Synthetic pathway questions

1. What is the order?
2. What is the rate limiting step?
3. In which organ does the final step occur?

1. Tyrosine --> DOPA --> Dopamine --> Norepinephrine --> Epinephrine
2. Tyrosine --> DOPA (tyrosine hydroxylase)
3. Adrenal medulla

Termination of catecholamine action

What is the primary mechanism for catecholamine termination? What is the secondary mechanism? What is the primary mechanism for metabolism? The metabolites?

1. Uptake-1 (active transport into presynaptic nerve terminal; blocked by cocaine, TCAs)
2. Uptake-2 (active transport into postjunctional cell, only important if Uptake-1 is blocked)
3. Monamine oxidase/MAO (high level of activity in mitochondria of nerve terminal)
4. VMA (excreted in urine)

I say...

1. Alpha-1
2. Alpha-2
3. Beta-1
4. Beta-2
5. Beta-3

You say...

1. Vasoconstriction (located postsynaptically)
2. Presynaptic:autoreceptors, postsynaptic:decreased sympathetic outflow
3. Heart (HR, CV, FOC)
4. Relaxation
5. Fat (free fatty acid production)  

Constriction and contraction = Increase intracellular calcium

Relaxation = Decrease in intracellular calcium

D1 in kidney arterioles stimulate adenylyl cyclase, dilate renal blood vessels.

In stressful situations, blood flow to the kidney is shutdown; dopamine agonists preserves renal function. Side effects = alpha-1 activation and vasoconstriction

What is the receptor selectivity of...

1. b1
2. b2
3. a1
4. a2

1. ISO > EPI >= NE > DA
2. ISO > EPI >> NE >> DA
3. EPI >= NE > DA >> ISO
4. CLO >EPI >=NE >> ISO

Define...

1. Tachyphylaxis
2. Desensitization
3. Tolerance

1. Instant decrease in responsiveness (occurs with indirect acting sympathomimetics)
2. Loss of receptor function to agonist
3. Long term decreased effectiveness after REPEATED or PROLONGED exposure 

1. Which fibers are cholinergic (nicotinic)
2. Which fibers are cholinergic (muscarinic)
3. Which fibers are adrenergic (norepinephrine)

1. PREganglionic fibers and somatic motor
2. POSTganglionic parasympathetic (some sympathetic)
3. POSTganglionic sympathetic

1. Non-selective alpha/beta agonist (more alpha-1 receptors, but B2 receptors more sensitive), potent vasopressor 
2. Increase MAP (SP > DP increase), increase pulse pressure, direct increase in HR/FOC (B1 response), vasoconstriction (A1 response) with reflexive vagal HR slowing, increase in TPR (due to a1 response) countered slightly by b2 response
3. Increase in HR (higher than rapid infusion due to lack of vagal reflex), overall decrease in TPR, decrease in DP, slight increase SP

1. Elevation of blood glucose and lactate (α1 and ß2)
2. Elevation of FFAs (ß3)
3. Inhibition of insulin secretion (α2>ß2)
4. Increased glucagon 
5. Increased renin

1. Asthma, allergic/anaphylactic reactions, prolonging local anesthetics, cardiac arrest
2. Anxiety, cerebral hemorrhage, cardiac arrhythmias
3. Halogenated hydrocarbons (increase cardiac sensitivity), beta blockers (unopposed α vasoconstriction; DO NOT co-administer)

1. Activation of α and ß1 receptors -->increase SP, DP, PVR and MAP... direct increase in HR but vagal reflex overrides ß1 elevation, leading to overall HR decrease. NO REDISTRIBUTION OF BLOOD FLOW
2. Similar to EPI, seen with higher doses
3. Overdose --> hypertension, increased risk of arrhythmias with halogenated hydrocarbons

Nonselective ß receptor agonist.

