Week 3: muscarinic blockers, Ach release inhibitors, sympathomimetics, sympatholytics, adrenergic blockers Flashcards

1
Q

Describe the mechanism of action as well as physiologic actions of atropine

A
  • Atropine is a muscarinic blocker, binds to all 5 types of muscarinic receptors
  • competitive: competes with muscarinic agonist for receptor
  • blocks parasympathetics
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2
Q

List the signs and symptoms of muscarinic blocker overdose

A
  • loss of light reflex -mydriasis
  • difficulty reading-loss of accommodation for near vision vision
  • inhibits salivary secretion: dry mouth
  • inhibits bronchial secretion
  • dilates bronchial relaxation
  • tachycardia
  • inhibits sweat glands: heat stroke
  • CNS actions increase heat set point and cause hallucinations
  • constipation
  • difficulty urinating
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3
Q

Describe a drug and mechanism of action for ameliorating the CNS effects of toxic doses of atropine

A
  • usually no antidote needed, metabolized by liver (t1/2=4 hours)
  • can give cholinesterase inhibitor that crosses BBB so that Ach builds up and can compete with atropine for binding sites
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4
Q

Comare and contrast the actions of botulinum toxin with the actions of atropine

A

Atropine:
-has mydriasis, dry mouth, hyperthermia leading to death
-no skeletal muscle weakness
Botulism:
-Has mydriasis, dry mouth, death by respiratory paralysis, and skeletal muscle weakness
(botulism inhibits Ach release from parasympathetic and motor nerves)

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5
Q

Do muscarinic antagonists increase bp?

A

-yes, indirectly by increasing heart rate–>increases cardiac output–>increase in bp

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6
Q

What is potentiation?

A

When the pharmacological effect is greater than the sum of the action of each drug

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7
Q

What is summation?

A

when the pharmacological effect is equal to the sum of the action of each of the drugs

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8
Q

Compare and contrast the actions of non-depolarizing and depolarizing neuromuscular blockers

A
  • non depolarizing: Binds to nicotonic receptors in neuromuscular junction and blocks Ach binding (antagonist). Zero intrinsic activity.
  • depolarizing: activates muscle cells, depolarizing cell so that no further stimulation will activate muscle contraction (agonist)
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9
Q

Compare and contrast the actions of cholinesterase inhibitors on non depolarizing and depolarizing neuromuscular blockers

A
  • non depolarizing: can treat with cholinesterase inhibitor if overdose. The ChE inhibitor will increase Ach to be able to compete with the non depolarizing neuromuscular blocker (tubocurarine) for nicotinic receptor binding sites
  • depolarizing: succinylcholine is broken down by ChE, so adding an ChE inhibitor will prolong the effect of succinylcholine
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10
Q

Compare and contrast the actions of quaternary and tertiary amines as cholinesterase inhibitors and action on the nicotinic receptors

A
  • tertiary: can cross BBB, only have cholinesterase blocking actions, no agonist actions by binding to nicotinic receptors
  • quarternary: cholinesterase inhibitor and agonist of nicotinic receptors–>potentiates increasing concentrations of Ach and reverse effect of tubocurarine more quickly
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11
Q

What are neuromuscular blockers used for? list examples of neuromuscular blockers.

A

-skeletal muscle relaxation for surgical procedures
-facilitate endotrachial intubation
Non depolarizing: tubocurarine
depolarizing: succinylcholine
-they work at the skeletal muscle end plate

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12
Q

Describe the actions of a direct acting sympathomimetic.

A
  • combine with receptors on target tissues and exert an effect
  • drugs are similar in structure to epinephrine and norepineprhine
  • bind to specific receptors: a1, a2, b1, b2, b3.
  • activation of b receptors stimulates adenyl cyclase, activation of a1 copied with 2nd messenger, activation of a2 inhibits adenyl cyclase
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13
Q

what are the possible mechanisms that are used by indirect acting sympathomimetics?

A
  1. stimulate release of norepineprhine
  2. block vesicular monoamine transporter (VMAT)-trasports NE that has been taken back into the neuron into the secretion granule
    - vesicle is depleted of NE (indirect symp antagonist)
  3. Block reuptake of norepineprine into cell by norepinephrine transporter (NET). NE stays in synapse and continues to be available.
  4. block metabolism of enzyme that metabolizes NE (e.g. MAO)
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14
Q

What physiologic actions occur when activating alpha 1? Name a specific drug that is specific for this receptor.

A
  • constriction of arteries and veins
  • dilation of pupil of eye
    e. g. Phenylephrine-specific alpha 1 agonist, used for nasal decongestion. Alpha 1 agonist also used to induce mydriasis and for hypotension
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15
Q

What physiologic actions occur when activating alpha 2? Name a specific drug that is specific for this receptor.

