1. Drugs Affecting the Sympathetic Nervous System
CHAPTER 6
Drugs Affecting the Sympathetic Nervous System

2. Sympathetic NS Mobilizes the body for “fight or flight”
It uses norepinephrine & epinephrine (adrenalin) as neurotransmitters to bind to and activate adrenergic receptors

3. Adrenergic receptors – EPI & NE
Alpha receptors (ά) – on arteries & veins – tone and blood pressure
Beta one receptors (β1) – on heart –stimulatory
Beta two receptors (β2) – on bronchioles of lung – bronchodialation –relaxes smooth muscle

4. Adrenergic Nerve Endings
The adrenergic nerve ending synthesizes and releases norepinephrine (NE)
Released norepinephrine stimulates adrenergic receptors located on cardiac and smooth muscle membranes to initiate sympathetic responses
In emergency situations the adrenal medulla releases epinephrine (EPI) which also stimulates adrenergic receptors and sympathetic activity
NE and EPI are inactivated by neuronal reuptake back into the nerve ending for reuse or metabolism by monoamine oxidase (MAO)

5. Alpha-Adrenergic Receptors
Alpha-adrenergic receptors (ά) are located on smooth muscle membranes and cause smooth muscle contraction when stimulated by NE, EPI, or drugs
Alpha receptor stimulation causes vasoconstriction of most arteries and veins
Alpha receptor stimulation of the radial muscle of the pupil causes pupillary dilation or mydriasis
Contraction of the smooth muscle sphincters in the urinary and intestinal tracts inhibit urination and intestinal motility

6. Alpha receptors
Constant low level stimulation is responsible for “vascular tone” - normal non-stressed BP
Under stress
Peripheral resistance ↑  BP↑
Marked vasoconstriction of skin, kidney & viscera

7. Beta-Adrenergic Receptors
Beta-1(β1) receptors are located primarily in the heart and cause increased heart rate, force of contraction, and atrioventricular conduction & ↑ cardiac output
Beta-2 (β2) receptors are mostly located on smooth muscle and cause relaxation of smooth muscle, especially bronchiolar, uterine smooth muscle & skeletal muscle A
Beta-3 receptor stimulation also causes vasodilation and increased blood flow to coronary and skeletal muscle blood vessels

8. Norepinephrine and Epinephrine
Norepinephrine is released from adrenergic nerve endings and primarily stimulates alpha and beta-1 receptors, it is not effective at beta-2 receptors
Epinephrine is released from the adrenal medulla into the blood where it travels as a hormone to stimulate all alpha and beta receptors

9. Drugs affecting sympathetic function
Agonists – Sympathomimetic – stimulate receptor function
Antagonist – Sympatholytic – block receptors – stop function
Antagonist – NE depleting drugs – act at NMJ to deplete stores of neurotransmitter

10. Alpha-Adrenergic Drugs
Alpha-adrenergic drugs are used clinically to cause vasoconstriction of blood vessels
In hypotensive states, drugs such as norepinephrine (Levophed)and metaraminol (Aramine), are given by IV injection to raise blood pressure
In allergies and colds, drugs such as phenylephrine (Neosynephrine) and tetrahydrozoline (Visine) are administered as nasal sprays or drops, and oral tablets to decongest nasal and ocular tissues

11. Beta-Adrenergic Drugs
Beta drugs are used clinically to stimulate the heart, bronchodilate respiratory passageways, and relax the uterus during preterm labor
Selective beta-2 drugs are usually administered by oral inhalation for the control of asthma
Epinephrine (ά,β1, is injected subcutaneously in allergic and cardiac emergencies to stimulate the heart, promote bronchodilation, and maintain blood pressure

12. Chemical structure of Adrenergic Agonists
Catecholamine – related to naturally occurring NE & EPI
Epinephrine
Norepinephrine (Levophed)
Isopraterinol (Isuprel)
Dopamine
Noncatecholamines – synthetic, long acting
Phenylephrine, ephedrine, amphetamine

13. Action of sympathomimetics - agonists
A. direct acting – bind to receptors  effect
EPI – stimulate ά, β1 & β2 – asthma & allergy
NE – stimulates ά, β1 – Not β2 – not for asthma
Isopreterenol – β1 & β2 - for shock
Dopamine – β1 & D - renal perfusion in shock
Dobutamine – β1 - CHF
Phenylephrine – ά - topical nasal decongestant
Albuteral – short acting β2 – bronchodilator
Salmeteral – long acting β2 - bronchodilator

