Day 1.2 Pharm Flashcards
What is the neurotransmitter for the nicotinic receptor?
ACh
What drug is a nicotinic receptor antagonist?
Hexamethonium
What does Hexamethonium block?
Nicotinic receptor antagonist- blocks ACh receptors at ALL autonomic ganglion- both sympathetic and parasympathetic
If hexamethonium blocks both SNS and PNS, how can you determine how it will affect an organ?
How it affects an organ depends on the dominant tone (SNS or PNS) in that organ. e.g. Dominant tone in vessels is SNS, so hexamethonium will act as a symp antagonist to blood vessels- so will decrease BP. (Most organs have dom PNS tone)
What is hexamethonium used for clinically?
Experimental only - to prevent vagal reflex response to changes in BP; prevents reflex bradycardia caused by NE
SNS to sweat glands: Preganglionic neurons go to what kind of receptor? Release which NT?
The sympathetic ganglion have a nicotinic receptor. ACh is the NT. All preganglionic neurons go to Nicotinic receptors.
SNS to sweat glands: Post-ganglionic neurons go to what kind of receptor? Release which NT?
Post-gang neurons go to sweat glands and synapse there with a Muscarinic receptor. ACh is the NT.
SNS to cardiac musc, smooth musc, gland cells, nerve terminals: Preganglionic neurons go to what kind of receptor? Release which NT?
The sympathetic ganglion have a nicotinic receptor. ACh is the NT. All preganglionic neurons go to Nicotinic receptors.
SNS to cardiac musc, smooth musc, gland cells, nerve terminals: Post-ganglionic neurons go to what kind of receptor? Release which NT?
Post-gang neurons go to cardiac musc, smooth musc, gland cells, and nerve terminals and synapse there with a adrenoceptor receptor (alpha or beta). NE is the NT.
SNS to renal vascular smooth musc: Preganglionic neurons go to what kind of receptor? Release which NT?
The sympathetic ganglion have a nicotinic receptor. ACh is the NT. All preganglionic neurons go to Nicotinic receptors.
SNS to renal vascular smooth musc: Post-ganglionic neurons go to what kind of receptor? Release which NT?
Post-gang neurons go to renal vascular smooth muscle and synapse there with a D1 receptor.
SNS to the adrenal medulla: what kind of receptor is at the adrenal medulla? Releases which NT?
There is a Nicotinic receptor at the adrenal medulla. The receptor is ACh. When stimulated, the adrenal medulla itself goes on to release NE and Epi
Somatic system: Nerves to skeletal muscle have what kind of receptor? What is the NT?
Nicotinic receptor; ACh is the NT.
PNS pre-ganglionis neurons go from the medulla all the way to the ganglion located right by the organ they will stimulate. What kind of receptor is in the ganglion? What is the NT?
The parasympathetic ganglion have a nicotinic receptor. ACh is the NT. All preganglionic neurons go to Nicotinic receptors.
PNS post-ganglionic nerves (short) go to cardiac and smooth muscle, gland cells, and nerve terminals. What is there receptor at these locations? What is the NT?
Muscarinic receptor; ACh is the NT.
What are the Nicotinic receptors (what kind of channel/protein)?
Ligand-gated Na+/K+ channels.
Nn for autonomic (SNS, PNS) ganglia
Nm for the NMJ (somatic)
What are the Muscarinic receptors (what kind of channel/protein)?
G-protein-coupled receptors, which act through 2nd messengers.
5 subtypes: M1, M2, M3, M4, M5
Cholinergic Nerve: What kind of NT does it produce?
ACh
ACh goes to a cholinocepor- either a M receptor or N receptor.
Noradrenergic Nerve: What kind of NT does it produce?
NE
Noradrenergic (SNS) goes to an adrenoceptor (alpha or beta receptor)
Cholinergic Nerve: how is ACh produced?
Choline is brought along with Na+ via the Na+ cotransporter. Choline is combined with Acetyl-CoA with the help of ChAT (choline acetyltransferase). Ca2+ helps release of ACh into synaptic cleft.
Cholinergic Nerve: What is the rate-limiting step in ACh synthesis?
Bringing choline in. (Via Na+ cotransporter)
Cholinergic Nerve: what inhibits choline from being brought into the cell?
Hemicholinium
Cholinergic Nerve: What inhibits release of ACh into the cleft?
Botulinum toxin, which causes flaccid paralysis (floppy baby)
Cholinergic Nerve: What toxin stimulates the release of ACh into the cleft?
