2.2. sympathetic nervous system - adrenergic

— inhibitors of tyrosine hydroxylase

• metyrosine → decrease tyrosine neurotransmitters

— inhibitors of VMAT2 (vesicle mono-amino transporter 2)

• reserpine

  • hypertension (no longer used)

• tetrabenazine and deutetrabenazine

  • tardive dyskinesia

  • huntington’s chorea

• dectroamphetamine

  • ADHD

  • narcolepsy

adrenergic neurotransmission

• MAO — monoamine oxidase

• COMT — Catechol-O-methyltransferase

metabolizers of catecholamines

sympathetic — fight or flight

parasympathetic — rest or digest

sympathetic vs. parasypathetic

Epinephrine

Norepinephrine

Dopamine

vasopressors

Dobutamine

Isoproterenol

inotropes

Phenylephrine

Phenylpropanolamine

Midodrine

a1 agonists

Clonidine

Brimonidine

Methyldopa

Dexmedetomidine

Tetrahydrozoline

Guanfacine, Guanabenz

Tizanidine

a2 agonists

Oxymetazoline

Cyclometazoline

Naphazoline

a1-a2 agonist

Albuterol

Levalbuterol

Procaterol

Formoterol

Salmeterol

Vilanterol

Indacoterol

Olodaterol

Terbutaline

Isoxuprine

B2 agonist

Mirabegron

Fenoldopam

B3 agonist, D1 agonist

Pseudoephedrine

Ephedrine

Mixed and central adrenergic drugs

Alfuzosin

Tamsulosin

Prazosin

a1 blocker

Yohimbine

Rauwolscine / isoyohimbine

Tolazoline

a2 blocker

Phenoxybenzamine

Phentolamine

a1-a2 blocker

Propanolol

Penbutolol

Metoprolol

Esmolol

Lebatolol

Bisoprolol

Carvedilol

Timolol

Betaxolol

Atenolol

B-blocker

PRINCIPLE

• interact with many receptors, dose-dependent  • Direct vs. reflex actions

— Indication

• >30mmHg (mm of mercury) drop of bp OR >60mmHg decrease in mean arterial pressure

  • px must be at risk of dying

  • if px is hypovolemic → correct hypovolemia first by administering more fluids

principle and indication of vasopressors

MOA	agonist, a1 = a2 = B1 > B2 1. A1, A2 agonist — Vasoconstriction → ↑ svr, ↑bp, ↓mucosal edema 2. B1 agonist — +inotropy, +chronotropy, +dromotropy 3. B2 agonist (high dose) in lungs = vasodilation → ↓svr, ↓bp; bronchodilation in uterus = uterine relaxation mast cell stabilization (for allergies) basophil stabilization (for anaphylactic shock)
ABSORPTION	Poor oral bioavailability due to degradation by COMT; almost no effect orally
ROUTE	1. IV (central venous catheter/large veins) 2. Nasal, inhalational, intraocular (indication specific)

— indication

1. 1st line: anaphylactic shock due to massive histamine release

2. Cardiac arrest → use for cardiopulmonary resuscitation

   • chest compression ensures that the heart will continue to pump blood so that organs will not die while waiting for the heart to be stimulated by epinephrine

   • epinephrine is the one that restarts the heart

3. Hypotension during coronary artery bypass grafting (CABG)

4. Severe, refractory Asthma (B2 = bronchodilation)

5. local anesthetic combined with Epinephrine

   • epinephrine will cause localized vasoconstriction → anesthetic will stay longer in site and therefore will have longer effect

6. Bradicardia (B1 = ↑ heart rate)

   • for resuscitation, alternative of atropine

— adr

1. tachycardia

2. leukocytosis (rare)

epinephrine / adrenaline

MOA	a1 = a2 > B1 1. A1 and 2 — vasoconstriction, ↑↑svr, ↑bp 2. B1 initial = +inotropy, chronotropy → ↑cardiac output, ↑BP reflex action = Vagal effect — reflex bradycardia, ↓CO, ↓HR
ROUTE	IV

— indication

1. 1st line: septic shock (↓bp due to infection)

2. Cardiac arrest → use for cardiopulmonary resuscitation (but less used than Epinephrine)

3. Cardiogenic shock, hypovolemic shock

— adr = reflex bradycardia

norepinephrine / levarterenol

must be administered in big veins because it is a strong vasopressor and would cause vasoconstriction to smaller veins (drug will not be distributed in the body and site will be ischemic/lose oxygen)

why must epinephrine be administered via a central venous catheter

MOA

D1, D2 >> B1 >> a1 1. low dose — selective action at d1/d2 = ↑urine output, natriuresis, afferent and efferent renal arteriolar vasodilation (theoretically) → help px with kidney problems — in practice, there is no renal dose 2. moderate dose — ↑CO and ↑SVR; vasodilation (B1 agonist — +inotropy, +chronotropy, +dromotropy) 3. high dose — ↑↑svr; a1 → vasoconstriction predominates (not always a good thing)

