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Pharm Exam 1 > Wakade - Adrenergic Pharmacology III > Flashcards

Wakade - Adrenergic Pharmacology III Flashcards

1
Q

Receptors in the vascular beds of kidneys:
EPI/NE effects
ISO effects

A

Kidney: mostly alpha1 receptors

EPI/NE: vasoconstriction
ISO: slight vasodilation

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2
Q

Skeletal muscle receptors:

Results in:

A

Skeletal Muscle: alpha1 and beta2 receptors

Can result in vasoconstriction or vasodilation, depending on the sympathomimetic amine used and its concentration

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3
Q

Skeletal muscles:

NE and PE: only act on

Effect of concentration of EPI

A

NE and PE: only act on alpha1 R –> only cause VASOCONSTRICTION

EPI gives vasodilation at lower concentrations, but vasoconstriction at higher concentrations.

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4
Q

Effects of ISO on skeletal muscle vasculature

A

Over wide range of ISO there is only vasodilation (beta2).

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5
Q

Attraction of EPI to alpha and beta receptors in skeletal muscle vasculature.

Effects

A

Apparently EPI has higher affinity for beta-than for alpha-receptors here, but as beta receptors become “saturated” at higher concentrations of agonist, action mediated by alpha-receptors dominate and results in vasoconstriction.

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6
Q

Receptors types in liver and splanchnic areas:

Effects of low vs high EPI:

A

Liver and Splanchnic Area: alpha1 receptors (and a small beta R component)

Low [EPI]: some vasodilation

Higher [EPI]/NE: good vasoconstriction

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7
Q

Coronaries:

Type of receptors:

NE/EPI/ISO effects:

Important Point

What does increased stimulation of the heart cause?

A

Coronaries: beta2 receptors

NE/EPI/ISO: dilation of blood vessels (partly due to action on beta2 R)

Important Point: dilation of the coronaries by these amines only PARTLY due to action on beta2 receptors

When heart is stimulated (ie. exercise), increased mechanical activity causes vasodilation by action of ADENOSINE on smooth muscle

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8
Q

Pulmonary Circulation: type of receptors

Effects of EPI/NE

A

o Pulmonary Circulation: alpha and beta receptors are both dominant
 EPI/NE: some vasoconstriction, but weak compared to that in other organs

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9
Q

Vascular beds of the pancreas:

Receptor types in alpha cells:
Beta cells:

A

Alpha cells: betaR –> stimulation of secretion of glucagon

Beta cells: alphaR –> inhibition of insulin secretion

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10
Q

Low [EPI] effects on blood pressure:

Systolic effects
Diastolic effects
Change in blood pressure

A

Systolic increase: due to increase in CO
- CO increase: due to ↑ venous return + ↑ force of contraction

Diastolic decrease: decrease in TPR
- TPR decrease: beta2 activation  vasodilation in skeletal muscles

Mean BP: small increase or no change

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11
Q

High NE/[EPI] effects on blood pressure:

Systolic effects
Diastolic effects
Change in CO
Eventually what happens? 
- Give atropine:
- Cut vagus
A

Systolic increase: due to ↑ TPR and ↑ force of contraction

Diastolic increase: ↑TPR
o TPR increase: alpha1 activation –> vasoconstriction in skeletal muscle

CO: only slightly changed or even decreased (HR not increased for long)
o Initial ↑ in HR (stimulation of pacemaker cells by NE)

Eventually, vagus stimulation –> release of ACh –> ↓HR

  • Give atropine (AChR blocker): no decrease in HR
  • Cut vagus: no decrease in HR
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12
Q

Isoprenaline (ISO) effects on blood pressure:

Systolic effects
Diastolic effects
TPR effects
If vasodilation is too extreme:
Effect on mean BP
A

Some systolic increase: due to ↑ force of contraction (beta1 stimulation of heart)

Large diastolic decrease: due to ↓ TPR

TPR decrease: beta2 activation –> vasodilation in skeletal muscle

Important point: if vasodilation is too extreme, blood may pool in capacitance vessels and ↓ venous return –> ↓ CO

Mean BP: decreased

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13
Q

Broncial smooth muscles:
Receptor types:
How to bronchodilate:

A

Bronchial: beta2 receptors

Bronchodilation: use of agonists in asthma

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14
Q

Iris Radial Muscle smooth muscles:
Receptor types:
How to contract radial smooth muscles:

A

Iris Radial Muscle: alpha1 receptors

Contraction of radial smooth muscles: mydriasis (dilation of pupil)

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15
Q

GI tract smooth muscles:
Receptor types:
Causes:
Exception:

A

GI Tract: alpha1 and beta2 receptors (both cause inhibition*)

Both cause relaxation

Activation of alpha1 R causes hyperpolarizaion –> prevents APs from firing

Exception: sphincters (stimulation of alpha1 R causes contraction)

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16
Q

Bladder smooth muscles:
Receptor types:
What is dominant in detrusor?
What is dominant in trigone?

