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Pharmacology and Medical Chemistry I > Exam 4 - Lecture 37-38, Pharmacology of Sympathomimetics > Flashcards

Exam 4 - Lecture 37-38, Pharmacology of Sympathomimetics Flashcards

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1
Q

Primary endogenous neurotransmitters in the SNS

A

NE, E, DA

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2
Q

Primary drug targets in the SNS

A

a and b adrenergic receptors

Dopamine receptors

Monoamine transporters biosynthetic pathways

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3
Q

What does SNS do

A

Releases E and NE

Increases Heart and Lung action

Constricts bodily blood vessels, but increase blood flow to muscle

Increase BP, HR, BS, and fats

Releases Glucagon (increase glucose)

Inhibit digestion, relax bladder and inhibit erection

Promote clotting

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4
Q

Neuronal Membrane Transporters

A

NET, DAT, SERT

transport monoamines, rely on Na gradient to passively transport monoamines

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5
Q

Vesicular monoamine transporter

A

responsible for pacing monoamines into vesicles preventing MAO degradation.

relies on trans-vesicular proton gradient for driving force

Vesicles contain ATP and chromogranin A

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6
Q

Extraneuronal monoamine transporter

A

Passive transport, no ATP

Bind 1 molecule or ion, changes conformation and releases cargo opposite side of membrane

Transports HA, 5HT, NE, DA, MPP+

Found on SM, Cardiac Muscle, Endothelium

inhibited by drugs of abuse; cocaine, MDMA, amphetamines

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7
Q

Selectivity

A

Describes the property of a ligand having greater affinity for one receptor over another

Can be “overcome” with high concentrations of ligand, when other receptors experience binding and activation

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8
Q

Receptor Activation

A

Depends on drug structure, dose, receptor number, receptor status, physiology, disease state, polymorphisms, species

Also mood, atmosphere, place, diet, will, spirituality

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9
Q

Histamine greatest affinity for…

A

Vmat2 over Vmat 1

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10
Q

EMT vs Neuronal MT

A

EMT as quick transport and has higher saturation than Neuronal MT

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11
Q

Alpha 1a,1b,1d distribution

A 
Bronchi
GI tract
GI sphincters
Uterus
Bladder sphincter
Seminal tract
Iris (radial muscle)
Liver (hepatocytes)
Salivary gland
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12
Q

Alpha 2a,2b,2c

A

GI tract
Directly on Pancreatic islet (beta cells) + Platelets
Brain stem
Nerve terminals

Predominantly presynaptic nerve terminals on brainstem causing presyanptic inhibitory effect

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13
Q

B1

A

HEART and salivary gland

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14
Q

B2

A

BRONCHI and uterus, heart, mast cells, liver

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15
Q

B3

A

Bladder detrusor
Skeletal muscle
Fat

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16
Q

Skeletal muscle contraction

A

Calcium binds troponin allowing for troponin to interact with actin/myosin allowing for muscle contraction

Fast and direct mechanism, little pharamcological activity

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17
Q

Cardiac muscle contraction

A

Still fast but has a plateau period (~100ms) after initial rapid depolarization. Cardiac specific RyR Ca channels release Ca2+ from sarcoplasmic reticulum.

contractile machinery of Troponin/Ca troponin resembles SKM

Ca2+ release from RyR Ca channels may cause arrhythmia. Of interest in adrenergic blockers

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18
Q

Smooth muscle contraction

A

Large organ variance in contraction.

** Not entirely dependent on depolarization as GPCR ligands by IP3 trigger Ca2+ release from the ER.

cAMP regulates myosin Lc kinase and myosin phosphatase to balance contraction/relaxation

several ways to have smooth muscle contraction

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19
Q

Alpha 1 receptor Signaling

A

Epinephrine> Norepinephrine affinity (but effect same)

a1 stimulates Gq coupled to PLC; PLC gets phosphorylated (activated)

PLC then hydrolyzes phosphoinositides, produces IP3 and DAG

DAG activates PKC and leads to cellular response

IP3 releases stored intracellular Ca and activates Ca channels

increased cytoplasmic Ca activates Ca dependent kinases leading to cellular response

Predominantly found in SM, all types of SM (except GI tract) contract in response to stimulation of a1-adrenoceptors

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20
Q

a1 effect on Bronchi

A

Contraction (narrowing)

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21
Q

a1 effect on GI tract + GI sphincter

A

relaxation(decrease motility) + contraction (decrease motility)

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22
Q

a1 effect on uterus

A

contraction (child birth/miscarriage)

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23
Q

a1 effect on Bladder sphincter

A

contraction (narrowing)