A
  • on presynaptic terminals
  • inhibit release of norepinephrine
  • ->results in inhibition of sympathetic effect
    e. g. clonidine
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16
Q

What physiologic actions occur when activating beta 1? Name a specific drug that is specific for this receptor.

A
  • located in the heart
  • can bind to SA node and stimulate rate of contractions (positive chronotropic effect)
  • stimulates positive inotropic (stronger contraction) effect
  • e.g. Dobutamine
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17
Q

What physiologic actions occur when activating beta 2? Name a specific drug that is specific for this receptor.

A
  • cause vasodilation and bronchodilation
  • e.g. albuterol
  • skeletal muscle vasculature only contains beta 2, most other vascular beds have a1 and b2
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18
Q

What receptors does norepinephrine bind to? What effect does this have? What is the effect on cardiac reflex?

A
  • a1 and b1 receptors. Minimal affinity for b2.
  • a1: vasoconstriction–>increase peripheral resistance–>increase diastolic bp
  • b1: increase force of contraction and rate of contraction–>increase systolic pressure
  • overall effect: increase in mean bp
  • cardiac reflex: decrease in hr
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19
Q

What receptors does isoproterenol bind to? What effect does this have? What is the effect on cardiac reflex?

A
  • b1, b2
  • b1: increase force and rate of contraction–>increase systolic pressure
  • b2: vasodilation and bronchodilation–>decrease peripheral resistance–>decrease diastolic pressure (more so than epinephrine since no opposing a1)
  • overall: drop in bp, increase in hr (b1)
  • cardiac reflex: increase in hr
20
Q

What receptors does epinephrine bind to? What effect does this have? What is the effect on cardiac reflex?

A

-a1, b1, b2
-a1: vasoconstriction
-b1: increase force and rate of contraction
-b2: vasodilation and bronchodilation
low dose: b2>a1
high dose: a1>b2
-overall: at low dose, vasodilation is greater than vasoconstriction, there is a drop in bp and increase in hr
-cardiac reflex: mean pressure is the same, increase in systolic pressure from b1 and decrease in diastolic pressure from b2. No cardiac reflex

21
Q

What physiologic actions occur when activating dopamine (D1) receptor?

A
  • receptor in renal, coronary, and cerebral vascular beds.
  • activation stimulates vasodilation and is effective in treating hypertension
    e. g. fenoldopam at low doses
22
Q

What is the mechanism of action of cocaine and what are the effects?

A
  • blocks uptake of NE and dopamine from synapse back to presynaptic nerve via NET transporter
  • ->NE accumulation in synapse
  • symptoms: mydriasis, tachycardia, elevated bp, vasoconstriction induced hyperthermia
23
Q

What is the mechanism of action of amphetamines and what are the effects?

A
  • block uptake 1 (NET transporter) and reverses it
  • stimulate release of NE from nerve terminal
  • ->increase of NE
    e. g. ephedrine and pseudoephedrine
  • vasoconstriction of vessels and reduce congestion
24
Q

What is the mechanism of action of tyramine and what are the effects?

A
  • tyramine is metabolic product of tyrosine, in wine and cheese
  • taken up by synaptic vessels and displaces NE from the vessels
25
Q

What is the mechanism of action of reserpine and what are the effects?

A
  • blocks VMAT uptake of NE and dopamine (VMAT takes free NE and puts it in synaptic vesicles)
  • reduces amount of NE available to secrete
  • anti-hypertensive
26
Q

List the drug names of direct acting sympathomimetics and the receptor that they bind to.

A
  1. phenylephrine - a1
  2. clonidine - a2
  3. dobutamine - b1
  4. albuterol -b2
  5. isoproterenol -b1, b2 agonist
27
Q

List the drug names of indirect acting sympathomimetics and their mechanism of action.

A
  1. amphetamines, cocaine - uptake 1 inhibitor
  2. tyramine -NE displacement from vesicles
  3. reserpine - VMAT blocker
28
Q

What are sympatholytics?

A
  • drugs that inhibit sympathetic neurotransmission

- Examples: adrenergic blocking agents, false neurotransmitter, inhibition of NE synthesis, blocking uptake 1

29
Q

How does a false neurotransmitter reduce sympathetic activity?

A

Methyl DOPA

  1. taken up by neuron and converted to methylnorepinephrine
  2. methylnorepinephrine taken up in vesicle and secreted into synapse
  3. methyl-NE has high affinity for a2 receptors
  4. activation of a2 inhibit release of NE
    - no longer used, instead have:
    clonidine: directly activates a2
30
Q

How does methyl tyrosine inhibit NE synthesis?

