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Pharm > ANS Pharmacology > Flashcards

ANS Pharmacology Flashcards

1
Q

Autonomic nervous system

A

Smooth muscle
Cardiac muscle
Exocrine glands

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2
Q

Adrenergic receptors

A

Catecholamine

Epi, adrenaline, norepinephrine, noradrenaline

Adrenergic neuron, Adrenergic synapse, Catecholaminergic neuron, Catecholaminergic synapse, Adrenergic receptors
Adrenoreceptors

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3
Q

Cholinergic receptors

A

Acetylcholine

Cholinergic neuron, Cholinergic synapse, Cholinergic receptors

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4
Q

Cardiac response to adrenergic receptors

A

Inc heart rate
Inc contractility/conduction
Inc AV conduction
Inc ventricular contractility

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5
Q

Cardiac response to Cholinergic receptors

A

Dec heart rate
Dec atrial contractility
Dec AV conduction
Dec ventricular contractility

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6
Q

Anatomy of sympathetic nerves

A

Short preganglionic neuron
Long postganglionic neuron

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7
Q

Anatomy of parasympathetic neurons

A

Long preganglionic
Short postganglionic neuron

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8
Q

Anatomy of somatic neuron

A

One neuron

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9
Q

Transmitter at somatic neuron

A

ACh

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10
Q

Transmitter at sympathetic neurons

A

Preganglionic - ACh

Postganglionic - NE
(EXCEPTION —> ACh in sweat glands**)

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11
Q

Sympathetic ONE NEURON system (i.e. exception)

A

Adrenal medulla - direct release of Epi/NorEpi

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12
Q

Transmitter at parasympathetic neurons

A

Preganglionic - ACh
Postganglionic - ACh

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13
Q

Biochemistry of Catecholamine synthesis

A

Synthesis in adrenergic nerve terminals

Rate limiting step: tyrosine hydroxylase

Feedback (end product) inhibition - norepi

Dopamine —> norepi —> (in adrenal) epi

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14
Q

Synthesis of epinephrine

A

In adrenal medulla w/in chromaffin cells (vesicles 80% EPI, 20% norepi)

Whole process occurs in adrenal gland —> same scheme as NorEpi, but final reaction to produce EPI

NE (last step in vesicle) —> EPI conversion in cytoplasm by PNMT (transported back into vesicles for release)

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15
Q

PNMT

A

Not found in nerve terminals

Converts norepi to epi in ADRENAL MEDULLA

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16
Q

Uptake of norepi vs epi

A

Active re-uptake of NE in neurons

Epi NOT re-uptake in adrenal gland

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17
Q

Release of Catecholamines from adrenal gland

A

Stimulation of preganglionic fibers —> release of ACh onto chromaffin cells —> direct release of EPI/NE into blood stream

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18
Q

Mechanism of synaptic transmitter release

A

Nerve depolarizes —> voltage-gated Na/Ca channels open —> Ca dependent vesicle fusion / exocytosis —> diffusion of NT into synaptic cleft —> receptor binding/activation —> NT action termination / metabolism

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19
Q

Transporters at the synapse

A

Vesicular monoamine transporter (brings NE into vesicles)

Presynaptic Autoreceptor (feedback inhibition)

Plasma membrane transporter (re-uptake)

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20
Q

Fate of catecholamines after uptake

A
  • reuptake into vesicles
  • metabolized (MAO, COMT)
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21
Q

Monoamine oxidase (MAO)

A

Norepinephrine in cytoplasm degraded by MAO (in outer membrane of mitocondria in nerve terminal)

Competition between vesicle uptake + MAO degradationi

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22
Q

Catechol-o-methyl transferase (COMT)

A

Located in SYNAPTIC CLEFT
In liver

Metabolizes norepinephrine —> excreted in urine

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23
Q

Receptors for catecholamines

A

7TM Receptor structure (GPCR)