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24
Q

a1 effect on Seminal tract

A

contraction (ejaculation)

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25
Q

a1 effect Iris

A

contraction (small pupils)

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26
Q

a1 effect Liver

A

Glycogenolysis (increase glucose synthesis)

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27
Q

a1 effect salivary gland

A

K+ release (profuse saliva)

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28
Q

Alpha 2 receptor signaling

A

receptor found in blood vessels, presynaptic GI NMJ, pancreatic Bcells, platelets, brain stem and nerve terminals

Common effects due to negative feedback on presynaptic nerves to inhibit further release of NE from presynaptic nerve terminal

Gai, inhibit Adenylate Cyclase, decrease cAMP + PKA

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29
Q

a2 effect on Blood vessels

A

constriction (a2b) or dilation (a2A)

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30
Q

a2 effect on GI tract

A

Presynaptic relaxation (decrease motility)

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31
Q

a2 effect on Pancreatic B cells

A

Decreased insulin release

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32
Q

a2 effect on platelets

A

Aggregation

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33
Q

a2 effect on brain stem

A

inhibit sympathetic flow

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34
Q

a2 effect on Nerve terminals

A

Adrenergic: Decrease NE release
Cholingeric: Decrease ACH release

Locus ceruleus: Sedative
Dorsal horn: Analgesic effects

35
Q

Beta receptor Signaling

A

receptor all signal by increase cAMP/PKA

B1 Primarily in heart (also salivary glands)
B2 receptors in SM, Heart, SKm, mast cells, nerve terminal

B3 small pharmacopeia, found in bladder SKm and fat

36
Q

B1 activation

A

Increase HR, Force of contraction

Increase amylase secretion salivary gland

37
Q

B2 activation

A

Increase HR, force of contraction

Bronchi Dilation

Relax Gi tract, uterus, bladder, seminal tract, ciliary muscle

Mast cell: inhibit histamine release (stop allergic reaction)

SKm: tremor, increase mass, speed of contraction and glycogenolysis

Adrenergic nerve terminal: increase Ne release

38
Q

B3 activation

A

** Bladder detrusor: relax (increase flow) **
SKm: thermogenesis (“burn rate”)
Fat: increase lipolysis and thermogenesis

39
Q

Dopamine Receptor signaling

A

D5R and D1R = Gs ( up cAMP)

D4R, D3R, D2R = Gi (down cAMP

40
Q

D1 receptor activation

A

Increase HR and cardiac output

Improved renal perfusion and urine output in kidney

Can cause arterial vasodilation

41
Q

Dopamine

A

Equal affinity for D1 and D2 receptor

Used for heart failure, shock and unstable bradycardia

42
Q

Fendolpam

A

Hypertensive crisis/hypertension

43
Q

methyldopa

A

increase inhibitory effect of a2

44
Q

Epinephrine (Adrenaline)

A

released from adrenal medulla during excitement/stress

Potent alpha and beta agonist, highest affinity at a2, medium b1, b2 lowest…potent bronchodilator

Releases sugar stored in liver

increase strength of HR muscle contractions, increase HR and BP due to constrictions of blood vessels at higher doses

Lower eye pressure

45
Q

Effect of epinephrine on vascular smooth muscle

A

number of a1> b2 receptors

At low doses, epinephrine selectively stimulates B2 leading to vasodilation (muscle relaxation and decrease in peripheral resistance)

At higher doses, epinephrine can activate a1 leading to vasoconstriction

as conc increase, predominate effect will vasoconstriction

46
Q

Norepinephrine

A

released presynaptically

used to increase BP in hypotensive states

Good to use with anesthetics

Can be given IV,IM or SC but orally ineffective due to GI MAO

47
Q

Dopamine usage

A

activates Dopamine receptors and B1 receptors, at high doses also a1 receptors

positive iontropic and chrontropic effects

At low doses, dilates renal (kidney) and mesenteric (intestinal) arteries via D1 receptors

Vasodilation - vascular D1 receptors respond at low concentration

48
Q

Direct Acting drugs

A

at postsynaptic receptors

Mimic E, NE, DA

49
Q

Indirect Acting drugs

A

blocking the breakdown or reuptake of neurotransmitters, or stimulating production and release of catecholamines

Increase levels of E,NE, DA

50
Q

Fenoldopam (Dopamine receptor analog)

A

D1 partial agonist, no B receptor activity
May have a1 and a2 antagonist activity

Side effect:
Tachycardia, arrhythmias
headache and flushing

Contraindications: patients with asthma may have adverse effect to metabolites; avoid use in glaucoma and in patients on beta-blockers

