Pharmacology (Melega) Flashcards
Steps in neurochemical transmission
Synthesis
Storage
Release (Ca2+ triggers exocytosis)
Receptor interaction
Reuptake (into nerve terminal) or Inactivation (by metabolism)
NE synthesis/storage
Tyr gets into cytosol without regulation –> TH turning Tyr into L-DOPA is rate-limiting –> L-DOPA turned into DA by AAAD rapidly in cytosol –> DA into vesicles by vesicular monoamine transporter-2 (VMAT) –> DA turned into NE by dopamine beta hydroxylase (DBH) in vesicles and stored there
Autoreceptors
Receptor on presynaptic membrane that binds NE after it’s been released into synaptic cleft
Ex: alpha2 autoreceptor on presyn membrane responding to NE
Provides feedback–inhibits NE release
Heteroreceptors
Receptor on presynaptic membrane that responds to input from another neuron (and different NT, ie Ach)
Ex: muscarinic receptor on adrenergic nerve terminal
Inhibitory–reduces NE release
Norepinephrine transporter (NET)
Reuptake of NE, located on presynaptic membrane
Called Uptake 1
Catechol-O-methyltransferase (COMT)
Metabolizes NE –> normetanephrine
Metabolizes Epi –> metanephrine
(Metabolites have lower affinity for binding receptors)
Monoamine oxidase (MAO)
MAO-A and MAO-B
Metabolizes NE by oxidizing it to aldehyde
(Then aldehyde further acted on by aldehyde reductase or aldehyde dehydrogenase)
MHPG and VMA
Terminal metabolites of NE metabolism
MHPG and sometimes VMA used as index of NE turnover when measured in CSF
Can be produced when MAO acts then COMT, or vice versa!
Which receptors does NE bind?
Alpha1
Alpha2
Beta1
Which receptors does Epi bind?
Alpha1
Alpha2
Beta1
Beta2
Which receptors does isoproterenol bind?
Beta1
Beta2
Adrenal medulla
Located in central part of adrenal glands
Site of synthesis and storage of catecholamines
Responds to impulses from preganglionic sympathetic fibers that release Ach and bind nicotinic receptors
Secretes mostly 80% epi and 20% NE directly into circulation via chromaffin cells
Synthesis of epinephrine
DA taken up into vesicles, converted to NE by DBH –> NE transported out of vesicles into cytosol –> NE converted to EPI by PNMT –> EPI transported back into vesicles
Alpha1 adrenergic receptor signal transduction pathway
EPI/NE binds alpha1 receptor –> G-coupled protein activates PLC –> PLC creates DAG and IP3 –> IP3 binds to IP3-receptor gated Ca2+ channel to let Ca2+ into cytoplasm from SR –> Ca2+ binds calmodulin and activates MLCK –> MLCK activates myosin to bind actin and contract
Beta1 adrenergic receptor signal transduction pathway
EPI/NE binds beta1 receptor –> G-coupled protein activates adenylyl cyclase –> increased cAMP –> activation of PKA –> phosphorylation of L-type Ca2+ channels –> muscle CONTRACTION –> heart has increased contractility
Beta2 adrenergic receptor signal transduction pathway
EPI binds beta2 receptor –> G-coupled protein activates adenylyl cyclase –> increased cAMP –> activation of PKA –> phosphorylation of MLCK –> muscle RELAXATION
Note: same pathway for beta1 and beta2 but opposing effects because of LOCALIZED action
EPI effects at low and high concentrations
Low [EPI]: stimulates beta2 > alpha1; vasodilation
High [EPI]: stimulates alpha1> beta2; vasoconstriction
Note: more alpha1 receptors overall, but have lower affinity for EPI. So when enough EPI to bind to alpha1, they bind to lots of alpha1’s and this effect overrides the few beta2 receptors that are occupied by EPI
At physiological concentrations, what do NE and EPI do?
