Neuropharm03

8/9/2019 Neuropharm03

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08/04/2009 19:39:00

3/10/09

GluRs Metabotropic glutamate receptors: mGluRs L-glutamine

(via glutaminase)

L-glutamate (mitochondrial)

-ketoglutarate (mitochondrial)

dicarboxylate carrier outside of mitochondria

-ketoglutarate (cytoplasmic)

L-glutamate via AA (cytoplasmic)

GS or GAD (in glia)

L-glutamine GABA (inhibitory neurons)

Na+- dependent:

Excitatory Amino Acid Carrier-1 (EAAC-1)

Glu Transporter-1 (GLT-1)

Glu Aspartate Transporter (GLAST)

H+ and Mg2+ dependent:

Vesicular ATP-ase Glutamate Transporter (VGlu-T)

Na+ and H+ dependent:


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Glutamine Transporter (Gln-T)

Current structural model of mGluRs Homodimers

Regional expression varies: mGluR1, 5, 6 due to experience!!

Class Io mGluR1 and mGluR5

o IP3 and Ca2+

Class II

o mGluR2 and mGluR3

o cAMP

Class III

o mGluR4 and mGluR6-8

o cAMP

mGluR Functional Attributes

Involved in:

o perception of pain

o mood/affect, especially anxiety

o learning and/or memory

o blood flow / headache

Modulation of the activity of:

o Voltage-dependent ion channels

o Transmitter release

o Ca2+-dependent ion channels (K+)


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o Ligand-gated ion channels

Group I Effecter Mechanisms

Glu

mGluR1/mGluR5

Gq

PLC & PIP2

IP3 + DAG

Ip3R PKC

AGO (competitive)

Glu endogenous

Ibotenate

DHPG (3,5-dihydroxyphenylglycine)

ANT (competitive)

CPG (carboxyphenylglycine; especially 4-CPG)

Group I agonist can increase excitability

There is no AHP after DHPG is added; spike-frequency accommodation blocked

and easily excited

But both pre and postsynaptic effects are observed

cause headaches & reduce transmitter release by reducing Ca2+ influx


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Group II, III Effector mechanism

Glu

Group II, III

Gi

AC

cAMP

PKA

Group II

AGO

o Glu

o NAAG (N-acetylaspartylglutamate)

ANT

o EthGlu (ethylGlu)

Group III

AGO

o Glu

o AP4

ANT


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o MAP4

GABABRs II GABA biosynthesis and metabolism

Glu

(GAD)

GABA

(GABA-T) *blocked by GABAculine

Succinate Semialdehyde

(SSDH) *blocked by Valproate

Succinate

Valproate strongly facilitates CNS inhibition

It facilitates the GAD enzyme and prevents the breakdown of GABA. This

increases the transfer from Glu GABA. This causes inhibition!


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GABA Transporters (GAT) Pharmacology

VGAT (vesicular GABA transporter): GABA

o Nipecotate

o Vigabatrin GAT1 (neuronal, glial): GABA

o Nipecotate

GAT2 (pia, arachnoid): GABA, Beta-alanine

o Nipecotate

GAT3 (neuronal, glial): GABA, Beta-alanine

o Nipecotate

GABAergic synapse

Package GABA into vesicles and release it onto GABARs that generate IPSPs.

Presynaptically there was an action potential. GABABR are foundposynaptically

andpresynaptically. There are differences in their interaction tho. The GABA can

be transported backpresynapticallyand it can be transported into mitochondria

or broken down they can also be broken down in glial cells.

Two Subunits: Co-expression

GABA B receptors are obligate hetero-dimers: one GABA b1 and one

GABAb2 subunits are needed. One binds the g-protein and one binds to

the GABA.

GABA b1 and GABA b2 subunits exist and co-expressed in the same cells and

regions and rate.

If you only express GABA b1 then they are stuck in the endoplasmic membrane

and doesnt make it to the plasma membrane. If only gabab2 are expressed

then the GABA doesnt interact with the receptor.


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GABABR-Effector coupling

GABA binds to one of the two components of the dimmer and activating the g-

protein on the other part of the dimmer.

The Gi/o family of proteins;

o The subunit the AC

o The subunit VDCCs (blocking depolarization) and the activity of

VDKC (decreases the resting potential).