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24
Q

Adrenoceptors

A

Stimulate cardiac ionotropy, vascular muscle contraction, skeletal muscle tremor

Relax urinary bladder muscle, uterine muscle, bronchiole muscle

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25
Q

Drug affinity

A

How tightly a compound binds a receptor

Measured experimentally by a “saturation binding isotherm”

Kd = concentration that compound occupies 50% of receptors at equilibrium

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26
Q

Agonist

A

Ligand that activates receptors

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27
Q

Antagonist

A

Ligands that block activation of receptors by cognate agonist

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28
Q

Efficacy

A

Intrinsic activity of an agonist

maximal amount of system stimulation achievable in presence of saturating concentration of agonist

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29
Q

Potency

A

Described by EC50

Concentration of drug that results in 50% maximum stimulation

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30
Q

“Rank order” of potency

A

Comparison of compounds by their EC50

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31
Q

Partial agonist

A

Does not reach the same maximum response of a full agonist

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32
Q

Potency vs Efficacy

A

Shifted left —> more potent

Shifted up —> more efficacious

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33
Q

How does activation of adrenergic receptors have different effects in different tissues?

A
  1. Relative affinity/potency of amine in activation of alpha or beta receptors
  2. Density/ratio of receptor type/subtype
  3. Autonomic tone of organ
  4. Reflex that organism makes in response to response to Catecholamine action
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34
Q

Adrenergic receptors in the heart

A

No alpha receptors in atria/ventricles

Beta response —> inc HR, inc conduction velocity, dec refractory period, incr contractility (beta1 receptors)

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35
Q

Cutaneous blood vessel adrenergic receptors

A

No beta receptors

Alpha receptors —> vasoconstriction

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36
Q

Skeletal muscle adrenergic receptors

A

Both alpha and B2 receptors (constriction, dilation, respectively)

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37
Q

Interaction of EPI with B2 and a1 receptors

A

Higher affinity for B2 than a1, but more a1 receptors

At low dose epi: B2 bound - relaxation dominates

At high dose epi: a1 also bound - contraction dominates

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38
Q

Distribution of adrenergic receptors

A

Heart - beta only
Vessels (skeletal muscle) - a + b
Bronchioles - beta only
GI - a + b
Urinary bladder - trigor/sphincter a only
Eye - radial muscle a; ciliary muscle b
Metabolism - beta (O2 consumption, glycogenolysis, lipolysis)

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39
Q

How activation of adrenergic receptors has different effects in tissues

A
  1. Relative affinity/potency of amine in activation of alpha or beta receptors
  2. Density / ratio of receptor type and subtype in organ
  3. Autonomic tone of organ
  4. Reflex (homeostatic adjustment) in response to Catecholamine action
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40
Q

Autonomic tone on blood vessels

A

Sympathetic autonomic tone predominates

Vasoconstriction with norepi —> antagonist causes vasodilation

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41
Q

Arterioles

A

Sympathetic tone

Adrenergic receptors

Vasoconstriction

Block: vasodilation/hypotension

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42
Q

Heart

A

Parasympathetic tone

Cholinergic receptors

Bradycardia (response)

Block: tachycardia

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43
Q

Sweat glands

A

Sympathetic tone

Cholinergic receptors

Response: hidrosis

Block: anhidrosis

44
Q

Administration of beta-blocker to healthy human - effect on heart

A

No significant change

Heart predominated by parasympathetic —> under basal conditions, little NE effect (therefore an antagonist to NE has little effect)

45
Q

Administration of muscarinic anatongist to normal person - effect of atropine (ACh receptor blocker)

A

Increase HR

ACh keeps heart rate down by Cholinergic receptor; administration of antagonist will result in tachycardia

46
Q

Baroreceptor (vagal) reflex

A

Slows the heart and dilates blood vessels to decrease BP

Baroreceptors detect pressure increase and signal compensatory pathways to decrease BP