A
  • inhibits tyrosine hydroxylase so that tyrosine can’t be converted to L-DOPA
  • stops production of NE
31
Q

How does blocking uptake 1 NET transporter reduce sympathetic activity?

A
  • drug is taken up into synaptic vesicle, blocks reuptake of NE.
  • drug is secreted into synapse but has not binding affinity for adrenergic receptors
32
Q

How does blocking VMAT transporter reduce sympathetic activity?

A
  • Reserpine
  • blocks transport of all monoamines into synaptic vesicles (NE, dopamine, etc)
  • depletes vesicles of NE
33
Q

Compare the actions of competitive and noncompetitive blocking agents with regard to max response and shifting the dose vs effect curve to the right

A
  • Competitive adrenergic blockers: bind to adrenergic receptors and compete with agonists. Right shift to curve. No change in max response.
  • Non-competitive: depression of max response without shift parallel shift to right
34
Q

What is the effect of a1 adrenergic blockers on cardiovascular fxn when sympathetic tone is low vs. high?

A
  • low sympathetic tone: only slight effect of a1 blocker, minimally lowers bp
  • high sympathetic tone: much greater drop in bp
    e. g. prazosin -also used for prostate hyperplasia to relax smooth muscle and increase urine flow
35
Q

What is phenoxybenzamine used for?

A
  • long lasting selective a1 blocker, irreversible
  • treat pheochromocytoma (hyperplasia of adrenal medulla)
  • works well in severe hypertension
36
Q

What is phentoalamine used for?

A
  • short acting, non selective alpha blocker

- used to be used to treat erectile dysfunction

37
Q

What is yohimbine used for?

A
  • selective a2 blocker.

- was once used to treat impotence

38
Q

What are the effects of b1 selective blockers on the cardiovascular system? What are examples of drugs of this type?

A
  • blood pressure and heart rate decrease, no reflex tachycardia since chronotropic action blocked
    e. g. atenolol and metoprolol
  • used for hypertension, supra ventricular arrhythmias and angina pectoris
39
Q

What is an example of a broad spectrum beta blocker? (b1=b2). What are the effects?

A
  • propanolol
  • b1 blocker: slows heart rate and contraction strength
  • b2 blocker: blocks bronchodilation, increases resistance in bronchial tubes=bronchoconstriction
  • to treat angina, cardiac arrhythmias, and hypertension
40
Q

What is labetolol and what are its effects?

A
  • selective a1 blocker, and b1,b2 blocker
  • a1: blocks vasoconstriction
  • b1: blocks increase in contraction rate and strength
  • b2: blocks vasodilation
  • used for hypertension and hypertensive emergencies
41
Q

What are catecholamines synthesized from? Where is the pre-cursor molecules from?

A
  • synthesized from tyrosine
  • phenylalanine–>tyrosine by phenylananine hydroxyls (availability controlled by liver)
  • mutations in this enzyme lead to phenylketones building up=neurotoxins=PKU disease
  • tyrosine also from high protein foods
42
Q

What is the first step in catecholamine synthesis?

A

Tyrosine–>L-DOPA (dihydrophenylananine)

  • via Tyrosine hydroxylase (TH)
  • rate limiting step
  • TH inhibited by alpha-methyl-tyrosine and lead
43
Q

How is TH activity regulated in L-DOPA biosynthesis?

A
  • short term: phosphorylation (increase activity) and dephosphophorylation
  • Long term: transcriptional regulation by neurotransmitters, hormones, caffeine, nicotine
44
Q

What enzyme converts DOPA to dopamine (DA)? What converts dopamine to NE? What converts NE to epinephrine?

A

DOPA decarboxylase, aromatic acid, or dihydroxy phenylalanine decarboxylase (AAADC?AADC)

  • Vit B6 is cofactor
  • Dopamine–>NE by dopamine beta-hydroxylase
  • NE–>epinephrine by phenylethylamine-N methyl transferase
45
Q

How are catecholamines broken down?

A
  • monoamine oxidases (MAO): convert amino group to aldehyde
  • followed by aldehyde reductase and aldehyde dehydrogenase that breaks down further to OH and COOH groups
  • 1-Deprenyl is a MAO B inhibitor-increases half life of dopamine and used for treatment of parkinson’s
46
Q

How is smoking related to catecholamine catabolism?

A

-smoking inhibits MAO-B activity-may be important in smoking addiction

47
Q

What are some abnormalities in catecholamine catabolism

A
  1. MAO-A mutation associated with abnormal and violent behavior
    - HVA and MHPG are break down products from catabolism and are indicators of DA and NE activity in the CNS respectively