A

Bladder: beta2 and alpha1 receptors

Beta2 R: dominant in detrusor muscle –> activation causes RELAXATION

Alpha1 R: located in trigone region –> activation causes CONTRACTION

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17
Q

Uterus:
Receptor types:

NE stimulates:

EPI stimulates:

Specific beta2 agonists:

A

Uterus: alpha1 and beta2 R

NE: stimulates contractions

EPI: biphasic effects

Specific beta2 agonists: cause relaxation (used in delaying premature labor)

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18
Q

Spleen:
Receptor types:
Contraction results in:

A

Spleen: alpha1 receptors

Contraction: results in blood expulsion

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19
Q

Vas Deferens and seminal vesicles:

Receptor types:
Contraction results in:

A

o Vas Deferens and Seminal Vesicles: alpha1 receptors

Contraction: alpha1 activation causes membrane depolarization and generation of AP –> expelling of contents

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20
Q

Metabolic effects of Beta-R Activation

A

Beta R Activation: in ALL tissues discussed, activation associated with an ↑ in synthesis of cAMP

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21
Q

Beta R Activation

Results in: (4)

A

 Hyperglycemia
 Hyperlactemia
 Increase in free fatty acids
 Overall increase in calorigenic effect

22
Q

Beta R Activation

Increase in cAMP leads to activation of: (2)

A

Increase in cAMP leads to activation of protein kinases, which:

Activate lipases (break down triglycerides to glycerol and FFAs, which can enter the Kreb’s cycle to increase production of ATP)

Activate phosphorylases (help break down glycogen to glucose to form ATP)

23
Q

Direct Acting Sympathomimetic Amines (NE/EPI) and the BBB:

A

Do NOT CROSS the BBB readily

24
Q

CNS effects of EPI: (3 manifestations)

A

EPI: when given systemically, may cause CNS manifestations

  • Respiratory stimulation (or apnea of BP rises rapidly)
  • Restlessness
  • Anxiety
25
Q

CNS effects of NE

A

NE: may also produce the same CNS manifestations as EPI, but to a LESSER degree

Note: not clear if these effects result from action in the CNS or as the indirect result of systemic effects

26
Q

Effects of Adrenergic Neurons in the Brain:

Neurons containing NE located in:

A

Adrenergic Neurons in the Brain:

Neurons containing NE located in locus cereleus

Presence of adrenergic receptors and NET have also been confirmed

27
Q

Role of Adrenergic Transmission in the Brain: many possibilities, including the following: (4)

A

 Modulating mood
 Sleep-wake cycle
 Motivation
 Pain

28
Q

INDIRECT ACTING SYMPATHOMIMETIC DRUGS:

General:
Indirect acting agents: (4)

Mechanism:
Stimulate what?
Cause release of NE from:
Ca req?
DBH?
A

Indirect Acting Agents:
o Phenylethylamines: tyramine, amphetamine and ephedrine
o Dopamine: recall indirect effects

Mechanism:
o Do not directly stimulate adrenergic receptors
o Cause release of NE from SS neurons via a non-exocytotic process (diffuses out)
 Ca++ not required
 DBH and other synaptic vesicle contents not released along with it

29
Q

Tyramine:

Effects;

Mechanisms:

Source:

Issue with MAO-Is

BBB

A

Effects: dose-dependent increase in BP, HR and other effects mimicking NE (last several minutes)

Mechanism:
o Tyramine enters adrenergic neurons via NET
o Enters synaptic vesicles in nerve terminal and displaces NE –> Diffuses out of nerves
o Delays oxidation of NE by MAO (also a substrate for it) –> Also causes diffusion out of nerves

Source:
o Occurs naturally in aged cheeses and wines (product of decarboxylation of tyrosine)
- Normal Metabolism of Tyramine:
o Ingested into gut –> Oxidized by MAO in the gut mucosa and liver