Black widow spider toxin
What are the 4 fates of ACh once it’s in the synaptic cleft?
- Bind to the Ach cholinoceptor (either M or N) on the post-syn cell
- Bind to a pre-synaptic auto-receptor
- Be degraded (metabolized) by AChE (can block this with anti-AChE - the -stigmines)
- Diffuse away
Noradrenergic Nerve: How is NE produced?
Tyrosine is brought along with Na+ via the Na+ cotransporter. Tyrosine is converted to L-Dopa with the help of Tyrosine Hydroxylase. L-Dopa is converted to Dopamine, and Dopamine is converted to NE. Ca2+ helps release of NE into synaptic cleft.
Noradrenergic Nerve: What converts Tyrosine to L-Dopa?
Tyrosine Hydroxylase (imp in biochem!)
Noradrenergic Nerve: What drug blocks Tyrosine Hydroxylase? What happens if it’s blocked?
Metyrosine. Blocking Tyrosine Hydroxylase means that Tyrosine will not be converted into L-Dopa.
Noradrenergic Nerve: What are the two ways for NE to have effects on the pre-synaptic cell once it has been released?
- Can undergo reuptake
2. Can bind to release-modulating receptors (M2, Alpha2, AngII)
What are the 4 fates of NE once it has been released into the synaptic cleft?
- Bind to adrenoceptor (alpha1,2, beta1,2) on post-syn cell
- Bind to pre-syn autoreceptors (M2, alpha2, AngII)
- Undergo reuptake
- Be metabolized by COMT or MAO
Noradrenergic Nerve: What are the 3 auto-receptors for NE on the pre-synaptic cell, and what are their effects?
M2: inhibits release of more NE
Alpha2: inhibits release of more NE
Angiontensin II: stimulates release of more NE
Noradrenergic Nerve: What are the 3 things that prevent reuptake of NE? What is the effect of preventing reuptake?
Cocaine
TCAs
Amphetamine
When reuptake is inhibited, NE stays in the cleft for longer, so increased HR, BP, euphoria.
Noradrenergic Nerve: What drug blocks the conversion of Dopamine to NE?
Reserpine
Other than L-Dopa, what is Tyrosine converted to?
Thyroxine (thyroid hormone)
Other than Dopamine, what is L-Dopa converted to?
Melanin
Noradrenergic Nerve: What 2 drugs inhibit the release of NE into the cleft?
Guanethidine
Bretylium (anti-arrhythmic K+ chnl blocker)
Noradrenergic Nerve: What 3 drugs stimulate the release of NE into the cleft?
Amphetamines
Ephedrine (formerly OTC diet drug)
Tyramine
How is NE metabolized in the cleft?
Methylated by COMT (catechol-O-methyltransferase)
or oxidized by MAO (monoamine oxidase)
What inhibits MAOs?
MAO-Is. (MAO inhibitors). These are anti-depressants. Work by preventing metabolism of NE.
What are the two kinds of anti-depressants that work on NE?
- MAO-I prevent NE metabolism so more stays in cleft
2. TCAs inhibit reuptake so more NE stays in cleft
What should you not take if you’re on MAO-Is?
Tyramine. Tyramine stim’s release of NE into cleft. MAO-I inhibits metabolism of NE. So you have extra NE in cleft, plus you’re not metabolizing it - leads to HTN crisis. (MAO-I work in gut, where Tyramine will go if eaten)
What are the byproducts of NE breakdown? When are these seen in excess?
VMA, metanephrine, normetanephrine
Seen in pheochromocytoma, an adrenal tumor that releases excess NE and Epi.
Which drug reverses NMJ blockade (from paralytics)?
Neostigmine
What is the G-protein class for alpha1,2, beta 1,2?
QISS: alpha 1 = q alpha 2 = i beta 1 = s beta 2 = s
What is the G-protein class for M1, M2, M3?
QIQ:
M1 = q
M2 = i
M3 = q
What is the G-protein class for D1, D2, H1, H2, V1, V2?
SIQ, SQS D1 = s D2 = i H1 = q H2 = s V1 = q V2 = s
What is “HAV 1 M&M”
H1, alpha-1, V1
M1 and M3
all use Gq
(cutsies have 1 m&m)
What is MAD 2’s?