47
Q

Rank order of potency against alpha adrenergic receptors

A

EPI >= NE > DA&raquo_space; ISO

48
Q

Rand order potency of beta adrenergic receptors

A

ISO > EPI >= NE > DA

49
Q

Isoproterenol

A

Non-selective beta agonist

Beta1 and beta2

50
Q

Low does EPI

A

Beta effects predominate

51
Q

Norepinephrine activity

A

Poor activation of B2

52
Q

Increase HR + force of contraction with no change in vascular resistance

A

Increase BP

53
Q

Vasodilation of blood vessels with no change in cardiac output

A

Decreases BP

54
Q

Response to alpha1

A

Vasoconstriction

55
Q

Response to B1

A

Inc HR, Inc force of contraction, Inc CO

56
Q

Response to B2

A

Vasodilation

57
Q

Low dose Norepinephrine

A

Activates B1 in heart —> ^ HR, FC, CO

Activate a1 in vessels —> vasoconstriction —> ^ peripheral resistance

Vagal reflex —> initial increase in BP —> activates reflex —> decrease HR (via ACh)
*** force of contraction still high bc no effect of ACh on ventricles

58
Q

Low dose epinephrine

A

Activates B1 in heart —> ^ HR, FC, CO

Activates B2 in vessels —> vasodilation —> dec peripheral resistance

No significant increase in BP —> no vagal reflex

^ HR, FC, CO

59
Q

High dose epinephrine

A

Looks like low or high norepi

If concentration high, bind both beta (relaxation) and alpha (contraction) receptors —> overall vasoconstriction

Alpha1 predominate in vasculature —> vasoconstriction

60
Q

Isoproterenol (low or high dose)

A

Activates B1 in heart —> ^ HR, FC, CO

Activates B2 —> vasodilation —> dec peripheral resistance

Mean BP unchanged - no vagal reflex

(Looks like low dose epi)

61
Q

Dopamine

A

Neuro modulator in CNS
Precursor to NE/EPI synthesis

Highest affinity for DA receptors; but some for a1, a2, b1; really low for b2

Low conc —> activates a1,a2,b1
High conc —> activates a1,a2,b1,someb2

Low vs high DA ~ low vs high EPI

62
Q

Low dose dopamine

A

Minimal b1 activation in heart —> ^ HR, FC, CO

No activation of B2
Minimal activation of a1 —> minimal vasoconstriction
Significant D1-mediated vasodilation of mesenteric, renal, coronary vascular bed (peripheral resistance dec)

No vagal reflex

63
Q

High dose EPI

A

Activation of B1 in heart —> ^ HR, FC, CO

Significant activation of a1 —> vasoconstriction / inc peripheral resistance
A1 overcomes D1 mediated vasodilation

Vagal reflex —> dec heart rate

64
Q

Alpha1 adrenergic agonists

A

Phenylephrine (nasal decongestant)
Oxymetazoline
Tetrahydrozoline (eye redness)

No action on heart
Vasoconstriction (a1 on vessels) —> inc peripheral resistance —> vagal response (slows HR)

Long duration (poorly metabolized by MAO, COMT)

65
Q

Alpha2 adrenergic agonists

A

Activation of presynaptic a2 autoreceptor —> dec in NE release from neurons
Activate a2 autoreceptors in CNS —> dec sympathetic outflow to periphery
Stimulate postsynaptic a2 receptors in periphery on VSMC (vascular smooth muscle cell) —> vasoconstriction —> inc BP

Clonidine, xylazine

66
Q

Potential side effect of a2 adrenergic agonists

A

Activation of a2 in certain vascular smooth muscle cell beds —> vasoconstriction —> inc in blood pressure

67
Q

Use of a2 adrenergic agonists

A

Antihypertensive medications (originally nasal decongestant —> but caused hypotension)

68
Q

Clonidine

A

Initial hypertensive effect —> reverses to hypotension (biphasic response)