Issue with MAO Inhibitor Drugs:
o Tyramine taken in orally –> Not oxidized in the gut –> Effects potentiated and large amounts of NE released –> Hypertensive crisis

Does NOT cross the BBB*

30
Q

Amphetamine and Ephedrine:

Mechanism/difference from tyramine:

BBB

Duration

A

Mechanism: similar to mechanism to tyramine
o Major Difference: have a high affinity for MAO but are NOT metabolized by it (presumably due to branched chain)
- Ingestion  NOT inactivated in GI tract –> Accumulate in adrenergic nerves

Cross the BBB: produce CNS arousal by releasing NE and/or DA

Duration of Action: several hours

31
Q

Amphetamine and Ephedrine:

Effects: 
on CV and smooth MM:
CNS effects:
Acute overdose:
Chronic overdose:

Tachyphylaxis:

A

CV and Smooth Muscle: similar to NE

CNS Effects: restlessness, tremor, reduction of fatigue, loss of appetite

Acute Overdose:
 CNS: severe confusion and anxiety
 CV: increased BP, angina, cardiac arrhythmias

Chronic Overdose: can produce psychotic behavior

Tachyphylaxis:
o Chronic administration may lead to development of tolerance for some autonomic effects
o Occurs due to gradual depletion of NE stores, resulting in a decrease in the release of NE
 Endogenous stores being depleted with no chance to regenerate

32
Q

Difference Between Amphetamine and Ephedrine:

A

Very similar, except ephedrine also has minor direct agonist effects on adrenergic receptors

Ephedrine is no longer used in the US

Former use: management of asthma and to dilate pupils

Pseudoephedrine: isomer that is used as an OTC decongestant

33
Q

Antihypertensive Agents:
- General:

Most important use:
Interferes with:
Lower SS tone:

A

Most important use of adrenergic drugs in the management of high blood pressure disease

Interfere with sympathetic neurotransmission at different steps

Reduce release/action of NE to lower SS tone in vascular smooth muscle and heart

Actions lead to fall in BP

34
Q

Alpha-Methyl Tyrosine:

Historical use:

Mech:

former uses:

Side Effects:

A

Historical importance only: no longer used

Mechanism: specific inhibitor of tyrosine hydroxylase enzyme

Former Uses: pheochromocytoma (catecholamine releasing tumor of chromaffin cells) prior to removal of tumor

Side Effects: had to use extremely high doses that crystallized in the kidney tubules, causing damage

35
Q

Adrenergic receptors responsible for inducing mydriasis are:

A

alpha 1

36
Q 
Which one of the following ranks of order of potencies of adrenergic drugs in the heart is correct
A. EPI>NE>ISO>>PE 
B. NE>>PE>ISO>EPI
C. ISO> EPI>>PE>NE
D. ISO>EPI>NE>>PE
A

C. ISO> EPI»PE>NE

37
Q 
Which one of the following compounds will NOT produce increase in force of contraction of the
heart in a heart–transplanted patient.
A. NE 
B. EPI 
C. Tyramine 
D. ISO 
E. excess cAMP ( cell permiable form)
A

C. Tyramine

38
Q 
Which types of adrenergic receptors are associated with inhibition or relaxation of intestinal
smooth muscle?
A. Beta1 
B. Beta2 
C. Alpha1 
D. Alpha2 
E. Alpha1 plus Beta2
A

E. Alpha1 plus Beta2

39
Q

Reserpine:

Mech:

Other effects:

A

Mechanism:

Progressive loss of tissue NE stores by influencing NE storage:

Reserpine irreversibly blocks the vesicular monoamine transporter (VMAT)

Blocks NE carrier of synaptic vesicles (blocks NE transport and permits NE to accumulate in cyosol where it is metabolized by MAO)

May block DA transport into synaptic vesicles, impairing the synthesis of NE in the ANS and depleting DA from the brain

Other Effects:
 Depletes 5HT from serotonergic neurons
 Depletes histamine from platelets

40
Q

Reserpine:

Effects:
Duration:
Use:
SEs:

A

Effects: most pronounced in neurons that are very active

Duration: irreversible (can persist for longer than 1 week after the last dose)

Use: one of first drugs for essential hypertension

Although rarely used, some doctors will still use it in low combinations with a diuretic for the treatment of HTN

Side Effects: PS function not impaired, so SE profile can be predicted
 Miosis
 Hypersecretion (salivation, gastric secretions etc.)
 Hyperperistalsis and diarrhea
 Bradycardia and hypotension
 Severe emotional depression in tremors (CNS effects)

