Adrenergic Drugs & Immunopharmacology

Question 1

. List the types and subtypes of adrenergic receptors, where they are located, their signal transduction pathways, and the physiological effects they mediate.

Answer 1

Adrenomimetic (sympathomimetic) drugs: mimic catecholamine activity 
o	Mixed acting (nonselective) agonists
o	α1 agonists → Gq
o	α2 agonists → Gi
o	β1 agonists → Gs
o	β2 agonists → Gs

Adrenolytic (sympatholytic) drugs: inhibit catecholamine activity
o Mixed acting (nonselective) antagonists
o α1 agonists antagonists
o α2 agonists antagonists
o β1 agonists antagonists
o β2 agonists antagonists (none used clinically)

Question 2

. Describe the major difference in mechanism between direct and indirect acting sympathomimetic drugs

Answer 2

Direct acting (activate adrenoceptor):
o Alpha agonists
o Beta agonists

Indirect acting (increase concentration of endogenous catecholamine NT in synapse): 
o	Releasers (amphetamine)
o	Reuptake inhibitors (cocaine)

Question 3

List the major endogenous adrenergic agonists and their relative selectivity for adrenergic receptor subtypes.

Answer 3

• Epinephrine: α1, α2, β1, β2
• Norepinephrine: α1, α2, β1
• Dopamine: α1, α2, D

Question 4

. List the major alpha-adrenergic antagonists and their relative selectivity for adrenergic receptor subtypes

Answer 4

o Phenoxybenzamine: α1
o Phentolamine: α1 & α2
o Prazosin: α1
o Tamulosin: α1

Question 5

Explain the mechanistic difference between irreversible and reversible antagonists, e.g.
phenoxybenzamine and prazosin

Answer 5

Irreversible: (phenoxybenzamine) noncompetitive antagonist
o Forms stable covalent bond with α receptors

Reversible (prazosin): competitive antagonist

Question 6

. List the major beta-adrenergic antagonists and their relative selectivity for adrenergic receptor subtypes

Answer 6

o	Atenolol: β1
o	Metroprolol: β1
o	Pindolol (partial agonist) non-selective
o	Propranolol: non-selective
o	Timolol: non-selective

Question 7

Identify steps in the process of chemical neurotransmission that can be interfered with by drugs and give examples of specific drugs that target individual steps.

Answer 7

Presynaptic nerve terminal:
o	Membrane conductivity
o	Transmitter biosynthesis
o	Transmitter storage
o	Transmitter release
Synapse
o	Transmitter reuptake
o	Transmitter metabolism
Post-synaptic cells
o	Post-synaptic receptors

Question 8

Explain the utility of monoamine oxidase inhibitors and the rationale for dietary restrictions when using these drugs

Answer 8

• First class of antidepressants discovered
• Increase monoamine NT activity by inhibiting metabolism of 5-HT, DA, NE
• Effects persist after parent drugs are undetectable in blood
o Must DC 2-3 weeks before giving sympathomimetic drugs
• AVOID tyramine-containing foods with MAOIs
o Can produce hypertensive crisis: HT, tachycardia, severe headache, fever, mydriasis
o Ex. Aged/ fermented foods: wine, beer, sherry, aged cheese, yeast extract, soy sauce, smoked meats, pickled poultry, fermented sausage, over-ripe fruit

Question 9

Describe serotonin syndrome and what conditions may precipitate it

Answer 9

Precipitating drugs:
o	SSRIs
o	2nd generation antidepressants
o	MAOIs
o	Linezolid, tramadol, meperidine, fentanyl, ondansetron, sumatriptan, MDMA, 
o	LSD
o	St. John’s wort
o	Ginseng
Clinical presentation (onset within hours)
o	Hyperthermia
o	Hyperrreflexia
o	Tremor
o	Clonus
o	HT
o	Hyperactive bowel sounds
o	Diarrhea
o	Mydriasis
o	Agitation
o	Coma
Therapy
o	Sedation (benzodiazepines)
o	Paralysis
o	Intubation and ventilation
o	Consider 5-HT block with cyproheptadine or chlorpromazine

Question 10

List the four classes of current immunosuppressive drugs

Answer 10

• Glucocorticoids (prednisone)
• Signal transduction inhibitors (calcineurin inhibitors, proliferation signal inhibitors)
• Purine synthesis inhibitors (azathioprine, mycophenolate, mofetil)
• Immunosuppressive antibodies (muromonab-CD3, basiliximab, adalimumab)

Question 11

List general effects that current immunosuppressive drugs induce

Answer 11

• Inhibit intracellular signaling
• Inhibit costimulation
• Neutralize cytokines
• Inhibit gene expression
• T cell depletion
• Cytotoxic gents
• Inhibit lymphocyte-target interactions

Question 12

Time course for T cell initiated acute rejection process

Answer 12

• Minutes to hours: signal transduction transcription factor activation (NF-AK)
• Hours: cytokine production (IL-2)
• 24 hours: T cell proliferation
• 3-4 days: effector T cell differentiation
• 7 days: allograft rejection reactions