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Block 2: Cardio, Renal, and Respiratory > Pharmacology (Melega) > Flashcards

Pharmacology (Melega) Flashcards

1
Q

Steps in neurochemical transmission

A

Synthesis

Storage

Release (Ca2+ triggers exocytosis)

Receptor interaction

Reuptake (into nerve terminal) or Inactivation (by metabolism)

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2
Q

NE synthesis/storage

A

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

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3
Q

Autoreceptors

A

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

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4
Q

Heteroreceptors

A

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

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5
Q

Norepinephrine transporter (NET)

A

Reuptake of NE, located on presynaptic membrane

Called Uptake 1

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6
Q

Catechol-O-methyltransferase (COMT)

A

Metabolizes NE –> normetanephrine

Metabolizes Epi –> metanephrine

(Metabolites have lower affinity for binding receptors)

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7
Q

Monoamine oxidase (MAO)

A

MAO-A and MAO-B

Metabolizes NE by oxidizing it to aldehyde

(Then aldehyde further acted on by aldehyde reductase or aldehyde dehydrogenase)

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8
Q

MHPG and VMA

A

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!

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9
Q

Which receptors does NE bind?

A

Alpha1

Alpha2

Beta1

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10
Q

Which receptors does Epi bind?

A

Alpha1

Alpha2

Beta1

Beta2

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11
Q

Which receptors does isoproterenol bind?

A

Beta1

Beta2

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12
Q

Adrenal medulla

A

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

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13
Q

Synthesis of epinephrine

A

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

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14
Q

Alpha1 adrenergic receptor signal transduction pathway

A

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

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15
Q

Beta1 adrenergic receptor signal transduction pathway

A

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

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16
Q

Beta2 adrenergic receptor signal transduction pathway

A

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

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17
Q

EPI effects at low and high concentrations

A

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

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18
Q

At physiological concentrations, what do NE and EPI do?

A

NE = vasoconstriction (via alpha1)

EPI = vasodilation (via beta2)

Both increase HR, contractility (beta1 (and beta2 for EPI))

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19
Q

Direct mechanism of action

A

Drug binds adrenergic receptor

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20
Q

Indirect mechanism of action

A

Causes response by provoking release of NE from presynaptic terminal, or by interfering with NE reuptake

Do not have direct actions on postsynaptic receptor

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21
Q

Mixed mechanism of action

A

Combination of direct and indirect mechanisms

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22
Q

Reuptake inhibitor

A

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)

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23
Q

Neurotransmitter-releasing

A

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

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24
Q

Sympatholytic/Adrenolytic

A

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

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25
Q

Pheochromocytoma

A

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

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26
Q

Reflex increase in heart rate

A

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

27
Q

What are beta blockers generally used for?

A

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

28
Q

Beta1 selective blockers

A

Metoprolol (penetrates BBB)

Atenolol (doesn’t penetrate BBB)

Effects: decrease HR, decrease conduction velocity, decrease contractility, decrease lipolysis, decrease renin secretion

29
Q

Non-selective beta blockers (beta1 and beta 2)

A

Propranolol

Carvedilol (ALSO an alpha1 antagonist)

30
Q

Things you need to think about before giving a patient a beta blocker

A

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

31
Q

What are possible mechanisms for how beta blockers combat hypertension? (Even though we don’t really understand this yet)

A

Lowered CO

Inhibition of renin release

Centrally mediated lowering of sypathetic activity

32
Q

Does “selective” mean that it only binds to that one receptor?

A

NO! Selective beta1 blockers will bind and block beta2 at high doses!

33
Q

Can beta blockers stimulate beta receptors?

A

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

34
Q

Effects of EPI

A

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.

35
Q

Effects of NE

A

(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.

36
Q

Effects of ISO

A

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.

37
Q

Where are cholinergic synapses located?

A

Presynaptic PNS and SNS (autonomic ganglia)

Postsynaptic PNS (smooth muscle contraction, etc)

Postsynaptic SNS sweat glands

Brain

Neuromuscular junction (voluntary contraction)

38
Q

Acetylcholine synthesis

A

Choline transported into terminal with Na+ (rate-limiting step)–> Choline + Acetyl CoA into ACh by choline acetyltransferase –> ACh into vesicles by exchange with H+

39
Q

Mechanisms to inhibit ACh release

A

1) Presynaptic autoreceptors (M2)
2) Heteroreceptors (NE on alpha2 receptors on cholinergic presyn terminal)

40
Q

Nicotinic receptors

A

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

41
Q

Muscarinic receptors

A

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

42
Q

How is ACh inactivated?

A

Hydrolysis by acetylcholinesterase in synaptic cleft

43
Q

Effects of ACh

A

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

44
Q

Acetylcholinesterase inhibitors

A

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)

45
Q

Pralidoxime

A

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”

46
Q

NO-mediated relaxation

A

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)

47
Q

Muscarininc Agonists

A

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

48
Q

Muscarinic Antagonists (Atropinic Agents)

A

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

49
Q

Botulinum Toxin (BoTx)

A

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)

50
Q

Injected NE (pharmacological) versus neuroeffector NE (natural/physiological)

A

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)

51
Q

Which receptor does ACh bind more strongly?

A

Muscarinic

52
Q

Why can’t stimulation of vagus nerve cause vasodilation?

A

Vagus nerve does not innervate vascular smooth muscle (no connection to blood vessels!)

53
Q

Alpha agonists

A

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)

54
Q

Beta agonists

A

EPI (and alpha1, alpha2)

NE (beta1, and alpha1, alpha2)

ISO

Dobutamine (beta1)

Tertbutaline (beta2)

55
Q

Alpha antagonists (alpha blockers)

A

Phenoxybenzamine (irreversible)

Phentolamine (competitive)

Prazosin (competitive alpha1)

Terazosin (competitive alpha1)

Doxazosin (competitive alpha1)

56
Q

Beta antagonists (beta blockers)

A

Propranolol (beta1 and beta2)

Carvedilol (alpha blocker too)

Metoprolol (beta1)

57
Q

Indirectly acting sympathomimetics

A

Cocaine

d-Methamphetamine

d-Amphetamine

Ephedrine

Pseudoephedrine (also alpha and beta blocker)

Tyramine

58
Q

Sympatholytics

A

Reserpine

Alpha-Methyldopa

59
Q

Cholinergic agonists

A

Nicotine (nicotinic receptors)

Pilocarpine (muscarinic receptors)

60
Q

Acetylcholinesterase inhibitors

A

Physostigmine

Neostigmine

Organophosphate inhibitors (irreversible)

61
Q

Cholinergic antagonists (ACh blockers)

A

Atropine (muscarinic)

Scopolamine (muscarinic)

Tiotropium (muscarinic, only in periphery)

Ipratropium (muscarinic, only in periphery)

62
Q

Pseudocholinesterase

A

Hydrolyzes ACh in plasma, liver, glia

(Like AChE, but different locations!)

63
Q

Acetylcholinesterase (AChE)

A

Hydrolyzes ACh at postsynaptic membrane of synapse, and in RBCs

Block 2: Cardio, Renal, and Respiratory (36 decks)

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