  • activation of a2 on VSMC > transient hypertensive phase
  • a2 activation in Brainstem > dec in sympathetic tone > dec in BP
  • a2 on peripheral nerves > vascular smooth muscle vasodilation
69
Q

Xylazine

A

Analgesia / sedation

CNS-located a2 receptor-mediated

70
Q

Rebound phenomenon

A

Abrupt withdrawal of medication —> condition even worse that before treatment

Fast withdrawal of a2 agonist > rebound hypertension

Fast withdrawal of a1 agonist > rebound nasal congestion

Continued use > downregulation of receptors > if stop, regular release of NT, but fewer receptors > increased response

71
Q

Nonselective beta adrenergic agonist

A

Isoproterenol

Selective for beta over alpha
Activity b1=b2

Cardiac stimulation - b1
Bronchodilator - b2

72
Q

B1 adrenergic agonist

A

Dobutamine (chiral; d - b1 agonist; l - some a1 agonist)

Increases force of cardiac contraction; minimal impact on HR —> DOES NOT inc O2 demand on heart

Short term treatment of heart failure

73
Q

B2 adrenergic agonists

A

Albuterol, metaproterenol

B2-specific at low dose; increase b1 as increase dose (spillover)

Inc bronchodilation, smooth muscle relaxation

Asthma, prevent premature labor (uterine smooth muscle)

74
Q

B3 adrenergic agonist

A

Treatment of obesity?? - receptors in brown adipose tissue (fat metabolism) - effective in mice, not humans

Overactive bladder treatment (myrbetric)

75
Q

Indirect sympathomimetics

A

Transported into nerve terminals (plasma membrane transporter)

Increase release of endogenous catecholamines

DOES NOT induce release of EPI from adrenal gland (no plasma membrane Catecholamine uptake transporter)

Also bind directly to adrenergic receptors

Tyramine, amphetamines, ephedrine

76
Q

Catecholamine reuptake blockade

A

Cocaine, imipramine, amitryptyline

Competitively block reuptake of NE from synaptic cleft > inc conc/time NE in cleft

77
Q

Ephedrine

A

Sympathomimetic

Release of endogenous NE + direct binding to adrenergic receptors

Not degraded by MAO/COMT > long duration

Inc BP, dec bladder sphincter incompetence, inc bronchodilation

Side effects: hypertension, cardiac arrhythmia

78
Q

Related to ephedrine

A

Phenylephrine
Pseudoephedrine

79
Q

Mechanisms of adrenergic neuron blocking agents

A

Blockade of transmitter release
Vesicular storage blockers
False transmitter release
NE synthesis blockade

80
Q

Guanethidine

A

Accumulates / replaces NE in vesicle, but no transmitter activity; doesn’t cross BBB - no CNS NE effect

Triphasic effect > used as anti-hypertensive

81
Q

Blockade of transit terminal release

A

Guanethidine
Bretylium
Clonidine

82
Q

Bretylium

A

Blocks NE release from terminal (doesn’t accumulate or replace)

DOES NOT cross BBB; no CNS effect

Not affect EPI from adrenal

83
Q

Clonidine

A

A2 agonist > stimulates presynaptic autoinhibitory receptor
Decrease NE release

Antihypertensive

84
Q

Vesicular storage blockers

A

Affect Vesicular transporter (VMAT)

Reserpine

85
Q

Reserpine

A

Vesicular storage blockage

Does NOT require trasnporter

Prevents accumulation of NE in vesicles (blocks uptake of DA/NE into vesicles by VMAT)

Extracytoplasmic NE degraded by MAO > dec amount of NE

Can dec EPI storage in adrenal, but lesser degree

Long acting horse tranquilizer

86
Q

False transmitter release

A

Alpha-methyl-DOPA > taken up and converted to a-methyl-NE

Transporter NOT required

a-methyl-NE > weak/low affinity for a1 receptors —> when release in place of NE, dec activity

