Intro to CNS drugs and Hypnotics Flashcards
Areas in BBB not fully developed
- Area postrema -vomiting
2. Hypothalamus
Early classes of antihistamines
diphenhydramine
later classes of antihistamines
Levocetirizine -less lipophilic
Dopamine is very polar so it cannot get through the BBB
There are receptors that allow molecules tthat are polar to get into the brain by tricking and by making the molecule look like an amino acid . L dopa is tricking the body to incorporate it into CNS… L-dopa decarboxylase , when L dopa enters, it gets decarboxylated to getit in to the BBB .
80-90 % of receptors of CNS drugs focus on proteins of what happens in the synapse other will focus on
propagation of action potential
Epilepsy and local anesthesia are targeted by drugs that
Focus on act pot propagation
Treatment of epilepsy , which type of ion channel
voltage gatedm
Known influx of sodium, efflux of potassium, influx of chloride
depol-Na in
hyper pol-K out
hyper pol -Cl in
Ligand gated ion channel are expressed in
pre and post synaptic neurons
Two ligand gated ion channels
- GABA-A receptors
2. Nicotinic receptors
GABA-A
inhibitory due to it being a chloride ion channel
Nicotinic receptor is
excitatory -triggers rerelease of sodium and calcium
Metabotropic receptors have no
ion pores
Metabotropic receptors affect opening of voltage gates channels by two mechanisms
- Causing the beta gamma subunits to open up (adrenoreceptors)
- Second messengers causes opening of voltage gated ion channels. (DAG, cAMP- these activate kinases to phosphorylate the proteins of ion channels.
IPSP
Cl influx
EPSP
Na Ca influx
When affecting how NT are produced and excreted we can use drugs that are
analogues to certain molecules - these molecules can either increase secretion, synthesis, storage, release.
NT are synth in the
presynaptic and stored in vesicles that can degranulate using a calcium dependent mechanism
Limitations with NT are
releasing more than what is produced (amphetamines over stimulation)
Not all NT that are released bind to receptors
Ach broken down by
Ach-esterase
Ach is recycled by
inhibiting Ach esterase
Amino acid derivative to know (excitatory)
Glutamate- main excitatory NT in brain– epilepsy drugs block glutamate
Ach -ionotropic ,nicotinic receptors -in flux of Ca Na
and Muscarinic receptor is metabotropic.
Receptors for glutamate
Two ionotropic which are NMDR, AMPAR.
One metabotropic which is mGluR
Amino acid derivative to know (inhibitory)
GABA-A -main inhibitory - If stimulated will treat anxiety, insomnia
Glycine
GABA-A receptor
ionotropic -5 subunits -allows Cl influx
Monoamine NT
Dopamine
Serotonin
Norepi
Histamine
Neuropeptide NT
Substance P Endorphins Somatostatin Neurotensin Orexin
*Anandamide- binds to CB1 and CB2 -natural endocannabinoid
First drugs used in the 20s, 30s, 40s, had a very narrow therapeutic index. This means there was a narrow range b/t
desired effect and toxic dose
Used to treat epilepsy as a last resort when other treatments aren’t working?
Phenobarbitial
Old gen barbiturates
Phenobarbital , pentobarbital, thiopental, glutethimide, chloral hydrate
Features of benzos
benzene ring .. long carbon chain.. halogenated
Benzos discussed in class
diazepam , chlordiazepoxide, flurazepam,, flunitrazepam..triazolam,, alprazolam
New generation or Z hypnotic
zolpidem, zalepon, eszopiclone
Benzo, barb, Z-hyp, all interact with
GABA-A
These drugs mimic the effects of melatonin
Ramelteon… Tasimelteon
Used to treat depression. Partial agonist of serotonin, used as anxiolytic, safer option.
Buspirone.
These CNS lipophilic molecules go through rapid
redistribution –distributed fast to other organs to be excreted from the body
Barbituates can
self stimulate their own metabolism –due to this , they may effect other drugs such as oral contraceptives.
Benzos can also
self stimulate their own metabolism, and can form active metabolites . Caution with liver.
Easy overdose with
barbiturates
Speeding up excretion of these molecules such as barbiturates can be done by
giving sodium bicarb because the barbiturates are weak acids.
Drugs that affect GABA-A don’t bind to
GABA-A
GABA sub unit for GABA binding is
b/t alpha and beta subunit
Benzos and Z-hyp bind where
to a pocket b/t alpha and gamma subunit. Referred to as benzodiazepine receptors
Barbiturates bind to
to more lipophilic AA residues within the membrane
Antidote to Z-hyp and benzos
Flumazeril
Name the alpha 1 receptors
alpha 1,2,3,5,
Benzos bind to which alpha receptors
1,2,3,5
Z-hyp bind to which alpha receptors
1
alpha 1 receptor is involved in
hypnosis
Why is a Z-hyp not used for anesthesia
only binds to alpha 1 which is involved in hypnosis
Benzos can cause
anterograde amnesia - loss of men after given drug
Tolerance can come about two ways
- Pharmokinetic mechanism - body speeds up and speeds up metabolism requiring higher and higher dose.
- Pharmodynamic- overstimulation of NT receptors leads to decrease number of receptors, so dose muse be increased to get the same effect.
Two orexin receptors antagonist 1.
Mechanism 2.
almorexant and suvorexant -1.
These are antagonist of the orexin receptors which is involved the stimulation of wakefulness, so inhibition would give a hypnotic effect.