PTX (pertussis toxin blocks the Gi/o Proteins).

GABABR ligands

AGO

o GABA (endogenous)

o Baclofen (exogenous antispasmatic drug)

ANT

o Phaclofen

o 2-OHsaclofen

Effects of divalent cations on GABABR ligands binding

Some enhance GABA binding

o Mn2+ = NI2+ >Mg2+ >Ca2+

o Physiological [Mg2+] or [Ca2+

Some inhibitGABA binding

o Hg2+ > Pb2+

Phosophorylation of GABABRs enhances coupling to GIRKs; enhanced dissociation of

from Rs. Thephosphorylation of the dimmer causes the G protein to dissociate.


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mAChRsFound in:

LTN = laterodorsal tegmental n.

NDB = n. diagonal band

MS = medical septum

H = Habenula

NBM N Basilis of Meynert

ACh is involved blood pressure regulation and

Biosynthesis: ChAT(choline acetyl transferase) positive cholinergic neurons

Degradation: Multiple isoforms of AChE (Aceylcholinesterase)

**it is NOT taken up by glial cells or reuptaken. It is degradedin the synapse.

ACh biosynthesis and metabolism

Acetyl CoA + Choline

ChAT

ACh + CoA

AChE

Acetate and Choline

AChE ligands I: OrganophosphatesAChE ligands I: Organophosphates the ACh is left inside the synapse and the AChE isnt

able to do its job.


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Ligand Duration Use (dose dependant)

Long Irreversible Insecticide WMD

Sarin [GB] X XDDT X XDiazinon X X


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Inhibitor DurationShort Long

Donepezil (Aricept) X


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Physostigmine X


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Regenerator of AChEactivity

DurationShort Long


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Obidoxime X


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Vesicular ACh transporter (VAChT) proton dependant(requires 2 protons per

molecule ofACh. Protons must be pumped in via an ATPase from the cytoplasm into the

vesicle along with ATP via an ATP transporter.

5 Classes of mAChRs5 Classes of mAChRs


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Name M1 M2 M3 M4 M5Effectors Gq Gi Gq Gi Gq


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Evens

- AC

- Modulate IM

Odds

- PLC


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Uses/abuses of mAChR ligands

- Clinical

o reduce secretions (atropine)

o prevent motion sickness (scopolamine)

o treat Alzheimers (Donepezil)

o treat autonomic disorders (M3 ANT)

o dilate pupils for ophthalmic exams (M3 ANT)

o treat severe diarrhea (M3 ANT)

o slow heart rate (M2 AGO)

o treat mushroom/anti-AChE poisoning (atropine)

- Non-clinical

o dilate pupils for beauty (atropine)

*Newly discovered allostericmodulation

- Brucine: enhance muscarinic agonistbinding

mAChR AgonistsmAChR Agonists


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LIGAND Receptors

M1 M2 M3 M4 M5Acetylcholine(ACh)

X X X X X

Carbachol X X X X X

Muscarine X X X X XOxotremorine X X X X X


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Tropicamide X


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Smooth muscle contraction via M3 mAChRsvia IP3R mediated Ca2+ nM muscarine

Extremely slow IPSPs via M2 AChRs

Onset 30-90 s after mAChR ligand binding; amplitude 2-3 x normal AHP; GIRKs: Gi

subunits

After-depolarization; Ca2+ spikes (M1,3 mAChRs)

Activating T-Type Ca2+ channels

Slow depolarization: Gq subunits

Block of sAHP by m1, 5 AChRs

Block of HVA VDCCs by M1, 3 Rs

Mediated by Gq subunits

Im block by muscarinic agonists

Gq subunits

Dopamine (DA)

Central DA minergic pathways

MFB medial forbrain bundle (path from the SN and VTA to the rest of brain)

SN - Substantia Nigra basal ganglia

VTA - Ventral Tegmental Area the rest of the brain

Catecholamine biosynthesis

Tyr (tyrosine crosses BBB)

TH (tyrosine hydroxylase)

DOPA

AAAKC or DDC

Dopamine (in the VTA and SN this is the end)

DA Beta hydroxylase

Norepinephrine (adonergic)

PNMT

epinephrine (in adrenal cortex)

TH: The rate limiting enzyme

- it has several amino acids that can be phosphorylated. Cam-KII, PKA, PKC, ERK, and cdc-

like-K. PHosphorylating increases activity and phosphotases decrease activity.