14. Action of sympathomimetic agonists
B. Indirect acting - release stored catecholamine – use – hyperactivity, ADD, narcolepsy
Amphetamine
Ritalin
Dexedrine
C. Mixed – both binds to receptors &release stored NE – ephedrine - asthma – long acting bronchodilator

15. Adverse Effects Caused by Adrenergic Drugs
The main adverse effect caused by alpha drugs is excessive vasoconstriction resulting in hypertension or excessive dryness of the eyes and nasal sinuses when used as decongestants
Overstimulation with beta drugs causes excessive cardiac stimulation and increased blood pressure
Adrenergic drugs can also cause CNS stimulation resulting in tremors, restlessness, and anxiety

16. Adrenergic Antagonists - Sympatholytics
Bind to ά, β1, &/or β2 adrenergic receptors & prevent NE or EPI from binding & activating effect

17. Alpha-Adrenergic Blocking Drugs
Alpha blocking drugs are used clinically to lower blood pressure in hypertension and increase urine flow in benign prostatic hyperplasia
Alpha blocker drugs are usually administered orally
Common adverse effects of alpha blockade include nasal congestion, blurred vision due to pupillary constriction, and increased GI activity
Excessive lowering of blood pressure may cause hypotension, fainting, and reflex tachycardia

18. Alpha blockers
ά sympathetic receptors control vascular tone and arteolar resistance – resting BP
ά blockers – prevent vasoconstriction of peripheral blood vessels by endogenous catacholamines  lower BP
Block ά1A receptor found only in urinary bladder neck & prostate – internal urinary sphincter – improves urine flow

19. Alpha blockers Phenoxybenzamine - first one - not used
Phentolamine (Regitine) – Dx pheochromacytoma
Prazosin (minipres) –often used with
Terazosin (Hytrin) diuretic or β blocker
Doxazosin (Cordura)
Tamsulosin (Flowmax) used for BPH

20. Beta-Adrenergic Blocking Drugs
Beta blockers are used primarily for their beta-1 blocking activity
Drugs are used to treat hypertension, angina pectoris, tachycardia, and after myocardial infarction (MI) to reduce mortality
The most serious adverse effects are due to excessive beta blockade resulting in cardiac depression, bradycardia, congestive heart failure, and hypotension
In asthmatics, nonselective beta blockers in particular may cause bronchoconstriction

21. Beta adrenergic blockers
Only β1 (heart related) effects are usefull to block!
Β1 blockers ↓ BP by ↓ rate & contractility - ↓ cardiac output but do not produce postural hypotension because ά system still intact
Cardio selective – only β1 blocked
Non selective – both β1 & β2 blocked

22. Beta blockers Effective in Rx of Angina pectoris Cardiac arrhythmias
Myocardial infarction
Vascular headache
Stage fright – ½ of CSO on propranolol

23. Uses if β blockers Angina – reduces O2 requirements of heart
Decreases size of myocardial infarction, recurrence and lethality
Hypertension - primary use
Migraine & vascular headache
Stage freight – panic attacks

24. Propranolol (inderol)
First β blocker developed – nonselective
Diminishes cardiac output - BP
↓ ionotropic effect – heart rate
↓ chronatropic effect – force of contraction
Slows SA & AV node
Bronchoconstriction – β2 blockade
↓ renal perfusion  ↑ Na+ retention
Causes hypoglycemia

25. Selective β1 blockers Atenolol (Tenorman) 50 – 100 mg PO
Bisoprolol (Zbeta) 5 – 20 mg PO
Metoprolol (Lopressor) 100 – 400 mg PO

26. Adrenergic Neuronal Blocking Drugs
Adrenergic neuronal blockers decrease the synthesis and release of norepinephrine
These drugs are primarily used to lower blood pressure in hypertension
Common adverse effects are usually due to excessive lowering of blood pressure and increased GI activity
Methyldopa may also cause liver dysfunction and hemolytic anemia; reserpine can caused sedation and mental depression

27. Adrenergic nerve blockers
Drugs that effect neurotransmitter release at sympathetic postganglionic nerve endings or reuptake of NE by presynaptic neuron
Reserpine – stops the movement of NE, dopamine & serotonin into synaptic vesicles NE depletion & impaired synaptic function
Methyldopa (Aldomet) – false neurotransmitter
Guanethidine (Ismelin) – depletes NE

28. Adrenergic nerve blockers
Guanethidine – blocks release of NE from sympathetic nerve endings & NE depletion problems: postural hypotension & impotence
Cocaine – blocks reuptake of NE from synaptic cleft  NE accumulates & persists - greatly magnifies NE & EPI effects