Pccol drugs Flashcards
Aromatic L amino acid decarboxylase
It turns L DOPA into dopamine stopping it from entering clinically relevent site
Inhibitors of Aromatic L amino acid decarboxylase
Benserazide and carbidopa
Catechol o methyl transferase
It transfers a methyl group onto L dopa, stopping it from going into blood brain barrier.
What inhibits COMT
Entacapone, opicapone
What are strategies to improve L DOPA
INHIBIT
AADC
COMT
MAOB (monoamine oxidase B)
Dopamine agonists
These are compounds that activates dopamine receptors to mimic the effect of dopamine.
They mostly target D2
They are either ergotamine or non-ergotamine
Sideeffects of dopamine agonists
impulse control disorders cardiac fibrosis, excessive day time sleepiness hallucinations
Interferon beta effects
used to treat MS
1) Activate JAK/STAT signalling pathway via type 1 IFN receptors 1 binding=> gene expression=> antiviral, immunomodulatory and antiproliferation effects
interferon Beta side-effects
fetal malformations category D
Flu like symptoms, headache, thyroid disorders, autoimmunity, depression, allergic reactions, hepatic injury
FHF DATA
Glatiramer acetate
example of myelin basic protein mimics
competes with myelin for myelin reactive T cells
upregulate antiinflammatory responses in macrophages
decreases B cells and T cells
may promote remyelination by increasing proliferation and migration of oligodendrocytes
Glatiramer acetate sideffects?
no
Fingolimod
Sphingosine 1 phosphate receptor modulator
binds to S1P receptors and stops S1P from causing lymphocytes moving
sideeffects of Fingolimod
bradycardia, atriventricular block, opportunistic infections, cutaneous malignancies
heart and infections
Teriflunomide
interferes with pyramidine syntehsis and stops DNA replication of proliferating T and B cells
side-effects of teriflunomide
This stops T and B cells from proliferating by interfering with pyrimidine synthesis
It causes nausea, diarrhea, paraesthesia, limb pain, liver enzyme changes and hair thinning
Dimethyl fumarate
antioxidant. In CNS, it decreases cytokine production by activated microglia/astrocytes and increases number of oligodendrite precursor cells.
Common sideeffects of dimethyl fumarate
nausea, diarrhea, vomiting, flushing, upper abdominal pain
chemo drug
hobo3
nausea turns into flushing turns into vomiting
upper abdominal pain turns into diarrhea
cladribine
Prodrug phosphorylated to an active purine nucleoside analog that inters with DNA synthesis and repair, leading to cell death•Chemotherapeutic drug: also used to treat leukaemias•Preferentially depletes peripheral B and T lymphocytes, other immune and blood cells are preserved•Significant reductions in relapses and disease progression in RRMS •Resultant lymphopenia increases risk of severe infections, also higher rates of tumors •Oral treatment in short cycles with sustained therapeutic effects•Contraindicated in pregnancy (cat D) with on-going concerns about safety
What are three major classes of typical antipsychotics
Psychotic titan Baboons
The typical antipsychotics ameliorate positive symptoms of schizophrenia
their major classes are
1) phenthiazines
2) butyrophenones
3) thioxanthenes
They all are potent D2 dopamine antagnoists
they have moderate affinity for alpha adrenergic and 5HT2 receptors
80% receptor occupancy
weak to moderate affinity for D1 and D4 receptors, histamine and acetylcholine receptors
Classes of atypical antipsychotics
1)diazepines dibenzothizepine benzamide benzisoxazol quinolinone derivative
Different Dimension BBQ
Function of atypical antipsychotics
ameliorate both positive and negative symptoms of schizophrenia
comparison of atypical antipsychotics vs typical antipsychotics
atypical can ameliorate both positive and negative whereas typical can only ameliorate positive
fewer side effects for atypical
and effective in treatment resistant patients
How do atypical antipsychotics work
They antagonise D2 receptors with 60% receptor occupancy
clozapine