ROUTE

IV

— indication

1. Alternative in cardiogenic shock and other shock states BUT avoided in septic shock

— C/I = avoided in sepsis due to hypotension risk

— adr

1. hypotension at lower doses (due to vadosilation)

2. more tachycardia and dysrhythmias vs other vasopressors

3. produce less hyperglycemia vs. E and NE

dopamine

MOA	B1 > B2 >>>>>>>>> a1 1. B1 — in heart, (+)inotropy, chronotropy → ↑↑↑↑CO repeated stimulation = downregulation of B1R → tachyphylaxis → ↓effect of drug 2. B2 — in periphery, vasodilation → ↓svr reflex action due to excessive stimulation = bradycardia, slow HR → no change or lower CO 3. A1 — sobrang hinang effect
ROUTE	IV

— indication

1. cardiogenic shock – bridging therapy

   • DA less preferred due to more tachycardia and lack of renal improvement vs placebo

2. persistent hypoperfusion despite initial measure

— C/I = avoided in sepsis due to hypotension risk

dobutamine

MOA	non selective beta agonist; B1>B2 1. B1 → +Inotropy, chronotropy → ↑↑↑CO 2. B2 → vasodilation → ↓svr reflex action = bradycardia, slow HR → no change or lower CO
ABSORPTION	IV

— indication

1. Atropine-refractory bradycardia

2. Mg2+-refractory torsades de pointes (fatal arrhythmia)

isoproterenol

MOA	systemic vasopressor
ROUTE	IV, oral otc, eye drops

— indication

1. hypotension (iv) — reserved when NE is contraindicated due to arrhythmias or failed other therapies

   • not in pnf, made using special permit

2. oral (otc) — shocker, ineffective in nasal congestion in allergic rhinitis

3. ophthalmologic (eye drops) — adjunct to stimulate pupil dilation / mydriasis

4. iv — alt vasopressor (Esp with arrhythmias)

phenylephrine

INDICATION	1. Constrict bv 2. reduce appetite
ADR	1. Hemorrhagic stroke in brain at high dose

— indication

1. nasal congestion — not very established

— toxicity = formerly abused for weight loss leading tohemorrhagic stroke

phenylpropanolamine

— indication

1. orthostatic hypotension — drop bp when px stand up; when bp drop is so high, px may collapse; may cause htn when px is supine (nakahiga)

— S/E

1. reflex bradycardia (low bp → small diameter of bc → increased svr → increased bp → vagus nerve try to lower contraction of heart to balance effect of sudden hypertension due to the drug)

2. supine hypertension (avoid giving 3-4 hrs before bedtime) — increase bp when lying down

3. urinary retention

— toxicity (a1 agonist)

1. hypertension

2. tachycardia or reflex bradycardia

3. agitation

4. diaphoresis (sweat)

5. mydriasis

midodrine

MOA	a1 adrenergic receptor agonist → vasoconstriction of bv (arterioles) in eyes

— indication

1. conjunctival hyperemia (short term) — swelling of tissue that surrounds the eye

2. artificial tears (eyedrops)

— S/E

1. long term/sudden discontinuation = conjunctivitis medicamentosa, rebound redness

   • arteriolar constriction → ischemia → rebound effects on discontinuation

2. tachyphylaxis — receptor desensitization → drug will not act as good

3. follicular reactions, dilation, contact dermatitis

tetrahydrozoline

MOA	a2 agonist, I1 receptor agonist

— indication

1. hypertension — not 1st line, last line

   • due to presynaptic effect of a2 receptor. will modulate NE release → decrease in bp

   • still prescribed a lot in the philippines, especially for px with really high bp who are given sublingual tablets. however, it is not an evidence based practice and SL and PO administration have the same pharmacokinetics.