Transmitters vs false transmitters


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DAT

(DA transports)

NET

(NE transporter)

SERT

(5-HT transporter

Indatraline*

cocaine

Bupropion (wellbutrin)*

Nomifensine (merital)

Duloxetine (cymbalta)

Amphetamine

Reboxetine*

Atomoxetine**

Imipramine*

Amitriptyline*

Fluoxetine*(frozac)

Sertraline*

(Zoloft)

Citalopram*

(Celeza)

Paroxetine***

(Paxil)

Fluvoxamine*** (Luvox)


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Venlafaxine*

Clomipramine***


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*antidepressants

** ADHD

*** anxiolytics/antiOCD

Amphetamine and analogs

Amphetamine, detroamphetamine, methamphetamine

Analogs methylphenidate (Ritalin), cocaine, phenmetrazine, MDMA

Amphetamines increase synaptic DA

Block reuptake in 2 ways

1. compete for DAT

2. upregulate MAP-K phosphorylate DAT internalize DAT

DA-specific neurotoxins

MPTP glial MAO-B MPP+ (shuts down kreb cycle in mitochondria)

6-OH-DA

1. Both MPP and 6OH DA are substrates for DAT

2. Both are then taken into mitochondria

3. Both block oxidative metabolism

4. Both kill DA neurons selectively and dose-dependently

5. Both produce behavioral effects mimicking Parkinsonism

DARs are diverse!!

7 transmembrane segments; mono-, di-, and heterodi-meric (s. SST

(somatostatin), etc)

DAR types


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Betagammasubunitseffects

Decrease

VDCC, VDKC,

CDKC


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The ctx has D1-D5

Hypothalamus has D3 + D5

Corpus striatum has D1 + D2

DA agonists


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Ligand DA receptor type Other catecholaminereceptors

D1 D2 D3 D4 D5 Alpha betaDopamine X X X X X XApomorphine X X X X X

Dihydrexidine XX XBromocriptine X X XPraminpexole X XX


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DAR antagonists


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Ligand DA receptor type

D1 D2 D3 D4 D5Spiperone XXX XXX XX XX XXEcopipam XAmisulpride XXX X

Chlorpromazine* XX X XTrifluoperazine* XX X XHaloperidol* XX X XResperidone* XX X X

*out-patient drugs

Tardive dyskinesia intermittent inability to move. The receptors increases

and then they cant create more. They are taken off neuroleptic drugs they

return to the drugs after symptoms of origional problem comes back.


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Norepinephrine (NE)

Adreneric projections in the CNS

LC = Locus coeruleus - cerebellum

A1-A9 = reticular adrenergic nuclei regulatory on the hypothalamus

Methods to altertransmission**

- Alter synthesis

o facilitate, block, false transmitters

- Block vesicular storage

- Block release == Ca2+ blockers, etc.

- Direct receptor effects

o agonists, antagonists, suicide antagonists

- Block reuptake

- Block degradation

Uses/abuses of NE ligands

- Clinical

o Cardiac regulation (rhythm, rate, volume)

o Antihypertensive

o Bronchial dilation (asthma relief)

o Anti-depressant

o Anti-ADHD/ADD

o Anti-OCD

o Decongestant

- Recreational

o Hallucinogenic

o Amphetamine-like effects

Release blockers indirectly effect VNETs(vesicular norepinephrine

transporters)

- block Mg2+-ATPase proton pumps specific to NE neurons

- do not cross BBB; anti-hypertensive (guan-), block arrhythmias (bretylim)

- Sympathetic

- It is proton dependant

Degradation inhibitors (-Is)


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Enzyme

MAO-I COMT-I

A-specific

(NE, 5-HT)

A-orB-(no

nspecific)

B-sp

ecific(DA,HA)

In

hibi

Reve

rsible

Irreversible


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MAO-Is are still prescribed as antidepressants

Deprenyl in phase III for Alzheimers

**MAO-A doesnt have As in abr. (NE, 5HT)

**MAO-B has the As (DA, HA)

Classes of adrenoceptors (NE, EPI)- alpha

o 1: smooth muscle contraction - Gq

o 2: smooth muscle contraction Gi (inhibiting neurotransmitter release)

