Adrenergics and cholinergics

Question 1

Epinephrine Therapeutics

Answer 1

Therapeutic uses: hypersensitivity reaction (effect on beta 2)
Increase duration of action of local anesthetics (vasoconstriction so not washed out of tissue)
Bradyarrhythmias, opthalmic use on alpha 1 (mydriatic, decrease hemorrhage, conjunctival congestion

Low dose infusion: overall decrease in PVR and diastolic because B2 (dilation of some vascular beds) dilation in skeletal muscle
High dose infusion : then alpha 1 constriction of blood vessels in skeletal muscle
Skeletal muscle has both alpha 1 and beta 2

Question 2

Norepinephrine

Answer 2

Receptor selectivity: alpha 1, alpha 2, beta 1 
CV effects (alpha 1 mainly): increases PVR, mean BP, reflex bradycardia (baroreceptors sense and withdraw symp tone to heart)
Absorption, fate, excretion: not orally effective, short t1/2, parenterally admonished 
Therapeutics: Vasoconstrictor under intensive care situations (shock, hypotension in reduced sympathetic tone), spinal anesthesia/block which blocks tone to blood vessels so NE compensates

Question 3

Dopamine Dosing

Answer 3

CV actions (dose-dependent): 
Low dose (0.5 micrograms/kg/min)- "renal dose"; dilation of renal and mesenteric arteries which decreases PVR and diuresis and urine production (D1 receptor) 
Intermediate dose (5-10 microgram/kg/min)- "cardiac dose"; increases HR, contractile force and cardiac output (D1 + B1 receptor)
High Dose (10-20 ug/kg/min)- "pressor dose"; vasoconstriction and increase PVR (D1 + A1+ B1)

Question 4

Dopamine

Answer 4

Absorption, fate, excretion: similar to Epi; low F so administered IV (parenterally); dose titration to achieve desired effect

Therapeutic uses: severe decompensated heart failure, shock (cardiogenic, septic) and use pressor dose with low BP

Question 5

Isoproterenol

Answer 5

Receptor selectivity- beta 1, beta 2 (group on amine)
CV effects- decreased PVR , increased HR, contractile force, CO, Decreased mean blood pressure (systolic increase and diastolic decrease)
Respiratory effect: bronchodilation
Absorption, fate, excretion: metabolized by COMT, brief duration of action, parenterally administered
Therapeutic uses: emergency use to stimulate heart rate during bradycardia or heart block

Question 6

Dobutamine Structure

Answer 6

Asymmetric carbon-> (-) is alpha 1 and beta agonist, (+) is alpha 1 antagonist and beta agonist
Overall effect of racemic mixture function as beta 1 agonist
Catecholamines and large substitution on amino group so beta selective

Question 7

Dobutamine

Answer 7

CV effects: increased HR, contractility, CO, minimal change in PVR and BP
Absorption, fate, excretion: metabolized rapidly and brief duration of activity, parenterally administered
Therapeutic uses: short term treatment of cardiac decompensation (cardiac surgery, CHF, infarction), cardiac stress testing (if too weak to exercise then this mimics effects of exercise)
Heart failure causes volume overload with high BP so increase CO without affect on blood pressure

Question 8

Albuterol

Answer 8

B2 adrenergic receptor agonist (methyl hydroxyl on ring so not metabolized by COMT)
Administer by inhalation or orally
Short acting and rapid onset (gone 2-4 hours after inhalation)
Therapeutic use: rapid onset bronchi constriction
Adverse effects: tremor, anxiety, tachycardia (into systemic circulation and activate other beta 1 receptors)

Question 9

Salmeterol

Answer 9

B2 adrenergic receptor agonist (inhalation)
Long duration of action (>12 hours)–> lipophilic and deposits in tissue so stay in lungs for long time
Therapeutic Use: Chronic obstructive pulmonary disease, moderate to severe persistent asthma; slow onset so not suitable as mono therapy for acute bronchospasm

Question 10

Phenyleprine

Answer 10

Alpha 1 adrenergic receptor agonist
Increases systolic and diastolic BP
Reflex decrease in heart rate–> baroreceptors activity
Decrease blood flow in most vascular beds
Therapeutic uses:
Opthalmic (radial muscle)- midratic, decrease hemorrhage, congestion
Nasal decongestant (constrict vessels in nasal cavity)- oral or nasal spray
Use with local anesthetic to increase duration of action
Treatment of hypotension