2. anesthesia adjunct

3. ADHD — 2nd line, due to a2a CNS fucntion

4. Smoking cessation, opioid withdrawal, tourretes — 2nd line (ANS a2a and a2c)

— S/E

1. CNS: sedation

2. CV: orthostatic hypotension, rebound hypotension on abrupt withdrawal (reinstitute drug, taper slowly)

3. GIT: dry mouth, N/V

clonidine

MOA	Initial effect in a2B (eye) = vasoconstriction → decreased aq humor production delayed effect (1 week) = ciliary muscle contraction → increased uveoscleral outflow

— indication = open-angle glaucoma (alternative) → lowers intraocular pressure

— S/E

1. topical = hyperemia, ocular pruritus, allergic conjunctivitis (delay up to 1.5 years)

2. systemic = hypotension, sedation (CNS a2B/a2C receptors), dry mouth, fatigue

brimonidine

— indication

1. short-term sedation in mechanically ventilated px; procedural sedation — has longer onset than propofol

   1. anesthesia adjunct

2. adjunct for postoperative acute and chronic pain

— S/E

1. hypo/hypertension

2. bradycardia

3. nausea

4. afib

dexmedetomidine

indication = skeletal muscle relaxant

tizanidine

— false neurotransmitter

— indication = HTN (especially in pregnant women)

• although only gives mild effect and slow onset (3-6h), it is still useful

• most htn drugs (e.g. losartan) are C/I in pregnancy due to harmful effect on the formation of kidneys on developing fetus

— S/E

1. a2 adverse effects = sedation, dry mouth, mild orthostatic hypotension, nasal congestion

2. (+)-Coombs test → associated with hemolytic anemia due to lysis of rbc (RARE)

methyldopa

— not in Ph, more on textbook

— indication

1. alternative for hypertension

2. guanfacine = alternative for ADHD and Tourette’s

guanfacine, guanabenz

MOA	a2B agonist > a1A partial agonist
route	nasal spray

— indication = vasoconstriction of nasal passage blood vessels → tx nasal congestion

— S/E

1. transient irritation, sneezing

2. rhinitis medicamentosa (rebound congestion) due to receptors desensitization

   • efficacy gone and congestion is worse

   • do not use for more than 3 days!!

oxymetazoline, cylometazoline, naphazoline

MOA	found in lungs and cause bronchodilation
Indication	1. Asthma (main) 2. COPD 3. decrease uterine contractions in premature labor (alt; use only for <48-72 hrs)
ADR	tremor, hyperglycemia, hypokalemia, tachyphylaxis case reports: stress-induced (takotsubo) cardiomyopathy — heart becomes octopus trap shaped

B2 agonist MOA, indication and ADR

short acting β2 agonists (SABA)

— for rescue only (alternative)

1. albuterol (salbutamol) & levalbuterol

2. procaterol

SABA

long acting β2 agonists (LABA)

— a controller / maintenance medication

1. formoterol (+ CS) — 1st line, single combination inhaler maintenance and reliever therapy (SMART) in asthma

2. salmeterol

3. vilanterol (in combination)

4. indacoterol, olodaterol for COPD

LABA

— drugs that relax the uterus for pregnant px with threatening delivery → abort impending labor

1. terbutaline, isoxuprine

2. ritodrine

tocolytics

— indication = β3 for urinary retention

mirabegron

MOA	peripheral D1 selective agonist → peripheral arterial vasodilation
half-life	10 minutes; administer continuous iv infusion

— indication = not so much, calcium channel blockers more preferred

1. postoperative hypertension

2. hypertensive emergencies

— S/E

1. headache

2. reflex tachycardia

3. flushing

4. increased IOP

fenoldopam

a. pseudoephedrine

— controlled drug; for nasal congestion in US

b. ephedrine

— found in ma huang

— less potent vs epinephrine

— used in post-anesthesia hypotension

mixed and central drugs

MOA	a1 antagonist

— uroselective = alfuzosin, tamsulosin

— indication = benign prostatic hyperplasia

• prostate is an organ found in males. anatomically, the prostate is hugging the urethra. enlarging of prostate gland → naipit si urethra → difficult urinating

• hyperplasia = dumadami ang cells

• hypertrophy = lumalaki yung cells

— S/E

1. hypotension (1st dose phenomenon) — cause exaggerated response

   • a1 blockers 1st dose must be taken at bedtime to lessen risk of falls

   • syncope → fainting

2. headache, dizziness, nasal congestion

a1 blocker MOA, indication and S/E

MOA	a1A selective antagonist

— indication = urolithiasis (stone passage)

— S/E

1. ejaculatory dysfunction (decreased volume)

2. rare: intraoperative floppy iris syndrome (flaccid iris, prolapsed, miosis)

tamsulosin

MOA	a1 antagonist that penetrates BBB → fear response, REM sleep

— indication = post traumatic stress disorder (PTSD), nightmares

— issues

• dosing = supramaximal due to tolerance

• extinguishing nightmares = blocking trauma healing process

prazosin

added MOA	NE reuptake inhibition; H1, AChR and 5-HT antagonistm (HAM blockade)
duration	14-48 hrs; slow onset, long-lasting and enters CNS

