block 3-adrenorecptors Flashcards
adrenoreceptors(adrenergic receptors)
mediates the actions of adrenaline and noradrenaline
adrenaline
hormone= released by chromaffin cells in the adrenal medulla
noradrenaline
a neurotransmitter. released by noradrenergic neurons in the central and autonomic nervous system
noradrenaline in the CNS
-participate in modualling attention, perception,learning/memory and (sexual) arousal
-noradrenergic projections mainly originate from the noradrenergic nuclei. the largest noradrenergic locus oeruleus which sens projections that innervate the cortex, amygdala, hippocampus etc…
ganglion
A ganglion is a cluster of nerve cell bodies located outside the central nervous system that serves as a relay and processing centre for nerve signals, especially in the peripheral and autonomic nervous systems.
-the gap between cells
pre -ganglion neurotrasmitter on the parasympathetic neurone
-ACh acting on nicotinic acetylcholine receptors
pre-ganglion neurotransmitters at the in the sympathetic system
ACTh acting on the nicotinic acetylcholine receptors
post ganglion neurotransmitter in the parasympathetic system
-ACh acting on the muscarinic receptors
post ganglionic neurotransmitters in sympathetic system
-noradrenaline acting on adrenoreceptors
varocosities
-sympathetic innervation at the noradrenergic neuro-effector junction=the sympathetic nervous system is sending signals to a target tissue via nerve fibers that release noradrenaline, allowing the sympathetic nervous system to control or modulate the function of that tissue.
-here neurotransmitters are stored and released
adrenergic transmission step 1: synthesis
- noradrenaline is syntheised from the amino acid tyrosine which we absorb in our diets within the nerve terminal
-the rate-limiting enzyme for noradrenaline synethisis= tyrosine hydroxylase
-tyrosine is converted to DOPA= dopamine via DOPA decarboxylase
-dopamine is taken up by vesicles= noradrenaline via dopamine B-hydroxlase
-chromaffin cells on the adrenal medulla converts noradrenaline to adrenaline
adrenergic transmission step 2 storage/compartmentation
-Noradrenergic terminal vesicles possess a dopamine/noradrenaline
transporter that allows accumulation of noradrenaline at high concentrations (0.5 - 1 M) inside vesicles
adrenergic transmission step 3:release
-Noradrenaline release is triggered by depolarization of the nerve terminal
Ca2+ influx and vesicle fusion with the pre-synaptic plasma membrane.
adrenergic transmission step 4: signal transmission
Released noradrenaline can bind adrenoceptors located either pre- or post-
synaptically
adrenergic transmission step 5:siginal termination
Noradrenaline is rapidly removed from the synaptic cleft by a high-affinity
uptake mechanism (“Uptake-1” = noradrenaline transporter (NET)). Any
noradrenaline evading this mechanism is cleared by “Uptake-2”.
adrenal transmission step 6:metabolism
within the terminal noradrenaline can be metabolized into different end products
pharmacological manipulation of adrenergic transmission
-a-methyltyrosine= competitively inhibits tryosine hydroxlase, blocking noradrenaline synthesis
-a-methylDOPA=converts to a-methylnoradrenaline its differs to noradrenaline
-its not metabolised so accumulates in the vesicles
-it is a selective agonist at some adrenoceptors e.g. a2 -adrenoceptors
-Therefore, administering α-methylDOPA causes the accumulation of a
“false transmitter” that out-competes noradrenaline and results in
decreased transmission at sympathetic neuro-effector junctions
what’s the role of presynaptic receptors at a2-adrenoreceptor
- Presynaptic receptors often respond to the transmitter released by the
terminal (“autoreceptors”). This can result in an increased or decreased
likelihood of further transmitter - Presynaptic α2-adrenoceptors act as inhibitory autoreceptors decreasing
noradrenaline release from the terminal. - α2-adrenoceptors are Gi/o-coupled GPCRs that can decrease adenylyl cyclase
activity and decrease N/P/Q-type voltage-gated Ca2+ channel opening.
factors affecting drug absorption
- Site/method of administration
(ii) Molecular weight – main determinant of rate of diffusion
(iii) Lipid solubility – ability to cross lipid membrane by diffusion
(iv) pH and ionization
-At low pH weak acids will be mainly in un-ionized form
Only uncharged species can diffuse across lipid bilayer
Stomach (pH 3) - weak acids e.g. aspirin uncharged & absorbed
(v) Carrier mediated transport – active or facilitated
for polar molecules e.g. amino acids and metal ions
used by drugs similar to natural substances
DiffCoeff. α 1/√MWt
drug distrubution
Distribution of a drug based on permeability and lipid solubility of the different body compartments
blood brain barrier
-based if Paul Ehrlich injection experiment. found that if you inject dye into the brain it stays in the brain and doesn’t go to the rest of the body. same vice versa
-this is because Endothelial cells of blood vessels supplying the brain form tight junctions a barrier to systemically acting drugs
-Only small, fat-soluble drugs can usually cross, which is important to consider for designing medications that target brain conditions
-In cases of inflammation, these tight junctions may weaken or “leak,” allowing more substances to enter the brain. This can impact drug delivery and also make the brain more vulnerable to certain substances that normally wouldn’t get in.
drug metabolism
-enzyme modification prior to excretion occurs
-Normally abolishes pharmacological activity (are
exceptions eg. thienopyridines: prodrugs: P2Y12 inhibition)
-
drug metabolism phase 1
-usually oxidation, reduction or hydrolysis by
Cytochrome P450 (CYP) monooxygenase system (SmoothER)
CYP enzymes (family of enzymes) involved in drug
metabolism in the liver (93% of known drug metab)
e.g. CYP1A2 acts on caffeine, paracetamol
phase 2 of drug metabolism
conjugation – addition of substituent group
(eg.methyl, sulphate, acetyl) – normally inactivates the drug whereas phase 1 might not
(Both phases ↓ lipid solubility: thereby increase kidney clearance)
drug excretion
- via the kidney
-Glomerular filtration: ~20% of glomerular blood flow: cut-off ≈20kDa
(99% water reabsorbed: passive diffusion of lipid-soluble substances follows
-Active tubular secretion: many drugs, esp. weak acids,
important for plasma protein bound drugs
Renal disease can affect drug clearance - toxicity - penicillin rapidly cleared from the blood due to filtration
and active secretion vs diazepam cleared v. slowly - urine pH influences excretion of weak acids & bases
basic renal process
Glomerular filtration: non-discriminant
filtration of a protein-plasma free plasma
from the glomerulus into Bowman’s capsule
- Tubular reabsorption: selective
movement of filtered substances from the
tubular lumen into the peritubular
capillaries
-Tubular secretion: selective movement
of non-filtered substances from the
peritubular capillaries into tubular lumen
- Urine excretion: creation of the medulla
vertical osmotic gradient
what affects drug excretion ?
Renal disease can affect drug clearance - toxicity
half life (T)
-time for [drug] to decrease by 50%
drug absorption
-in most cases to circulate to tissue via the plasma
-Oral & swallowed (most small molecule drugs
-Sublingual (absorption from oral cavity: RAPID
-epithelial surfaces e.g. skin
-inhalation
-injection-= the most direct route
-via the rectum =usually when a patient can’t absorb drugs orally because of vomiting etc..