Question 11

Clonidine

Answer 11

Alpha 2 adrenergic receptor agonist (directly stimulates reduction of sympathetic outflow from central alpha 2 receptors)
Orally active
Therapeutic use: anti-hypertensive (blocks tone from central receptors to heart and vessels–> central not peripheral)
Major adverse effects: sedation (CNS function), dry mouth, sexual dysfunction, bradycardia, edema, rebound hypertension with sudden discontinuation

Question 12

Methyldopa

Answer 12

Alpha 2 adrenergic receptor agonist
Orally active pro-drug–> stored in nerve terminals as alpha-methyl dopamine and alpha-methyl norepinephrine and released with nerve stimulation
Both are alpha-2 receptor agonists which stimulate central receptors to reduce sympathetic outflow
Major therapeutic use: anti-hypertensive
Side effects: similar to clonidine

Question 13

Epinephrine

Answer 13

Receptor selectivity–> alpha 1, alpha 2, beta 1, beta 2
CV effects: potent vasopressor (alpha 1) but can dilate some vascular beds (beta 2), cardio stimulatory (beta 1)
Respiratory effects: bronchodilation (Beta 2)
Metabolic effects: increase blood glucose and fatty acids
Absorption, fate, excretion: not orally effective with rapid t1/2
Low dose: increase systolic and decrease diastolic

Question 14

Tyramine

Answer 14

Indirect acting on alpha and beta receptors
Normal: Tyramine is AA compound in food and absorbed and degraded by MAO in liver (foods= cheese, beer, sausage)
MAO inhibitor with tyramine rich food: tyramine absorbed but not degraded so then activate alpha and beta receptors to release NE and sympathetic surge
Complication of surge: alpha 1 receptor activated–> hypertension

Question 15

Amphetamine

Answer 15

Indirect release of NE
Orally bioavailability- long half life because no MAO degradation
Powerful CNS stimulation (adrenergic)–> Wakefulness, depress appetite, stimulate respiratory center (increase respiration)
Therapeutic Uses: Narcolepsy, attention deficit/ hyperactive disorder
Release NE and other biogenic amines (dopamine) from granules

Question 16

Pseudoephedrine

Answer 16

Direct alpha 1 and beta 2 agonist activity
Orally effective but minimal CNS stimulation
Therapeutic use:: Nasal decongestant
Absorbed orally and longer half life than catecholamines
Availability is restricted

Question 17

Guanethidine and Guanadrel

Answer 17

Inhibit NE release and deplete neuronal amine stores
Orally active, long lasting
Do NOT penetrate CNS
Taken into adrenergic nerves via NET and deplete stores of NE slowly (eventually inhibit adrenergic effects)
Drug requires NET so any other substance/drug that inhibits NET will affect activity (tricyclics antidepressants, coccaine)
Therapeutic use: essential hypertension
Side effects: Orthostatic hypotension, male sexual dysfunction, diarrhea (no opposition to parasympathetic tone), muscle weakness, edema

Question 18

Reserpine

Answer 18

Diffuse into adrenergic neurons (lipophilic no NET needed)
Deplete nerves of NT by inhibiting VMAT
Orally active
Therapeutic: Treatment of hypertension
Enter brain and adverse CNS effects including depression (suicidal tendencies) and sedation
Adverse effects: diarrhea, Orthostatic hypotension, increased gastric acid secretion (no opposition for parasympathetic tone)

Question 19

Phenoxybenzamine

Answer 19

Alpha 1 and alpha 2 adrenergic receptor
Irreversible antagonist –> binds to receptor with covalent bond so permanently binds and no receptor function till new receptors are made (Emax decrease but change in EC50)
Long duration of action
Therapeutic uses: pheochromocytoma (tumor produces lots of catecholamines so block alpha receptors to block blood pressure changes)
Side effects: limit usefulness of treating HTN
Hypotension
Reflex cardio stimulation ( tachycardia, ionotropy)

Question 20

Phentolamine

Answer 20

Alpha 1 and alpha 2 adrenergic receptor antagonist
Competitive, reversible antagonist–> overcome by increasing level of agonist
Orally active
Shorter duration of action (2-4 hours)
Therapeutic uses: Pheochromocytoma
Side Effects: limit usefulness for treating HTN
Hypotension
Reflex cardio stimulation (tachycardia and ionotropy)