— irreversible

— indication = preferred agent for preoperative preparation for pheochromocytoma (10-14 days before)

phenoxybenzamine

added MOA

mild 5-HT receptor antagonist, H1, H2 and M1 agonist

— indication

1. hypertensive crisis in pheochromocytoma or due to MAOI + tyramine

2. extravasation in vasopressor Tx

phentolamine

• Absorption = good BA except propanolol

  • propanolol = variable, depends on first-pass and absorption improved with protrein-rish diet

• distribution and clearance = rapid, moderate distribution

  • propanolol and penbutolol = lipophilic, cross BBB

  • propanolol and metoprolol = extensive liver metabolism

  • esmolol = half life = 10 mins → shoft half life = short effect → use as IV infusion

pharmacokinetics of B-blockers

— effect

1. B1

   • (-)inotropy and chronotropy (low CO)

   • suppression of renin release

2. B2

   • vasoconstriction (high SVR) → long term decrease (+ inhibit renin release)

   • bronchoconstriction

— indication

1. cardiovascular

   1. 2nd line for primary hypertension

      1. labetalol = hypertension in pregnancy

   2. stabilized congestive heart failure (after ACEI/ARB)

      1. bisoprolol

      2. carvedilol (IR and CR)

      3. metoprolol succinate XR (only tartrate PNF)

   3. 1st line chronic coronary syndrome / stable angina — usually develops moderate to severe chest pain; angina is still reversible

   4. acute myocardial infarction (after stabilizing) — tissue has already died

   5. B1 receptor blockade → negative ino/chronotropy → reduced myocardial O2 demand

      • heart does not have to work as heart and will have lower oxygen requirement, lessen hypertrophy

   6. adipose B receptor block → lipolysis inhibited → less free fatty acids producted → shift to carbohydrates metabolism (less FFA uptake by heart)

   7. arrhythmia

2. neurological (since it can cross BBB)

   1. propanolol = essential tremor (developed on its own, don’t know the cause

   2. Propanolol, Metoprolol = 1st line migraine prophylaxis

   3. PRN for stage fright

3. others

   1. open-angle glaucoma

      • inferior to prostaglandins, except for $$$

      • Timolol, Betaxolol

   2. hyperthyroidism (symptomatic) — Propanolol

   3. primary prophylacis in variceal (GIT) bleeding (alternative) — Propanolol

   4. infantile hemangiomas (entangled BVs under skin) — useful for vascular disorders in young patients

      1. uncomplicated — topical timolol, propanolol

      2. high-risk — propanolol (1st line)

effect and indication of B-blockers

— S/E

1. cardiac

   1. bradycardia (- inotropy)

   2. precipitation/worsening CHF

      • decrease CO, increase SVR

      • less with ISA

   3. BLACK BOX WARNING: withdrawal due to abrupt discontinuation → ischemic symptoms, myocardial infarction

      • discontinuation must be tapered

2. non-cardiac

   1. smooth muscle spasm

      1. airway resistance (non selective) → bronchoconstriction

         • caution for asthma, COPD

      2. cold extremities

      3. peripheral artery disease worsening (claudication)

   2. CNS (not just lipid-soluble drugs) = mild sedation, vivid dreams, depression

   3. metabolic

      1. masking hypoglycemia — can sometimes increase blood sugar, masking hypoglycemia sx and goes undetected; may develop life threatening hypoglycemia for px taking insulin

      2. slight weight gain

      3. increase in TGs, decrease HDL (older BBs)

         • peripheral vasoconstriction → insulin resistance

         • less with carvedilol, nebivolol

   4. others

      1. fatigue (limits exercise capacity)

      2. sexual dysfunction (erectile dysfunction) — rare, may be more nocebo

      3. hyperkalemia (non selective)

S/E of B-blockers

— more recent studies say that it is not that effective

1. B1 selective antagonist, no local anesthetic / membrane-stabilizing action

   • most dependent on renal elimination (up to 50%)

   • fetal growth restriction in pregnancy

2. vs placebo

3. vs active drug

atenolol for hypertension

metoprolol tartrate vs succinate for CHF

— when heart fails to pump blood → heart muscle overworked → edema, hypertrophy (increase in size) → makes contractions less efficient → mabilis hingalin

— beta blockers useful for CHF

— twice daily dosing