- beta: cardiac muscle contraction - Gs

Alpha 1 ( 1 ) Adrenoceptors


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Name 1A 1B 1DExpressed in:

(dont need

to know)

CNS,

heart,liver,

urogential

smoothmuscle

Resistance

vessels,kidney,

spleen

CNS,

aorta,lung,

bladder

Non-selectiveAGO

DA

NE

EPI

Phenylephrine (nyquil)

Ephedrine, Pseudoephedrine

SelectiveAGO

Tetrahydrozoline(eyedrops)

Selective

ANT(dont need

to know)

Niguldipin

e5-

methylura

padil

Cycloazosi

nSpiperone

Non-selectiveANT

Phentolamine

Prazosin

SuicideANT

Phenoxybenzamine


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G-protein Gq - IP3/DAG


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Alpha 2 ( 2 ) Adrenoceptors


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Name 2A 2B 2CExpressed in:

CNS,Lung,

vascularmuscle

Thalamus,liver,

vascular,spleen

CNS, lung

FunctionAutorecept

or;

Vasoconst

riction,

sedation,

analgesia,

anesthesia

Vasoconst

riction

Undeterimi

ned

Non-selectiveAGO

NE

EPI

Clonidine

SelectivepartialAGO

LSD-25

Nonselective ANT

Phentolamine

Prazosin

Yohimbine

-subunitGi


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-

subunits

Inhibit VDCCs, activate CDKCs


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Name 1 2 3Expressed in:

Neuronalcardiac,

kidney

Neuronal,cardiac,

bronchial

Neuronal,cardiac,

adipose

Non-

SelectiveAGO

NE

EPIIsoproterenol

Ephedrine

SelectiveAGO

Xamoterol Albuterol

Salmeterol

SelectiveANT

Atenolol Butozamine

Non-SelectiveANT

Propranolol


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G-protein Gs - cAMP


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Hertogeneous 5HT fiber systems

- Doral Raphe n. has diffuse projections

- Median Raphe n. has specific projections

Serotonin (5HT) synthesis and metabolism


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Compound Enzyme InhibitorsL-tryptophan

Tryptophan

hydroxylase

(TrpH)

Fenfluramin

e

L-tryptamine (Tra) aromatic

amino aciddecarboxylase

(DDC or

AAADC)

Carbidopa

5hydroxytryptamine (5HT) Monoamine

oxidase (MAO-

A)

MAO-Ainhibitors

5-

hydroxyindoleacetaldehyde Aldehyde

dehydrogenase (AD)


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5-hydroxyindoleacetate (5-

HIAA)


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SERTs

- ATPase pumps protons into the vesicle

- SERTs pump 5HT and Na+ & Cl- into the vesicle and 5HT and K+ outside the vesicle

5HT1Rs


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5-HT1A 5-HT1B

5-HT1

D

5 5

Tissu

e

Neuronal;

smoothmuscle

Rode

ntneuro

nalautor

eceptor;

smooth

muscle

constrictio

n

Hu

man

neuron

alaut

orecep

tor;smo

othmu

sclecon

striction

Widely

distributed

Ubiquitousagonist

5-HT

Quipazine

Se

lectivefullagonists

Buspirone

DMT

(dimetheyltr

yptamine)

Ergotamine (mold)

Sumatriptan

Selec

tiveantagonists

Spiperone Isamoltane


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Antagonist

Pindolol

G-Protein

G i/o


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Anziolytic (5HT1a agonist) Buspirone

Migraine therapy (5HT1b/1d agonists)

- Ergotamine hallucinogen- sumatriptan

**cause vasoconstriction stabilization of either state can feel dull; but reduces

migraines

5-HT2Rs


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G-Protein

Gq


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Psychedelic effects mediated by 5HT2ARs

- competitive antagonists do not block psychedelic effects

Indolaminergic psychedelics (5HT2A AGO)

- DMT

- Psilocybin

- LSD-25

Clinical use of 5-HT2 ligands

- satiety stimulants (5HT2C AGO)

- anti-schizophrenic (5HT2A ANT)

5HT3Rs


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5HT3Rs

Nonselective AGO 5HT

Quipazine

Selective AGO CBG

Selective ANT Ondansetron (keeps you from

vomiting)Zacopride


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Antiemetics (5HT3 antagonists) used extensively to alleviate nausea in

chemotherapy

- Ondansetron

- Zacopride- also used in IBS treatment

Nootropics (5HT3 antagonists) the problems is they dont cross the BBB and

would cost $100/dose/day to take enough drugs to cause the nootropic effects.

