA and PKC causes?
diuresis (loss of volume)
nhe antiport isoforms 1,2,3 locations.
5 isoforms - 12 transmembrane region
NHE 1 general (basolateral membrane)
NHE 3 epithelial cells apical membrane
NHE 5 brain, testis
Vesicular neurotransmitter antiporters (VMAT1, 2, VAChT) and inhibitor.
Proton antiporter (vesicular membrane antiporters, VMAT)
12 transmembrane segments
broad selectivity: epinephrine, norepinephrine,
dopamine, serotonin
VMAT1 brain, neuroendicrine cells
VMAT2 neurons, adrenal chromaffin cells
VAChT cholinergic synapses
Inhibited by H+ ionophores
abca1 and 3, abcb1, abcb4, abcc1, cftr
you suu good.
ABCA1 – cholesterol, phopholipid transport - reverse cholesterol transport
ABCA3 – translocation of pulmonary surfactant lipids
mutation: respiratory distress szindróma
ABCB1 (MDR1, multidrug resistence transporter)
- transport of lipophylic compounds – protection against toxins - increased expression in tumor cells: drug resistence
ABCB4 – canalicular membrane of hepatocytes
bile acid, phospholipid transport into the bile
ABCC1 (MRP-1, multidrug resistence protein)
- phospholipids, glutathione conjugates, anti-tumor drugs (also other
than lipophylic!)
CFTR (ABCC7, cystic fibrosis transmembrane conductance regulator)
Cl- flux in the apical membrane of epithelial cells
mutation: cystic fibrosis (thick mucus in the bronchi and pancreas
- blockage, infection, foetal ileus)
high affinity choline transporter uptake is inhibited by..
hemicholinium
inhibitor of vesicular acetylcholine transporter?
vesamicol
SNARE proteins in synaptic exocytosis
not synatpotagmin!!
In synaptic vesicles:
VAMP (vesicle-associated membrane protein) or synaptobrevin
In the plasma membrane:
Syntaxin 1A/B
SNAP-25 (synaptosomal-associated protein; 25 kD)
why shouldn’t I take botux?
Why should I know the chains it has?
Botulinum toxins
there’s 7 wonderful ways to kill myself.
7 neuro-toxin (BoNT- A,B,C,D,E,F,G) – inhibitors of the cholinergic neurotransmission
Light chain is the enzymatic part, heavy chain mediates uptake to the neuron.
It inhhibts release of the neuotransmitter.
don’t forget it is a Zn+ dependent endoprotease.
They love dem god damn Snare motifs.
If the person didn’t die from the botux he so willingly wanted, what should I give him (hint… it’s anti..)
heptavalent botulinum antitoxin
Ach muscarinic inhibitor,
Atropine.
If you got this wrong you killed at least 1 rabbit and 1 mouse (both simulated and a live one) for nothing.
-Topical atropine is used as a cycloplegic, to temporarily paralyze the accommodation reflex, and as a mydriatic, to dilate the pupils.
Ach Nicotinic inhibitor (It’s rhymes with cure, but not realy)
Curare
M1 muscarinic receptor
I added some receptors since it’s a nice revision.
– Gq – PLC-> PIP2 hydrolysis-> IP3-> Ca+ intracellular.
• Regulation of transmitter release
EPSP in autonomic ganglia[citation needed]
Secretion of catecholamines from the adrenal medulla[6]
Secretion from salivary glands
Gastric acid secretion from stomach[7]
In CNS (memory?)[8]
Vagally-induced bronchoconstriction[7]
Mediating olfactory behaviors (e.g aggression, mating) [9]
M2 muscurinic
heart Gi ↓ K+ channel activation ↓ Hyperpolarization ↓ Bradycardia
M3 muscurinic
Gastro-intestinal tract, Gq – [Ca2+]
– Smooth muscle contraction
– Secretion stimulation
it typically causes constriction of smooth muscle, such as that observed during bronchoconstriction. However, with respect to vasculature, activation of M3 on vascular endothelial cells causes increased synthesis of nitric oxide, which diffuses to adjacent vascular smooth muscle cells and causes their relaxation and vasodilation,
nicotinic receptor sunbunits
made up of 5 subunits, each one is 4 transmemb domain.
ligand binding, na+k+ (not selective) influx or efflux, depends on time bound on the receptor.
adult Ach muscle type subunits and his baby
baby / embryo- alph1, beta1, gama, delta (2:1:1:1:)
Adult- alpha 1, beta1, gama, epsilon (2:1:1:1)
specific inhibitor muscular type of nicotinic receptors
alpha-bundarotoxin.
binds to alpha subunit of nicotinic receptor (competitive inhibitor).
muscule paralysis.
malignant hyperthermia??