Indications:
Antihypertensive, decreases cardiac after load

FDA pregnancy/lactation:
Class B

51
Q

Dopamine as drug

A

B1 receptor agonist used in sever congestive heart failure

in low doses, vasodilation, increase sodium secretion

52
Q

Direct-acting a-receptor agonist

A 
Phenylephrine
Oxymetazoline
Methoxamine
Midodrine
Clonidine
Brimonidine
Guanfacine
53
Q

Direct-acting b-receptor agonist

A 
Dobutamine
Terbutaline
Albuterol/levalbuterol
Brimonidine
Salbutamol
Salmeterol
Clenbuterol
Mirabegron
54
Q

Phenylephrine (OTC)

A

Highly selective a1 agonist

Pregnancy class X 1st trimester, C 2nd trimester

Oral decongestant

Can be used in some hemorrhoid treatments

55
Q

Oxymetazoline (OTC)

A

Selective a1 agonist

Intranasal admin, nasal decongestant by vasoconstriction

t1/2 ~ 8hr

Pregnancy class C, potentially B due to low systemic absorption

56
Q

Midodrine

A

Prodrug, forms desglymidodrine (a1 receptor agonist)

** Only FDA approved to treat orthostatic hypotension **

Side effects:
Headache, flushing face (vasodilation), confusion/abnormal thoughts

Pregnancy class X: risk of fetal resorption, decrease fetal weight and increase risk of miscarriage

57
Q

Methoxamine

A

Alpha 1 receptor agonist

Used for BP maintenance during surgery (no b activity)

Contraindicated: patients with hypertension

side effects: Acute nausea/vomiting, headache, anxiety

58
Q

Droxidopa

A

Alpha 1 receptor agonist

Prodrug, converted into NE…it is orally viably available

Orphan drug designation: treat neurogenic orthostatic hypotension (DbH deficiency)

Blackbox warning: monitor supine BP before and during treatment, keep head elevated to prevent risk of hypertension

59
Q

Clonidine

A

** For exam, specific a2 receptor agonist **

Prototypic and classical a2 receptor agonist

FDA approval: Hypertension

Off label use: ADHD, Migraine, Nicotine dependence + withdrawal

Side effects: Drowsiness, orthostatic hypotension, edema and weight gain, rebound hypertension

Abrupt discontinuation can result in withdrawal agitation, headache, tremor, rapid HR

Pregnancy class C

60
Q

Tizanidine

A

a2 receptor agonist

muscle relaxant

Contraindications: benzo, alcohol, buprenorphine

Metabolized via CYP1A2, avoid fluoroquinolone (not cipro), antiarrhythmics, cimetidine, famotidine, acyclovir, oral birth control

Pregnancy class C

** Clinically significant differences may occur when switching between tablets or capsules; once a formulation has been selected, do not alter regimen **

61
Q

Brimonidine

A

A2 agonist

Used for ocular hypertension, open angle glaucoma, red eye

Remove contacts before admin

Side effects: hypertension, contact dermatitis, dry out (xerostomia), allergic conjunctivitis, fainting (syncope)

Alphagan P has a purite preservative, may be better tolerated by those with allergic reactions to other preservatives

62
Q

Apraclonidine

A

Alpha 2 agonist

Prophylatcis postoperative ocular hypertension for cataract and laser eye surgery, adjunct to intraocular pressure

No concomitant use of MAOIs

Side effects: allergic conjunctivitis, blurred vision, edema of eye lid, reduced visual acuity*

63
Q

Dobutamine

A

B1 selective, prototype B1 agonist

Chronotropic (HR) and inotropic (CO) actions without vasodilation

Used to treat hear failure and cardiogenic shock (ventricles stop working)

Off label: toxic shock syndrome, septic shock, pulmonary embolism shock

only given IV

Side effects: cardiac dysrhythmia, coronary arteriosclerosis, syncope, dyspnea

64
Q

Albuterol (salbutamol) ProAir/Ventolin

A

Prototypic B2 agonist

Fast-acting bronchodilator

Used for asthma, exercise asthma, COPD, premature infant respiratory distress syndrome

Pregnancy class: assume C

Caution in patients with Cardiovascular disorders, arrhythmias, hypertension, lactose intolerance

65
Q

Salmeterol

A

B2 agonist

Used in Asthma, COPD, Nocturnal asthma

Contraindicated for use in patients with cardiac disorders

Causes prolonged QT interval, can cause headache and musculoskeletal pain

FDA black box warning: long acting B agonist increase risk of asthma related death when used as monotherapy; pediatric population is at increased risk for hospitalization