5HT4-like receptors


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5HT4 5HT6 5HT7

Nonselectiveagonists

5HT

Quipazine

Selective

AGO

EMDT COAT

SelectiveANT

Amoxipine

Nonselective ANT

Clozapine

G-protein Gs

5HT5Rs

5-ht5a 5ht5b

Nonselective AGO

5HT

LSD

5HT specific neurotoxin

- PCPA: highly specific for 5HT neurons similar in mechanism to MPP+

Melatonin - just know that it is serotonin synthesizes melatonin in pineal

HistamineHistamine Peripheral HA

- Inflamation (in mast cells): H1Rs

orgasm

allergy

congestion

- Digestion: H2Rs

gastrin

Parietal cells create gastric acid

- Immune Response: H4Rs

basophils

neutrophils

bone marrow

HAminergic neurons: transport, synthesis, degradationHAminergic neurons: transport, synthesis, degradation

L-amino acid transporter takes HA into the cell (AAAT)

Histidine is converted by histidine decarboxylase (HD) into histamine and

transported into vesicles via Vesicular MonoAmine Transporter (VMAT).


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Histamine methyltransferase (HAMT) breaks down histamine into

telemethylhistamine

CNS HA : Hypothalamic tuberomamillary nuclei* (TMN) project to the

rest of the body. *(right above the mamilary bodies)

Tuberomamillary neurons (TMN)

- large soma, dendrites

- long thin poorly myelinated punctate axons (slow, large number of synapes

- adjacent to VLH hypocretin (hypothalamus cretine neurons)

HA: Role in waking and sleep.

The firing rate is high when you are awake and drops during SWS and almost turns off

during REM.

Antihistamines make you lethargic

Modafinil increases HA release, increases alertness

HAR TypesHAR Types


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Receptor H1H1 H2H2 H3H3 H4H4g-protein Gq Gs Gi GiNeuronallocation

Postsynaptic Postsynaptic Presynaptic postsynaptic -

Global

Function

Waking state;

arousal; appetitesuppression

Waking state;

arousallearning andmemory

Autoreceptor;

regulatetransmission;inhibit -waking

arousal

? -

OtherTissues

Mast cells Parietal cells Basophils;

neurophils;

bonemarrow;

smooth

muscle


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PeripheralFunction

Inflammation;

congestion;

orgasm

Acid release allergies


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Competitive Agonist HAR

H1H1 H2H2 H3H3 H4H4Histamine (HA) X X X XDimaprit XProxyfan (partial)

X


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Imetit X X


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Competitive ANT HAR

H1 H2 H3 H4Cetirizine* (zyrtec) XClorpheniramine* XDimenhydrinate** (Dramamine) XDiphenhydramine* (Benadryl) XDoxylamine*** (Unisom) XFexofenadine* (Allegra) XLoratadine* (Claritin) XMeclizine** (Antivert) X


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Promethazine** (phenergan) X

*allergy meds

**anti vestibular

***Sleeping pills

Other HAR antagonists, inverse agonistsOther HAR antagonists, inverse agonists

Competitive ANT HARH1 H2 H3 H4

Cimetidine (tagamet) XClobenpropit XInverse AGO ***Increases Neurotransmitter Release similar to the

antagonist.

Thioperamide

X

H2 agonists increase CA1 excitability

- If the H2 agonists is administered there is no afterhyperpolarization

H3 antagonists: nootropic and dietary benefits. Every learning task the H3 has

shown to enhance.

Exam know the receptors, antagonist, non-competitive. Know the

mechanism of action. Know the clinical uses digestion, asthma, and heart

rate information. Know the biosynthesis and the degradation of the

neurotransmitters and their enzyme and rate limiting. Know the

transports- vesicular and cell membrane transporters. Know the drugs that

blocks NETS SERTS ECT.

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