M2, alpha-2, D2
all use Gi
Alpha-1: G-protein class and mjr fns
Gq
Increases vascular smooth musc contraction (so increases BP), increases pupillary dilator musc contraction (mydriasis), increases intestinal and bladder sphincter musc contraction
Alpha-2:
G-protein and mjr fns
Gi
Decreased symp outflow (so vasodilation, decreased BP), decreased insulin release
Beta-1:
G-protein and mjr fns
Gs
Incrs HR, contractility
Incrs renin rls, incrs lipolysis
Beta-2:
G-protein and mjr fns
Vasodilates! (but HR increases to compensate for the dilation)
So incrs HR, contractility
Bronchodilation
Increased lipolysis, increased insulin rls
decreased uterine tone
M1:
G-protein and mjr fns
Gq
CNS, enteric nervous system
M2:
G-protein and mjr fns
Gi
decreases HR
decreases contractility of atria
M3:
G-protein and mjr fns
Gq
Increased exocrine gland secretions (sweat, gastric acid), incrs gut peristasis, incrs bladder contraction
bronchoconstriction
increased pupillary sphincter musc contraction (miosis), cilairy musc contraction (accomodation)
D1:
G-protein and mjr fns
Gs
Relaxes renal vascular smooth musc (so increases circulation to the kidneys)
D2:
G-protein and mjr fns
Gi
modulates transmitter rls, esp in brain
H1:
G-protein and mjr fns
Gq
increases nasal and brochial mucus production, contracts bronchioles, pruritis and pain (allergic responses)
H2:
G-protein and mjr fns
Gs
Increased gastic acid secretion
(use H2 blockers like cimetidine, renitidine to block this)
V1:
G-protein and mjr fns
Gq
Increased vascular smooth muscle contraction
V2:
G-protein and mjr fns
Gs
Increased H20 permeability and reabs in the collecting tubules of the kidney
(V2 is found in the 2 kidneys)
What does the Gq protein do?
Gq activates phospholipase C, which converts lipids to PIP2.
PIP2 is cleaved to IP3 and DAG.
IP3 increases intracellular Ca2+ (Ca2+ finds to calmodulin and activates CaM-kinase)
DAG activates Protein Kinase C
What does the Gs protein do?
Gs = stimulatory.
Stimulates Adnylyl cyclase, which converts ATP to cAMP.
cAMP activates Protein Kinase A
What does the Gi protein do?
Gi = inhibitory
Inactivates Adenylyl cyclase, which decreases cAMP
Decreased cAMP means decreased Protein Kinase A.
How is phospolipase C activated
Either the Gq pathway, or can be activated when a hormone/growth factor binds to the tyrosine kinase receptor
What are the 2 pathways which can occur when a hormone or growth factor binds to a tyrosine kinase receptor?
- It can activate phospholipase C (leading to IP3, DAG)
2. It can activate the Ras pathway
What is the Ras pathway?
Hormone/growth factor binds to tyrosine kinase receptor, activating adaptor protein.
Adaptor protein activates Ras-activating protein, which activates Ras
Ras activates protein kinase 1.
PK1 activates PK2
PK2 activates PK3
PK3 affects target proteins/genes
Many bacterial toxins use one of the G-proteins- which one?
Use Gs, for the purpose of activating adenylyl cyclase (and making cAMP, activating PKA)
What is a 7-pass transmembrane receptor?
a G-protein
List the direct sympathomimetics
Epinephrine, NE, Isoproterenol, Dopamine, Dobutamine, Phenylephrine, Metaproterenol, Albuterol (levalbuterol), Salmeterol, Terbutaline, Ritodrine
What is the selectivity of epinephrine?
a1, a2, b1, b2. (selective for ALL sympathetic receptors).
at low doses, selective for b1 (mne: Blow)
Clinical use for epinephrine?
Anaphylactic shock
Open-angle glaucoma
Asthma
Hypotension (d/t shock)
What is the selectivity of NE?
a1, a2 > b1
no b2 effect
Clinical use for NE?
Hypotension (but decrsd renal perfusion)- bc it causes vasoconstriction at a1 Septic shock (in shock have vasodilation, so use NE to counteract it)
What is the selectivity of Isoproterenol?
b1 = b2
ISOlated to beta; iso means equal
Clinical use for Isoproterenol?
AV block (rare)
Selectivity of Dopamine?
D1 = D2 > b > a
inotropic and chronotropic
Clinical use for Dopamine?
Shock (increases renal perfusion*), heart failure
*theoretically, not in actual practice