Pharmacology (Melega) Flashcards Preview

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

Flashcards in Pharmacology (Melega) Deck (63)
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1


Steps in neurochemical transmission


Synthesis

Storage

Release (Ca2+ triggers exocytosis)

Receptor interaction

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

2


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

3


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

4


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

5


Norepinephrine transporter (NET)


Reuptake of NE, located on presynaptic membrane

Called Uptake 1

6


Catechol-O-methyltransferase (COMT)


Metabolizes NE --> normetanephrine

Metabolizes Epi --> metanephrine

(Metabolites have lower affinity for binding receptors)

7


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)

8


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!

9


Which receptors does NE bind?


Alpha1

Alpha2

Beta1

10


Which receptors does Epi bind?


Alpha1

Alpha2

Beta1

Beta2

11


Which receptors does isoproterenol bind?


Beta1

Beta2

12


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

13


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

14

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

15


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

16


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

17


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

18


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))

19


Direct mechanism of action


Drug binds adrenergic receptor

20


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

21


Mixed mechanism of action


Combination of direct and indirect mechanisms

22


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)

23


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

24


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

 

25


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

26

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

27

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

28


Beta1 selective blockers


Metoprolol (penetrates BBB)

Atenolol (doesn't penetrate BBB)

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

29


Non-selective beta blockers (beta1 and beta 2)


Propranolol

Carvedilol (ALSO an alpha1 antagonist)

30


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