41
Q

Guanethidine:

Mechanism:
blocks
taken up by
method of exocytosis

Chronic use:

Use:

A

Mechanism: blocks exocytosis of NE vesicles
 Taken up by NET transporter
 Method of exocytosis block unclear (does not interfere with Ca++)

Chronic Use: can lead to reduced NE storage similar to reserpine

Use: formerly used for management of severe essential HTN
 Lowered BP, HR and renin secretion
 Similar SE profile to reserpine with marked postural hypotension
 No longer used in the US

42
Q

Guanethidine has 3 distinct pharmacological actions in adrenergic synapse:

A
  1. Enters sympathetic
    neurons and blocks transmission (acute).
  2. Blocks NE membrane transporter, NET (acute).
    3.Reduces NE stores (chronic).
43
Q

Clonidine:

Mechanism:
Acts on:

Use:

A

Mechanism: highly specific agonist of alpha 2 receptors

Acts on presynptic alpha2 receptors to decrease SS outflow

Also acts on imidazoline R to decrease SS outflow (activation in rostral ventrolateral medulla causes reduction in SS outflow to periphery)

Use:
 Essential HTN
 Diarrhea (?)- asked on discussion board
 Diabetic neuropathy
 Narcotic and alcohol withdrawal (analgesic effects)
 Quit smoking
 Reduce menopausal hot flashes

44
Q 
Comparison of receptor binding with:
Clonidine
Alpha-methyl NE
NE
phenylephrine
A

clonidine (alpha 2 receptors) > alpha- methyl- NE> NE> >&raquo_space; phenylephrine (alpha 1 receptors)

45
Q

Clonidine:

Side effects:
Sudden withdrawal:

A

o Side Effects:
Common: dizziness, nausea, impotence, dry mouth

Sudden Withdrawal: can be life-threatening
Over-activity of SNS causing a hypertensive crisis
Symptoms include nervousness, headache, tachycardia, HTN, sweating etc.

46
Q

Clonidine Related Agents and Their Uses:

A

Apraclonidine and Brimonidine: reduce intraocular pressure (glaucoma)

Dexmedetomidine and Tizanidine: analgesic effects and help in withdrawal symptoms from addictive drugs and alcohol

Other alpha 2 agonists: Treat HTN, ADHD and PTSD

47
Q

Methyldopa:

Enters CNS and is metabolized as:
Binds:

Alpha-CH3-NE is stored in:

interaction with imidazoline-R:

Overall effect:

Use:

A

Mechanism: similar to clonidine

Alpha- CH3 - DOPA—-> Alpha –CH3- DOPAmine–> Alpha- CH3- NE—> Binds Alpha 2 receptors

Alpha-CH3-NE stored in adrenergic neurons and released the same way NE is, but due to its high affinity for alpha2 receptors, will bind them and cause a reduction in SS activity

Unlike clonidine, has poor activity at imidazoline R

Overall Effect: reduce SS nerve impulse activity originating in the area of the nucleus tractus solitarus of the medulla by activation of these alpha2 receptors
- Also reduces renal vascular resistance

Use: hypertension

48
Q

TCAs

A

imipramine, desipramine, amitryptyline

49
Q

Imipramine and Desipramine

Block:
Enhance:
Desipramine is the most potent inhibitor of:

A

Imipramine and Desipramine: block neuronal membrane transport (NET) and ENHANCE action of NE

Desipramine is the most potent inhibitor of NET; also a weak inhibitor of 5HT transporter

50
Q

Amitryptyline:

A

Inhibits transport of both 5HT and NE equally well (20x less potent than desipramine)

51
Q

Cocaine:

Mechs
Low concentrations:

High concentrations:

A

Low Concentrations: reversibly binds to NET in CNS and periphery to block uptake of NE and EPI  Marked enhancement in responses of NE and EPI

High Concentrations: local anesthetic actions (blocks conduction of nerve impulses)

52
Q

Amphetamines:

Use:

Acute overdose:

A

Narcolepsy

ADHD (Methamphetimine/Ritalin, dextroamphetime/Dexedrine, Adderall)

Effects: causes CNS arousal and suppresses appetite and sleep

Acute overdoses produce severe confusion and anxiety, elevated B.P., angina, cardiac arrhythmia and other adrenergic effects.

Pharm Exam 1 (23 decks)

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