Question 21

Prazosin

Answer 21

Selective competitive antagonist of alpha 1 receptors
Short duration of action
Minimal tachycardia because little blockade of presynaptic alpha 2 receptors
Decrease vascular tone in resistance (arteries) and capacitance (veins) beds
Produce favorable effect on lipid profile
Clinical use: hypertension, short term treatment of heart failure
Side effects:
first dose phenomena–>Orthostatic hypotension

Question 22

Tamsulosin

Answer 22

Orally active for alpha 1 adrenergic receptor antagonist (alpha 1a vs. alpha 1B)
Favors blockade of alpha 1a on prostate
Treatment: Benign prostatic hyperplasia (BPH) with little effect on blood pressure
Not approved for treatment of hypertension

Question 23

Distinguishing feature someone B adrenergic receptor antagonist

Answer 23

Relative affinity for B1 and B2
Intrinsic sympathomimetic activity (acts as partial agonist)
Capacity to induce vasodilation
Pharmacokinetic properties

Question 24

B adrenergic receptor antagonists Pharmacological properties

Answer 24

CV: slow heart rate and decrease contractility, reduce sinus rate and activity of ectopic pacemakers (slow AV and atrial node conduction), anti-hypertensive (block renin release),
Pulmonary: bronchoconstriction
Metabolic: block sympathetic mediated mobilization of glucose and free fatty acids in the circulation

Question 25

B Adrenergic Receptor Antagonist Adverse Effects

Answer 25

CV: induce heart failure in susceptible patients, bradycardia, worsen peripheral vascular disease Pulmonary: increase airway resistance in those with asthma/COPD CNS: fatigue,sleep disturbances, depression Metabolism: blunt recognition of hypoglycemia and may delay recovery from insulin0induced hypoglycemia

Question 26

B adrenergic receptor antagonist: therapeutic uses

Answer 26

Cardiovascular diseases: hypertension, angina, acute coronary syndromes (MI), congestive heart failure Glaucoma: chronic open-angle glaucoma Other Use: migraine prophylaxis, anxiety provoking stimulus, essential tumors

Question 27

Propranolol

Answer 27

Non-selective (1st generation)--> B1 and B2 receptor antagonist Orally bio available but short half life and significant first pass metabolism Clinical uses: Hypertension, angina, cardiac arrhythmia, MI, pheochromocytoma, migraine prophylaxis, essential tremors

Question 28

Timolol

Answer 28

Orally bioavailability antagonist B1 and B2 First generation Beta blocker Therapeutics: hypertension, angina, cardiac arrhythmias, MI, Pheochromocytoma, migraine prophylaxis, essential tremors ALSO wide angle glaucoma

Question 29

Metoprolol

Answer 29

2nd generation --> Orally bioavailable B1 selective antagonist uses: Hypertension, angina, MI, cardiac arrhythmia, pheochromocytoma, migraine prophylaxis, essential tremor ALSO heart failure Adverse effects: less bronchoconstriction at lower doses

Question 30

Atenolol

Answer 30

``` 2nd generation (B1 selective antagonist) Orally bioavailable--> longer duration of action allowing once per day dosing and less penetration to CNS Therapeutic uses: MI, arrhythmia, hypertension, angina, essential tremors, pheochromocytoma, migraine prophylaxis Adverse effects: less bronchoconstriction at lower doses ```

Question 31

Labetolol

Answer 31

3rd generation--> alpha 1, beta 1 and 2 antagonist Orally bioavailable Therapeutic uses: essential hypertension (chronic), hypertensive emergencies

Question 32

Carvedilol

Answer 32

Second generation--> alpha 1, beta 1, beta 2 Anti-oxidant properties Blocks L-type calcium channels at higher doses Therapeutic uses: hypertension, Heart failure, MI

Question 33

Effects of Muscarinic Receptor Activation

Answer 33

CV: vasodilation (M3), decreased heart rate and AV nodal conduction (M2) Pulmonary: Bronchoconstriction (M3), Increased bronchial secretion (M3) Urinary Tract: detrusor muscle contraction, increase voiding pressure, ureter peristalsis (M3) GI tract: increase tone/amplitude of contractions and increased secretory activity (M3) Miscellaneous Peripheral effects: increase secretion from glands (M3) and miosis and accommodation for near vision (m3) CNS: cortical arousal

Question 34

Bethanechol

Answer 34

Muscarinic receptor agonist Choline esters (similar structure to Ach) Oral or subcutaneous (low bioavailability) Treat: urinary retention (post- op urinary retention, urinary retention with diabetic neuropathy, bladder disorders)

Question 35

Pilocarpine

Answer 35