type of atypical antipsychotic
high affinity for D4 receptors
rapidly dissociates from receptors
side effects with antipsychotics
tina lecture
Benzodiazepines for sleep
Hypnotic•Sedative•Anxiolytic •Amnesic (especially with alcohol, Rohypnol/flunitrazepam)•Produce strange sleep behaviors•Antiepileptic•Range of effects due to expression of GABAAreceptors of different make up expressed in different brain regions/neural circuits.•Benzodiazepine sensitive GABAAreceptors in many brain regions including:ØAmygdalaØPrefrontal cortexØHypothalamusØStriatumØBed nucleus of the striatumØHippocampus
GABA a1 subunit
regulate sedative/hypnotic, anticonvulsant
GABA a2 subunit
anxiolytic
GABA a3 and a5 subunits
myorelaxant
z drugs
many of same benefits and problems of Benzodiazepines
some show preference for a1
produces bizarre sleep behaviors
side effects of z drugs
produce bizarre sleep behavior
like daytime sedation
rebound insomnia on withdrawal
issues with benzodiazepine
dependence amnesia sleep behavior falls in elderly dangerous with other sedatives
San Francisco DAD
antihistamine
Histamine arousing – part of ARAS•First generation H1inverse agonists (often call antagonists) block this arousing effect•Most of the over-the-counter sedatives/hypnotics•X BBB as lipophillic, low molecular weight, not PGP target•Less effective than BZ (not targeting all systems)•More day-time sedation, fog, memory issues even when drug no longer present
sideeffects of antihistamine
rinary retention (tricyclics, antipsychotics H1antags)
Melatonin
Endogenous melatonin synthesized in pineal gland (light, via thalamus reduces melatonin production in pineal gland)•Role unclear but participates in circadian rhythm and sleep.•2 GPCR receptors: MT1:activation promotes sleep onset MT2: activation shifts circadian timing•Administration can ‘reset’ sleep pattern but use in non-circadian insomnia unsure•High doses can cause endocrine problems•Ramelteon, synthetic analogue, used for sleep onset problems and has less rebound insomnia, not controlled substance
benzodiazepine for anxiety
a2 receptor important for anxiety
no selective drug but alprazolam and clonazepam have higher a2 affinity
z drugs not a good choice as some show a1 prefere
SSRI for anxiety
fluoxetine, paroxetine
selective serotonin reuptake inhibitors These are often first choice treatment for anxiety - less side effects than some other drugs- may allow dual treatment for depression- but very slow to act (as for depression)- sometimes side effects difficult- have discontinuation syndrome•If not successful try another class of drugs
how do tetracyclic antidepressants work for depression
They block a2 adrenoceptors
they increase NA and 5HT release
preferred action on 5HT1
how do monoamine oxidase inhibitors work for depression
They inhibit the breakdown of noradrenaline and increase the cytoplasmic pool of monoamines to increase leakage of monoamines into synpase/extracellular space
How do selective serotonin repuptake inhibitors work?
Little action on mACh and histamine receptors •Preferred action of 5-HT on receptors causes side effects !NAT:SERT potencies <0.02 ie: >50 fold selectivity for SERT !cf. TCAs NAT:SERT potencies 10 – 0.2 (i.e. some up to 10 x more selective for NAT, some equipotent and others up to 5x more selective for SERT)
examples of monoamine reuptake inhibitors
Tricyclic antidepressants
Selective serotonin reuptake innhibitors
serotonin and noradrenaline reuptake inhibitors
noradrenaline reuptake inhibitors
How do drugs control seizures( antiseizure drugs)
1) modulating voltage gated ion channels-like phenytoin, carbamazepine, lamotrigine
2) enhancing GABA-mediated inhibition-like benzodiazepines
3) interacting with synaptic release machinery
- e/g levetiracetam which binds synaptic vesicle glycoprotein
4) blocking ionotropic glutamate receptors
THC
Acts on CB1 cannabinoid receptors abundant in cortex, hippocampus, striatum, ventral midbrain and cerebellum. Thc mimics endocannabinoids.