May have some a2 activity

Antihypertensive

87
Q

Norepinephrine synthesis inhibition

A

Alpha-CH3-p-tyrosine : blocks tyrosine hydroxylase; depletes NE stores (Try > DA conversion)

NE (end product inhibition)

Disulfiram : blocks BbetaH enzyme (DA > NE conversion)

88
Q

Blockade of Catecholamine metabolism - MAO inhibition

A

Monoamine oxidase inhibitor - pargyline, moclobemide

Inc in NE stored for release
Blocks deg ration of DA/serotonin in CNS

**need to be careful of tyramine (wine/cheese) intake > lack of metabolism by MAO > hypertensive crisis

89
Q

Blockade of Catecholamine metabolism - COMT inhibition

A

Tolcapone

NO clear pharmacological action attribute to COMT blockade

90
Q

Direct adrenergic receptor blockade

A

Antagonists - block binding / action of receptor agonists

91
Q

Uses of alpha-adrenergic receptor blockade

A

Hypertension
Congestive Heart failure
Peripheral vascular disease
Benign prostatic hyperplasia
Shock

92
Q

Irreversible alpha receptor blockers

A

Dibenamine
Phenoxybenzamine

Covalently alkylate receptor
Slow onset, long duration

Recovery requires de novo receptor synthesis

Dec peripheral resistance > hypertension treatment

93
Q

Reversible alpha receptor blockers

A

Phentolamine

Non-selective for a1 / a2
Short acting block

Dec peripheral resistance > treat hypertension

Can illicit cardiac complication (block presynaptic a2 NE release)

94
Q

Selective a1 blocker - prazosin

A

Prazosin
Reversible, specific/selective a1 blocker

Decrease a1 receptor mediated vascular tone

Does NOT inc NE release

Dec BP with no cardiac tachycardia

Hypertension therapy

95
Q

Selective a1 blocker - tamsulosin

A

Reversible postsynaptic a1a blocker

NOT for antihypertensive therapy
Genitourinary tract targeting > improve urination in men with benign prostatic hyperplasia

96
Q

Selective a2 blocker - yohimbine

A

Reversible specific a2 blocker

Inc NE release from nerve terminals, no significant direct effect on smooth muscle

Used for reversal of xylazine-induced sedation/analegsia

97
Q

Side effects of a receptor blockade

A

Postural hypotension
Reflexive tachycardia
Nasal stuffiness
Increased GI motility

98
Q

Therapeutic uses of beta blockers

A

Cardiac arrhythmias
Hypertension
Prophylactic (angina/ischemia)
Anxiolytic
Glaucoma

99
Q

Non-selective b-blockers

A

Propranolol
Pin do lol
Timolol

100
Q

Propranolol

A

Non-selective beta-blocker

Dec HR, contractility, CO

Membrane stabilization effect at high doses (block impulse conduction in cardiac tissue)

Significant withdrawal/rebound —> upregulation of B1 receptors —> if blocker removed, increased activity due to increased receptors

101
Q

Pindolol

A

Non-selective beta blocker

Less membrane stabilization effects

Partial agonist —> less withdrawal, less reduction in HR

High doses can inc HR, BP, cause bronchodilation

102
Q

Timolol

A

Non-selective beta blocker

Less membrane stabilization

Used for wide angle glaucoma

103
Q

Selective B1 blocker

A

Metoprolol

Cardioselective
As potential as propranolol on B1, but 100x less on B2

104
Q

Selective B2 blocker

A

But o amine

Selective for blocking smooth muscle contraction

No pronounced cardiac effects

105
Q

Side effects of beta blockers

A

Cardiac failure
Bradycardia
Bronchial asthma
Diabetics using oral hypoglycemics —> block compensatory mechanism of oral hypoglycemic —> hypoglycemic shock

Pharm (10 decks)

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