``` Muscarinic receptor agonist Choline esters Effects: xerostomia (dry mouth) Topically in ophthalmology for treatment of glaucoma and as a mitotic agent ```

Question 36

Common adverse effects of Muscarinic receptor agonist

Answer 36

SLUDGE (salivation, lacrimation, urination, defecation, GI upset, emesis) Diaphoresis (sweating) Diarrhea, abdominal cramps, nausea Difficulty with visual accommodation Hypotension Contraindications: asthma, COPD, urinary/GI obstruction, acid-peptic disease, CV disease with bradycardia or hypotension

Question 37

Muscarinic Receptor Antagonists Pharmacological Effects

Answer 37

CV (M2): tachycardia and facilitate AV nodal conduction, block reflex slowing of HR and AV nodal conduction, No direct effect on vascular tone and blood pressure Respiratory (M3): bronchodilation and decrease in secretions Eye (M3): dilation pupil, paralysis of accommodation GI tract (M3): decreased secretions and motility Other smooth muscle (M3): decrease contractions of ureter and bladder Sweat glands- temperature: decrease sweating CNS: CNS depression and drowsiness

Question 38

Atropine

Answer 38

Muscarinic antagonist (alkaloid class) Non-subtype selective Orally bioavailable Uses: Bradyarrhythmias, opthalmic uses (produce mydriasis and cycloplegia), uses during anesthesia (prevent reflexes in GI and bronchial secretions), anti-cholinesterase or muscarinic toxicity

Question 39

Scopolamine

Answer 39

Muscarinic Antagonist non subtype selective (alkaloid) Orally bioavailable More prominent CNS effects than atropine Uses: motion sickness and vestibular disease

Question 40

Ipratropium

Answer 40

Muscarinic antagonist non-subtype selective (semi-synthetic) Little penetration into CNS due to positive charge (Quat. Ammonium) Uses: Helps with COPD and night asthma because decreases secretion and causes bronchodilation --> long life

Question 41

Tropicamide

Answer 41

Muscarinic Receptor antagonist (Synthetic antagonist) Fast onset (20-40 min) and short duration of action (4-6 hours) Therapeutic use: Mydriatic and cycloplegic (dilation and paralyze muscle control of the eye)

Question 42

Oxybutynin

Answer 42

Muscarinic receptor antagonist (synthetic antagonist) Therapeutic use: overactive bladder, incontinence High incidence of anti-muscarinic side effects: xerostomia (mainly), blurred vision, constipation, drowsiness/confusion

Question 43

Darifenacin

Answer 43

Muscarinic receptor antagonist (synthetic) Therapeutic use: overactive bladder, incontinence Some selectivity for M3 receptor subtype results in less CNS side effects

Question 44

Glycopyrrolate

Answer 44

Therapeutic use: block parasympathomimetic effects during reversal of neuromuscular blockade with anticholinesterase agents Quaternary amine- no CNS penetration

Question 45

Muscarinic Receptor Antagonists Adverse effects

Answer 45

Xerostomia Blurred vision Dyspepsia, constipation, urinary retention Tachycardia Hyperthermia Cognitive impairment (drowsiness, confusion) Use with Caution: glaucoma, benign prostatic hyperplasia, angina, arrhythmias

Question 46

Muscarinic Antagonist Toxicity

Answer 46

``` Hot as a Hare Dry as a Bone Red as a Beet Blind as a bat Mad as a hatter ```

Question 47

Acetylcholinesterase Inhibitors

Answer 47

Therapeutic uses: Antony of smooth muscle of the intestinal tract and urinary bladder Glaucoma Myasthenia Gravis Reversal of paralysis by competitive neuromuscular junction blocking agents Pharmacological uses: Stimulation of muscarinic receptor response at autonomic effector organs Stimulation followed by depression and paralysis of all autonomic ganglia and skeletal muslce (nicotinic)

Question 48

Edrophonium

Answer 48