NE = vasoconstriction (via alpha1)
EPI = vasodilation (via beta2)
Both increase HR, contractility (beta1 (and beta2 for EPI))
Direct mechanism of action
Drug binds adrenergic receptor
Indirect mechanism of action
Causes response by provoking release of NE from presynaptic terminal, or by interfering with NE reuptake
Do not have direct actions on postsynaptic receptor
Mixed mechanism of action
Combination of direct and indirect mechanisms
Reuptake inhibitor
Type of Indirectly Acting Sympathomimetic
Drug binds reversibly to uptake transporter (ex: NET), blocking access for NT to be re-uptaken back into presynaptic terminal
Get increase in extracellular NT
Ex: Cocaine
Other ex: methylphenidate (Ritalin for ADHD increase NE, DA), tricyclic antidepressants (increase NE, serotonin), SSRIs (increase serotonin)
Neurotransmitter-releasing
Type of Indirectly Acting Sympathomimetic
Drug is taken up by presynaptic nerve terminals (through reuptake channel like NET) and enters vesicles, displacing NT from the vesicles, so NT gets into cytosol and is then pushed out of presyn membrane through channels (non-exocytosis exit)
Get increase in extracellular NT
Ex: Methamphetamine, Tyramine
Sympatholytic/Adrenolytic
Block NE effects
Direct Receptor Blocking Agents: Drug can be direct (competitive or irreversible) antagonist
Adrenergic Neuronal Blocking Agents: Drug can bind to vesicles and not allow DA in (so can’t be converted/synthesized to NE), or can not allow reuptake of NE into vesicle (so can’t be stored in vesicles and released into synaptic cleft), then DA and NE metabolized in cytosol by MAO
Pheochromocytoma
Rare catecholamine-secreting tumor derived from chromaffin cells of adrenal medulla that produces high NE and EPI, resulting in severe increase in BP
Can use Phentolamine or Phenoxybenzamine (although that not used much anymore because it’s irreversible) to treat hypertension caused by this
Reflex increase in heart rate
Happens when you block alpha1 and alpha2–get vasodilation then reflex increase in HR
Alpha2 presynaptic receptors usually decrease NE release, so if they are blocked you get more NE released, and this NE can go to beta2 receptors and stimulate increased heart rate
What are beta blockers generally used for?
Manage ischemic heart disease by decreasing myocardial O2 demand
Hypertension
Congestive heart failure
Abnormal heart rhythms
Chest pain (angina)
Sometimes in heart attack patients to prevent future heart attacks
Beta1 selective blockers
Metoprolol (penetrates BBB)
Atenolol (doesn’t penetrate BBB)
Effects: decrease HR, decrease conduction velocity, decrease contractility, decrease lipolysis, decrease renin secretion
Non-selective beta blockers (beta1 and beta 2)
Propranolol
Carvedilol (ALSO an alpha1 antagonist)
Things you need to think about before giving a patient a beta blocker
In diabetics: beta blockers can mask tachycardia they need to feel to know they’re getting hypoglycemic
In asthmatics: they need beta2 stimulation for bronchodilation, so be careful when giving nonselective beta blocker like propranolol or carvedilol
What are possible mechanisms for how beta blockers combat hypertension? (Even though we don’t really understand this yet)
Lowered CO
Inhibition of renin release
Centrally mediated lowering of sypathetic activity
Does “selective” mean that it only binds to that one receptor?
NO! Selective beta1 blockers will bind and block beta2 at high doses!
Can beta blockers stimulate beta receptors?
YES! When endogenous NE activity is low, beta blockers can become a weak agonist and stimulate beta receptors like NE does.
When endogenous NE activity is high, beta blockers block NE effects by competitively binding beta receptors.
OVERALL: beta blockers have low efficacy for receptors, and to have agonist activity, a lot of receptors must be occupied
Effects of EPI
Act on beta receptors and alpha receptors
Vasodilation from beta2 receptors on skeletal muscle causes decrease in resistance.
Beta effects on heart cause systolic to increase, but since peripheral resistance decreased, your diastolic goes down! Increase in HR because of direct effect of epi on beta receptors, AND baroreceptor reflex responds to decreased stretch so also wants to increase HR.
Effects of NE
(PHARMACOLOGICALLY)
Act on alpha1, alpha2, beta1.
Increase peripheral resistance because alpha1 on vasculature causes vasoconstriction. THAT drives increase in BP. Beta1 should produce increase of HR, but HR goes DOWN because baroreceptor reflex overwhelms direct effect of NE.
Effects of ISO
Act on beta receptors
Vasodilation by beta2 causes reduction in peripheral resistance. That causes decreased diastolic pressure. Causes increased HR directly and by baroreceptor reflex.
Where are cholinergic synapses located?
Presynaptic PNS and SNS (autonomic ganglia)
Postsynaptic PNS (smooth muscle contraction, etc)
Postsynaptic SNS sweat glands
Brain
Neuromuscular junction (voluntary contraction)
Acetylcholine synthesis
Choline transported into terminal with Na+ (rate-limiting step)–> Choline + Acetyl CoA into ACh by choline acetyltransferase –> ACh into vesicles by exchange with H+
Mechanisms to inhibit ACh release
1) Presynaptic autoreceptors (M2)
2) Heteroreceptors (NE on alpha2 receptors on cholinergic presyn terminal)
Nicotinic receptors
Ligand-gated ion channel; lets Na+ in (and K+ out) to depolarize membrane
Location:
CNS
On postsynaptic PNS and SNS neurons
On chromaffin cells
Neuromuscular junction
Muscarinic receptors
M1, 3, 5: Activate phospholipase C, increase DAG then PKC and IP3 then Ca2+ intracellular storage and smooth muscle contraction = vasoconstriction
M2, 4: Decrease cAMP for signal transduction and cell hyperpolarization and decreased HR
Location:
Blood vessel endothelium
Sweat glands
CNS
Heart
How is ACh inactivated?