Malignant hyperthermia (rare complication during inhalation anaesthesia) Mutation of the Ryanodin receptors Altered kinetics of Ca2+ channels Persistent large increase in [Ca+ ]i Hypermetabolism Persistent activation of the contractile system Fever and Muscle rigidity
Myasthenia gravis??
Antibodies attack your own ACH receptors
Muscle weakness and fatigue.
short-lasting drug is used
-Therapy of Myasthenia gravis – physostigmin, neostigmie (both are ACH esterase blocker) which are reversile blockers. longer lasting drugs -Eye drops – Glaucoma
diisopropyl flurophosphate???
irreversible anti-cholinesterase, used to treat glucoma, not sure how this is even relevent anymore to anything.
what do you give when you just have too much pressure from this idiotic drugs?
alpha-methyl-p-methyl
what do you give if the person near you has symptoms of parkinsons
L-Dopa
Uptake of norepinephrine/epinephrine/dopamine
into synaptic vesicles
VMTA 2 vesicular membrane transporter 2 -12 transmembrane domain -broad substrate-specificity to biogenic amines (triptamine, tiramine, amfetamin – compete with endogenous catecholamine)
what inhibits VMTA2?
reserpin (irreversible)
causes depletion of vesicles and degradation since free molecules in cytsol will be degraded by MAO.
MAO isoenzymes, function, location
outer mitochondria,
mao-A- important in catabolism of monoamines ingested in food.
Mao B-
mao a inhibitors
used as antidepressent because of their higher affinity for seratonin degredation.
Clorgilin
mao b inhibitor
Used for their prevenation of dopamine breakdown which is the main reduced neuostransmitter in parkinsons.
Two drugs: Deprenyl, Selegiline.
last product of Noreadrenalin in the brain.
And since you’re a doctor, diagnose what happens if his urine tastes of too much or too low MHPG levels.
MHPG- 3-methoxy-1-hydroxy-phenylglycol.
Low levels- Anorexia nervosa (the coolest type of anorexia)
Raised levels- Recent high sympathetic activity.
and also if you taste urine of peripheral metabolic product of norepinephrine
3-methoxy-4-hydroxy mandelic acid=VMA=Vanillymandelic acid. (peripheral neurones.. important fact…)
High amounts can indicate peripheral sympathetic activity, tumors such as phechromocytoma (whatever this is)
inhibitors of catecholamine reuptake… one you might want to try.
Cocaine, tricyclic antidepressents.
dopa-decarboxylase inhibitor drug
alpha-methyl-dopa (fake neuotransmitter), byproduct produces only 1/10 of the original product pressor effect.
mao b inhibitor,
and why
Deprenyl (Parkinson’s disease)
Selegylin.
Inhibition of this enzyme allows the preference of accummilating the conc. of dopamine, since MOA B degrades dopamine, you can minimize the symptoms of parkinsons.
alpha 2 receptors effects
intestinal smooth muscle relaxation
inhibition of lipolysis
platelet aggregation
alpha 1 receptor effects
α1
increased glycogenolysis (liver)
smooth muscle contraction
in blood vessels
beta 1 effects
stimulation of lipolysis
increased heart rate & force
beta 2 effects
ß2 increased glyconeogenesis (release insulin?? HSL inacativation?) increased glycogenolysis smooth muscle relaxation bronchi blood vessels intestine
dopamin D1+D5 receptors?
dopamine D2?
dopamin D3+D4?
1+5= Gs 2= Gi 3+4= unknown
dopamin vesicle transporter?
VMTA 2 vesicular membrane transporter 2 -12 transmembrane domain -broad substrate-specificity to biogenic amines (triptamine, tiramine, amfetamin – compete with endogenous catecholamine) -high affnity for reserpine irreversible inhibitor – depletion of vesicles -altered VMTA2 expression in bipolar disease (litium influences)
- homovanillic acid, what is it? how is it made? and what does the taste of high concentration (vanilla?) tell you?
- homovanillic acid appears in the urine - the amount in the urine indicates the functional state of dopaminergic neurons in Parkinson’s disease ↓ in Schizophrenia ↑
if the friend near you really suffers from parkinson, what would you like to give him, assuming you actually want to help him?
1) L-dopa- permeable to BBB (unlike dopamine which isn’t).
2) To prevent convertion of L-Dopa to Dopamine in the peripheray, you’ll also give him Carbidopa to inhibit this annoying peripheral decarboxylase ( or just don’t if you just want to screw with him).
3) Entacapone to inhibit another annoying COMT metabolic processor.
4) Selegiline (deprnyl) to inhibit MAO B thus increasing the effective dopamine levels in the brain.