``` Acetylcholineserase inhibitors (Non-covalent) Limited to periphery because of charge Rapid onset and short duration of action Therapeutic use: diagnosis of myasthenia Gravis, reversal of paralysis by competitive neuromuscular blocking agents ```

Question 49

Physostigmine

Answer 49

Achesterase inhibitor (reversible carbamate inhibitors) Alkaloid from Calabar bean Slowly reversible Tertiary amine (lipophilic)- CNS effects Therapeutic use: treatment of chronic wide-angle glaucoma and toxicity by anti muscarinic drug poisoning

Question 50

Neostigmine

Answer 50

Acetylcholinesterase inhibitor (reversible carbamate inhibitors) Synthetic Slowly reversible Quaternary amine so no CNS penetration Treatment: Myasthenia Gravis treatment , prevention and treatment of post-operative Antony of gut and bladder, reverse of paralysis by competitive neuromuscular blocking agent

Question 51

Organophosphorus Compounds

Answer 51

Phosphorylate serine in substrate binding domain of acetylcholinesterase Regeneration of enzyme is very slow and significant regeneration is not observed Return of activity depends on synthesis of new enzyme Nerve gas: sarin, tabun, soman Insecticides: Malathion (rapidly detoxified in higher organisms)

Question 52

Organophosphorus Compounds Toxicity and Treatment

Answer 52

Toxicity: symptoms manifest as nicotinic and muscarinic symptoms; most compounds lipophilic and penetrate CNS Symptoms include SLUDGE, hypotension, bradycardia, difficulty with visual accommodation, medullary respiratory depression, muscle paralysis because of depolarizing neuromuscular junction blockade, death due to respiratory failure Treatment: Remove poisoning, maintain open airway, treat convulsions and shock, atropine (block peripheral and central muscarinic effects and Pralidoxime )

Question 53

Pralidoxime

Answer 53

Antidote for Organophosphorus compound toxicity Reactivates acetylcholinesterase peripherally Takes phosphate off to regenerate the enzyme Use within 2-3 hours

Question 54

Competitive Neuromuscular Blocking Agent

Answer 54

Based on duration of procedure and minimizing cardiovascular compromise or other adverse effects with attention to modes of elimination in patients with hepatic or renal failure Antagonist of nicotinic receptors at Nm junction

Question 55

Rocuronium

Answer 55

Competitive Neuromuscular Blocking Agent Intermediate duration of action (30-60 minutes) Rapid onset (1-2 minutes) Elimination: hepatic Minimal CV effects No histamine release

Question 56

Atracurium

Answer 56

Competitive Neuromuscular Blocking Agent Duration of action: Intermediate (45 minutes) Onset 3 minutes Spontaneously degrades in plasma; metabolism by plasma esterase a Minimal CV effects Slight histamine release

Question 57

Vercuronium

Answer 57

``` Competitive Neuromuscular Blocking Agent Intermediate duration of action (40-45 minutes) Onset 2-3 minutes Hepatic and Renal elimination Minimal CV effects Histamine release: none ```

Question 58

Pancuronium

Answer 58

``` Duration of action: long (85-100 min) Onset: 3-4 min Renal and hepatic elimination Slight increase in HR No histamine release ```

Question 59

Depolarizing Neuromuscular Blockers

Answer 59

Activate nicotinic receptors at the neuromuscular junction (Nm) maintaining motor end plate depolarization and preventing transmission of another AP

Question 60

Succinylcholine

Answer 60

Depolarizing neuromuscular blocker Quaternary ammonium--> no CNS penetration not orally absorbed Very rapid onset and ultra short duration of action because rapidly metabolized by plasma pseudocholinesterase Onset 1-2 min, duration 5-8 min Used frequently for tracheal intubation Genetic variation ins pseucholinesterase activity

Question 61

Adverse effects of Neuromuscular Junction Blocking Agents

Answer 61

Prolonged apnea, CV collapse, effects due to histamine release like anaphylaxis Malignant hyperthermia --> contracture, rigidity, heat production from skeletal muscle resulting in severe hyperthermia, metabolic acidosis, tachycardia (genetics from mutation of ryanodine receptor of L-Ca channel) Hyperkalemia