66
Q

Terbutaline

A

IV B2 agonist, used to delay preterm labor in serious situations, PO should not be used to delay preterm labor

Contraindicated for use in patients with cardiac disorders and pulmonary edema

67
Q

Clenbuterol

A

b2 agonist

Used in sports due to “anabolic” attempt to increase muscle strength, those with asthma shouldn’t use this med

68
Q

Mirabegron

A

B3 agonist, prototypic

Used for Bladder muscle dysfunction, overactive

contraindicated patients with hypertension

side effects: nasopharyngitis, urinary tract infection, headache, constipation, diarrhea, and tachycardia

Inhibits CYP2D6, avoid drugs metabolized by this pathway

69
Q

Drugs that release NE

A

Tyramine
Amphetamine
Methylphenidate

70
Q

Drugs that inhibit release NE

A

Reserpine

Guanethidine

71
Q

Drugs affecting NE uptake

A

Duloxetine (NET blocker)
Lisdexamfetamine (NET blocker)
Imipramine (NET blocker)
Cocaine (DAT/NET Blocker)

72
Q

Amphetamine

A

Prototype

NE release, MAO inhibitor, NET inhibitor, CNS stimulant

Usage: narcolepsy, paradoxical benefits in children with ADHD

Abused as appetite suppression, drug of abuse

Side effects: tachycardia, hypertension, insomnia, acute psychosis with OD, can cause dependence

Well absorbed GI and cross BBB

Pregnancy Class: C

73
Q

Methylphenidate

A

Amphetamine variants

Used as ADHD med with similar mechanism as amphetamine

74
Q

Tyramine

A

product of tyrosine metabolism

cannot cross BBB

releases catecholamines

Found in cheese, cured meats, beer, fermented foods, critical interaction with MAOI

75
Q

Duloxetine

A

SSNRI

Clinical uses: Major depression disorder, fibromyalgia, neuropathic pain, generalized anxiety disorder (off label: appetite suppressant**)

Side effects: Nausea, dry mouth, constipation, fatigue, decreased appetite

76
Q

Imipramine

A

Pro drug, into desmethylimipramine

Blocks neuronal NET, also classified as TCA

Clinical use: Depression, IBS

Side effects: Atropine like effects (anti-slud), cardiac dysrhythmias in OD

77
Q

Lisdexamfetamine

A

Prodrug of dextroamphetamine

Mechanism and side effects: similar to amphetamine

Clinical uses: ADHD

Inhibition of CYP2D6, CYP1A2, CYP3A4, considerations for drug interactions

78
Q

Cocaine

A

inhibits NET by acting as substrate

Rarely used local anesthetic, maybe during ophthalmic procedures

Commonly abused

79
Q

Methyldopa

A

Treatment of hypertension during pregnancy (a2 action), orphan drug in Type 1 diabetes (off label pediatric use); hot sweats during menopause

Do not use with MAOI or populations with liver disorders

Common side effects: 20% patients ED, disordered ejaculations, dizziness

Serious side effects: colitis, Congestive Heart Failure, jaundice or Parkinsonism

80
Q

Reserpine

A

At v low conc blocks NE transport and VMAT, causing accumulation and degradation by MAO

Used to be used as antihypertensive, currently used only experimentally..still used in combo with hydrochlorothiazide

DO NOT prescribe to patients with active peptic ulcers, history of depression

Side effects: GI, Neurolgoic, psychiatric and congestion

Serious side effects: atrial fibrillation, cardiac dysrhythmia, GI hemorrhage

81
Q

Guanethidine

A

inhibit release of NE from nerve terminals, and accumulates in VMAT displacing adrenaline and preventing release

Abolish response of nerves to sympathetic nerve activation

Previously used as hypertensive

Severe Side effects: lost of sympathetic nerve reflexes, postural hypotension, diarrhea, nasal congestion and inhibition of ejaculation

82
Q

Ephedrine

A

Mixed sympathomimetics

used as decongestant, appetite suppressant, and treat hypotension associated wit anesthesia (hypothermia due to anesthetic with caesarean and spinal injury)

side effects: hypertension, palpitations, tachycardia, nausea, vomiting, dizziness and reslessness

Monitor renal function in at risk populations (elderly, renal impairment)

Commonly abused athletics

83
Q

Pseudoephedrine

A

1/4 potent as ephedrine

counsel patients purchasing to monitor blood pressure

commonly used as decongestion

No concurrent admin with MAOI

side effect: anxiety, restlessness, atrial fibrillation, myocardial infarction, insomnia

Pharmacology and Medical Chemistry I (30 decks)

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