1. Increases HR, decreases PVR (CO increases). 
2. Smooth muscle relaxation. 
3. Inhibits inflammation
4. Increases FFAs and leads to hyperglycemia

1. Low dose: D1 receptor, vasodilation (preserve renal perfusion)
2. High dose: ß1 receptors (NE stimulation)
3. Too high dose: α1 receptor (vasoconstriction)

1. ß1 selective
2. Positive inotropic effects (increase CO, with no effect on PVR)
3. Adverse effects: increase HR, BP, arrhythmias, ectopic pacemakers
4. Used as short term treatment of cardiac decompensation

1. Albuterol and terbutaline (more selective, terbut used parenterally for asthma) and metaproterenol (treatment of obstructive airway disease)
2. Dilates skeletal muscle and coronary vasculature, bronchodilation, decrease GI tone, decrease inflammatory agents
3. Resistant to MAO/COMT metabolism, can be inhaled

1. Clonidine
2. Activation of α2 receptors in lower brainstem (centrally acting) decreasing sympathetic outflow, BP and norepinephrine release
3. Hypertension; migraine, substance withdrawal, used with ritalin for ADHD and Tourette's
4. IMPORTANT: Dry mouth & sedation (50%), as well as orthostatic hypotension (sit-up slowly), contact dermatitis, sexual dysfunction, marked bradycardia. Withdrawal syndrome (rebound HTN)

1. Apraclonidine: glaucoma (may decrease aqueous humor by acting on α2 receptor in ciliary body)
2. Guanfacine: Tourette's
3. Methyldopa: Specifically activate α2 receptors to decrease sympathetic flow (metabolized centrally)

• Mechanism: Acts directly on α and ß receptors; indirectly increases NE release
• Effect: Increases HR, CO, PVR and typically BP (similar to EPI and NE, with longer duration)
• Use: CNS stimulant, bronchodilation, nasal decongestant, energy enhancer
• Side effects: Stoke, heart attack (papitation, insomnia hypertension)

Indirect acting sympathomimetic that induces release of catecholamines (uptake into presynaptic nerve terminal)

By-product of tyrosine metabolism (found in fermented food such as cheese, wine, soy sauce, etc), but metabolized by MAO in the liver

Hypertensive crisis in patients on MAO inhibitors

1. Block vasoconstriction of endogenous CA's; vasodilation --> lower preload and afterload, with lower BP
2. α1 blockers --> less reflex tachycardia, α2 blockers increase sympathetic outflow

1. Pheochromocytoma
2. Hypertensive emergencies (although other drugs are preferable)
3. Chronic hypertension (α1-selective agents are preferable)
4. Peripheral vascular disease
5. Urinary obstruction / BPH (in inoperable patients)

Nonselective, irreversible alpha blockers

Decreases PVR, increases CO; α2 blockade increases NE release --> reflex tachycardia

Decreases BP in upright position

Used in pheochromocytoma

Reversible, nonselective alpha blocker

Used in short term control of BP patients (with pheochromocytoma), treatment of hypertensive crisis following clonidine withdrawal or tyramine-MAO inhibitor interaction

Toxicity: hypotension, reflex tachycardia, myocardial ischemia

α1 selective blocker --> arteriolar and venous dilation. Used in hypertension and refractory CHF

No change in HR or reflex tachycardia (since no α2 autoreceptor blockade)

Adverse effect: first dose phenomenon -- postural hyptension and syncope

Selective α2 receptor antagonist; increase sympathetic outflow centrally, increase NE release peripherally 

Increase in α1 and ß1 activities (increase in BP, which doesn't occur in nonselective α blockers)

Limited use for treatment of male sexual dysfunction

• Prototypical nonselective ß blocker
• Inhibits chronotropic, inotropic and vasodilation effects (little effect on heart at rest
• Decreases depolarization of ectopic pacemakers, decreasing workload on heart, increased exercise tolerance

• Respiratory administration can lead to bronchoconstriction from ß2 block (less likely with ß1 selective blockers) -- patients with obstructive breathing disorder
• Metabolic effects can block glucose utilization in response to hypoglycemia -- diabetic patients
• Side effects = bradycardia, withdrawal supersensitivity, bronchoconstriction, CNS disturbances

• Hypertension
• CHF
• Angina/ischemic heart disease
• Supraventricular arrhythmias, ventricular arrhythmias (unpredictable, unless from excessive CAs/digitalis toxicity) 
• Post-myocardial infarction
• Hyperthyroidism
• Migraine prophylaxis
• Panic reactions
• Glaucoma
• Essential tremor