Hydrolysis by acetylcholinesterase in synaptic cleft
Effects of ACh
Decrease HR, decrease rate of conduction, decrease force of contraction
Vasodilation (not nerves, but via NO, cGMP and PKG)
Bronchoconstriction
GI motility increase
Urinary detrusor contraction and trigond/sphincter relaxation
Neuromuscular contraction
Acetylcholinesterase inhibitors
AKA anticholinesterase drugs
Cause increase in ACh
Reversible inhibitors: derophonium, ambenonium, tacrine, donepezil (compete with ACh for AChE binding site)
Slowly reversible inhibitors: physostigmine and neostigmine (carbamate esters which binds AChE and takes 20 minutes to inactivate it)
Irreversible inhibitors: organophosphates (interact only with esteratic site)
Pralidoxime
Treats organophosphate inhibition of acetylcholinesterase (irreversible AChE inhibition) by reactivating AChE
Interacts with anionic site of phosphorylated AChE. Must be used ASAP after exposure and before “aging of AChE”
NO-mediated relaxation
ACh on muscarinic receptor (and bradykinin, histamine, shear stress of blood flow) –> Ca2+ enters cell and triggers calmodulin to bind to membrane-bound endothelial NOS (e-NOS, aka c-NOS) –> e-NOS makes NO –> NO diffuses into nearby smooth muscle cells to cause cGMP and PKG (?)–> decreased Ca2+, K+ channels cause hyperpolarization, activation of MLCP –> Vasodilation (relaxation)
Muscarininc Agonists
AKA Cholinomimetics, parasympathomimetics
Not used much other than to treat glaucoma, postop urinary retention and ileus because many side effects
Bradycardia, vasodilation (so reflex tachycardia), bronchoconstriction, increased secretions of fluids, increased peristalsis, pupillary constriction/blurred vision
Muscarinic Antagonists (Atropinic Agents)
Competitive antagonist of ACh
Atropine
HR increase (but little effect on BP because no muscarinic on blood vessels ???)/contractility increase, AV conduction increase, reduced sweating/dry mouth, reduced bronchial mucous secretion, bronchodilation
Botulinum Toxin (BoTx)
Irreversibly blocks ACh release
Results in flaccid paralysis of muscles
Protease that cleaves specific proteins (SNAP25, synaptobrevin–SNARE proteins) involved in exocytosis
Cosmetic to reduce wrinkles, excessive sweating, strabismus (lack of parallelism of eyes)
Injected NE (pharmacological) versus neuroeffector NE (natural/physiological)
Injected: Floating around bloodstream, acts on smooth muscle and causes vasoconstriction (alpha1), does NOT act on heart at all
Neuroeffector: Released from synapse, acts on heart (SA node) to increase HR, contractility (beta1 and beta2). Also acts on smooth muscle to vasoconstrict (alpha1 and alpha2)
Which receptor does ACh bind more strongly?
Muscarinic
Why can’t stimulation of vagus nerve cause vasodilation?
Vagus nerve does not innervate vascular smooth muscle (no connection to blood vessels!)
Alpha agonists
EPI (plus beta1, beta2)
NE (plus beta1)
Phenylephrine (alpha1)
Midodrine (alpha1)
Clonidine (alpha2, so basically “sympatholytic”–decreases NE release!)
Oxymetazoline (partial alpha agonist)
Tetrahydrozoline (partial alpha agonist)
Naphazoline (partial alpha agonist)
Beta agonists
EPI (and alpha1, alpha2)
NE (beta1, and alpha1, alpha2)
ISO
Dobutamine (beta1)
Tertbutaline (beta2)
Alpha antagonists (alpha blockers)
Phenoxybenzamine (irreversible)
Phentolamine (competitive)
Prazosin (competitive alpha1)
Terazosin (competitive alpha1)
Doxazosin (competitive alpha1)
Beta antagonists (beta blockers)
Propranolol (beta1 and beta2)
Carvedilol (alpha blocker too)
Metoprolol (beta1)
Indirectly acting sympathomimetics
Cocaine
d-Methamphetamine
d-Amphetamine
Ephedrine
Pseudoephedrine (also alpha and beta blocker)
Tyramine
Sympatholytics
Reserpine
Alpha-Methyldopa
Cholinergic agonists
Nicotine (nicotinic receptors)
Pilocarpine (muscarinic receptors)
Acetylcholinesterase inhibitors
Physostigmine
Neostigmine
Organophosphate inhibitors (irreversible)
Cholinergic antagonists (ACh blockers)
Atropine (muscarinic)
Scopolamine (muscarinic)
Tiotropium (muscarinic, only in periphery)
Ipratropium (muscarinic, only in periphery)
Pseudocholinesterase
Hydrolyzes ACh in plasma, liver, glia
(Like AChE, but different locations!)
Acetylcholinesterase (AChE)
Hydrolyzes ACh at postsynaptic membrane of synapse, and in RBCs