These are presynaptic
fatty acid binding protein
Transport AEA (anandamide)
it is a fatty acid neurotransmitter and the first endocannabinoid to be discovered.
It is primarily degraded by fatty acid amide hydrolase.
AEA is mediated mostly by CB1 cannabinoid receptors.
2AG
2 ARACHIDONOYLGLYCEROL is an endocannabinoid and an endogenous agonist of the CB1 receptor and the primary endogenous ligand for CB2. The main difference 2AG has against anandamide is that it is calcium dependent. Broken down by MAGL enzyme
Degradative enzymes
MAGL (2-AG)
FAAH (AEA)
MAGL inhibitor
JZL184
FAAH inhibitor
PF3845
nicotine replacement
patch, gum, nasal spray, inhaler-eliminates smoke exposure
uncouples temporal cues of smoking from delivery of nicotine
Varenicline, cytisine
parital agonists -alpha4beta2 nicotinic receptors
They reduce craving, reduce smoking satisfaction
slightly better than NRT
Varenicline side-effect
nausea
Mecamylamine
is a non-selective, non-competitive antagonist of the nicotinic acetylcholine receptors
It blocks nicotine reward but has no effect on craving. It can potentially reduce smoking when combined with NRT
side effects of mecamylamine
significant drowsiness, dizziness and constipation
Different dimension cat
Antibodies produced to bind nicotine and preventing it to pass through blood brain barrier
No effect on craving
No better than placebo
Bupropion
is arguably the best approach for long term abstinence. It causes a modest reduction in craving. Mechanism is unknown. Lower seizure threshold and causes sedation
Naltrexone for alcohol
Naltrexone is an opioid receptor antagonist and it is able to basically stop the feeling of reward of drinking alcohol
Disulfiram
blocks metabolic enzymes and causes acetaldehyde to build up in liver, making alcohol become extremely unpleasant
Acamprosate
Used for alcohol addiction
act via inhibition of NMDA receptor
Could also act to change GABA or glutamate synaptic transmission
topiramate
used for alcohol addiction and epilepsy.
May alter phosphorylation of sodium, calcium, GABA and glutamate receptor channels
Unclear mechanism in addiction-may increase GABA and reduce glutamate synaptic transmission
SIgnificant reduction in drinking but variable results
NSAID
It inhibits cyclooxygenase and therefore stops the production of inflammatory prostaglandins. this decreases inflammation which is important in migraine theory
Ergotamine
5HT1d partial agonists
cause vasoconstriction
blocks trigeminal nerve transmission
triptans
Triptan is a serotonin 1 agonist
5HT1 agonists. tHEY BIND ONTO SEROTONIN RECEPTORS ON BLOOD VESSELS AND NERVE ENDINGS ON BRAIN They inhibit trigeminal nerve transmission peripherally and centrally
They inhibit the release of vasoactive peptides from meningeal blood vessels
They stimulate 5HT1b receptors causing vasoconstriction.
As these blood vessels are constricted, there is less secretion of proinflammatory neuropeptide release including CGRP and substance P
side effects with triptans
5HT1B receptors are on coronary arteries
beta adrenoceptor antagonists
propranolol, metoprolol
The Prime Minister has asthma and would die if she had been given beta adrenoceptor antagonists
mechanism of action unknown
not given to people with asthma as side effects include fatigue and bronchoconstriction
5HT2 receptor antagonists
pizotifen, cyproheptadine, methysergide
prevents 5HT2 receptor induced vasodilation and consequent inflammation
side effects of 5HT2 receptor antagonists
weight gain, antimuscarinic effects
tricyclic antidepressants
5HT and NA transport inhibitors. increases 5HT and NA concentrations
inhibition of spinothalamic neurons