Autonomics Means Easy A's

1. Atenolol (limited CNS penetration no ISA)
2. Metoprolol (no ISA, do not use in patients with acute MI)
3. Esmolol (short duration, given IV, no ISA)
4. Acebutolol: ISA

• Propanolol: highly lipophilic, extensive first pass metabolism, highly protein bounds; used for migraine and stage fright
• Nadolol: long duration of action
• Timolol: short-acting; used for glaucoma
• Pindolol: Prototype for ISA (paradoxical agonist/antagonist action), used for bradycardia
• Labetolol: also blocks alpha receptors, inhibit uptake-1, decreases BP (no reflex tachycardia)
• Sotalol: antiarrhythmic
• Carvedilol: also blocks alpha receptors 

• Sphincter (contract --> miosis)

• Ciliary (contract --> near vision and accommodation)

Direct cholinomimetic agent

Long duration of action, mixture of nicotinic and muscarinic action; used locally to produce miosis

1. Alcohols (edrophonium, donepezil) - bind irreversibly with AChE, short duration of action
2. Carbamate esters (physostigmine, neostigmine) - bind to AChE covalently to form stable intermedia longer duration of action
3. Organophosphates (DFP, soman, sarin) - irreversibly binds to AChE and phosphorylates enzyme

1. CV (to test patency of endothelium of coronary vessels), GI disorders, UR bladder disorders, ophthalmology (cataract extraction, wide angle glaucoma) 
2. Asthma (due to bronchoconstriction and increased secretions), hyperthyroidism (atrial fibrillation), coronary insufficiency, peptic ulcer (enhanced secretion)

DUMB BELSS

1. Diarrhea
2. Urination
3. Miosis
4. Bradycardia
5. Bronchoconstriction
6. Excitation
7. Lacrimation
8. Salivation
9. Sweating

Atropine for overdose, cholesterase reactivators for organophosphate poisoning (2-PAM?)

Note: atropine will rescue effector organs and CNS, but not NMJ

Regenerates AChE enzyme that has been phosphorylated by organophosphates. Should be given before phosphoryl bond "ages" and becomes more stable.

Organophosphates stored in body fat, requiring prolonged treatment

Edrophonium

Neostigmine, physostigmine, donepezil

Muscarinic antagonist (minimal action on nicotinic receptors in ganglia / NMJ); scopolamine (more CNS activity)

Salivation > bronchial secretions, sweating > pupillary response > HR > micturition > gastric secretion and motility > CNS (causes delirium, coma)

• Atropine: peripheral effects
• Scopolamine: motion sickness
• Ipratropium: obstructive pulmonary disease
• Cyclopentolate: ophthalmology
• Pirenzepine: GI tract
• Tolterodine: urinary urgency

Nicotine

Increase BP/HR/peristalsis and secretions. Excessive CNS stimulation.

Block nicotinic receptors at ganglia. Effect depends on predominant tone.

• Blood vessels = sympathetic (decrease PVR)
• Ventricles = sympathetic (decrease FOC)
• SA node = para (increase HR)
• Eye = para (cycloplegio, spasm of accommodation)
• GI tract = para (decrease tone and motility)
• GU tract = para (urinary retention)

Competitively blocks the nicotinic receptor of NMJ (muscles can still contract intrinsically)

Initially rapidly contracting muscles, going from limbs --> neck --> trunk --> diaphragm. Stimulation of histamine release

Depolaring NMJ blocker, stimulates rapid K+ release (neck --> limbs --> face --> respiration)

Used for skeletal muscle relaxation (general anesthesia, intubation)

Can cause hyperkalemia, interactions with digitalis and diuretics, cardiovascular collapse, bronchospasm, hyperthermia (treat with dantrolene)

• Anticholinesterases (decrease NMJ blocks of competitive blockers, increase NMJ block of succinylcholine)
• Inhalation anesthetics (synergisticically stablize post-junctional membranes)
• Aminoglycosides (syngergistic, inhibit ACh release by competing for Ca+)

• SA node (decrease HR)
• Atria (decrease contractility)
• AV node (decrease CV)

• Tone/motility increase
• Sphincter relax
• Secretions increase

Inhibits NE release in peripheral adrenergic nerve terminals. Used for hypertension.

"False transmitter"