5) Prayer from the lord.
Risk- double edged sword- you can actualy induce schizophrenia if you really screw with him by increasing the dopamine levels in the brain.
If your friend thinks that medical school is good and easy, you might assume he has schizophrenia.. why?
Concepts:
increased dopaminergic activity in the brain and/or
decreased glutamatergic activity
• increased dopamine level in the brain
• increased level of homovanillic acid in the liquor
• increased number of D2 receptors
My own note: You really screwed his parkinsons disease drugs.
Serotonin, where do you find it?
and what functions does it have?
Enterochromaffin cells, CNS (suu many nuclei raphe)
Regulate appetite, moof, and sleep, mood and learning this crap lectures.
also related to enkephalin release (pain relief)
Also connected to Suprachiasmatic nucleus, which is the circadian regulator for melatonin release.
how is serotonin made and from what?
Cofactors!!
Regulation
L-Tryptophan—> 5-Hydroxytryptophan—> Serotonin.
2x enzymatic rxns (Tryptophan hydroxylase, aminoacid decarboxylase)
Which means they also have use the regular- Tetrahydropterin, O2 and Iron.
PLP for Decarboxylase.
Amino acid decaboxylase is not a specific enzyme for this reaction.
Then taken up by VMAT 1 or 2.
Regulation of Tryptophan hydroxylase.
• Phosphorylation - short term
regulation
(CAMK II, PKC)
Synthesis of the enzyme is increased - long term regul
How is Tryptophan being moved to the brain?
Might have connection to the Seminars with metabolism exercise.
Large neutral amino acid trasporter (LAT1_
Preferential heterodimeric transporter for Branched chain (Valine, leucine, isoleucine) and aromatic (tryptophan and tyrosine).
expressed in the brain capillaries for BBB permeability.
How is melatonin made?
From begging lazy ass.
I wont mention the early enzymes.
Last two enzymes: 5ht- N-acetyl transferase enzyme.
then the last step is the conversion of N-acetyl serotonin to melatonin by the enzyme 5-hydroxyindole-o-methyltransferase.
• The amount of the enzyme in the glandula pineale daytime ↓ in darkness → increased sympathetic activity → ß receptor activation in the glandula pineale → cAMP → acetyltransferase activation → increased synthesis of melatonin
metabolism of serotonin steps?
final product?
MAO-A (why A all of a sudden? maybe because 80% is produced by enterochromaffin cells)
Then Aldehyde dehydrogenase producing-
5-hydroxyindoleacetic acid.
what does Amphetamine derivatives (e.g.: Fenfluramine,
Ecstasy) do?
inhibition of both transporters -
enhanced 5-HT release (inhibited by SERT inhibitors).
SERT actualy reverses it’s transport, transporting Serotonin outside rather than inside with one K+.
So does NET and DAT transporters revese.
SERT?
specific serotonin transporter.
doubles the transport with the influx of N and Cl-
cocaine and tca…
50 % homology with NAT & DAT
(TCA, cocain effect)
*Selective serotonin uptake inhibitors
are effective antidepressants
If you or your friends are depressed from learning about pharma in your second year as a medical student, which drugs and which serotonin receptor would you target?
Antidepressive drugs:
Inhibitors of MAO (selegiline?)
SERT inhibitors
5-HT1A receptor agonists- Novel anxiolytics.. flesinoxan.
5-ht1A receptor pathway…
gi.
present in brain and vessels.
5-ht2 receptor pathway andlocation…
g-q.
platlets, smoothmuscle, pns cns. gi.
you’re friend is both hallucinogenic and psychotic.
which drugs and target serotonin receptor would you like to screw up.
Antipsychotic effects are obtain by targeting (schizophrenia or bipolar)
1) DA receptor antagonists –typical)
2) 5-HT2 receptor inhibitors (effect also on DA receptors)
Hallucinogen drugs (LSD) can target to 5-Ht2 receptor and cause you to see smurfs.
5-ht3 receptor is.. and where
pns and cns
second messanger involves opening of a ligand gated non specific channel.
If you think you’re pregnant (nausea) or just took some chemo, which target serotonin receptor would you block
5-HT3 receptor antagonists against nausea Chemotherapy 5-HT release from the gastro-intestinal enterochromaffin cells visceral afferent neurons 5-HT3 receptors depolarization chemoreceptor activation NAUSE Drug- Ondansertron.
Migraine and leonys paracetamol wont help you?
which serotonin receptor
Migraines are thought to arrive from decreased serotonergic activity in the brain, which is thought to cause vasoconstriction of vessels in the brain and severse pain.
Take sumatriptan, it’s better than leonys drugs, agonist for type 5 receptors…
