PHARM Exam2- NeuroP- PNS

Basic Principles of neuropharm

Divided into:

• PNS (peripheral nervous system)

• CNS

Drugs Cause: Excitation or suppression (of systems above)

• Work to mimic or block neurological body processes

How Neurons send signals

• Neuron reaches action potential threshold, sends aciton potential down axon

• Releases neurotransmitter at synaptic cleft

• Neutoransmitter binds to recepter sight on postsyanptic cell

Sites of action: Axon vs Synapsis

1. Axonal conduction: NOT selective (local anesthetic)

   1. Some drugs will DECREASE or INCREASE conduction or the amoutn of aciton potential that fire, STOP ALL = NOT SELECTIVE

2. Synaptic transmission: Drugs that ALTER synaptic transmission, HIGHLY SELECTIVE

Receptor Action: IMPORTANT

Receptor: Ability of neuron to influence the behavior of another cell depends on ability of that neuron to alter receptor activity on target cell

• Neuron influence depends on:

  • Receptor presence

  • Type

  • Sensitivity

  • Distribution

Makes sense just think about

Producing Effects

• All neuropharm drugs (other than anesthetics) produce effect by ALTERING RECEPTOR ACTIVITY

• May increase or decrease receptor activity

  • Activated receptor causes incrased likelyhood of postsynaptic neuron to do action potential

Mort and Merv

Mort- All organs have same type of receptor

Merv- Organs have different receptors

• For MORT, drug selective action is NOT possible

• More types of different receptors = better ability to have selective affect

Approach to learning about PNS drugs (3 things) + Isoproterenol examples

1. Type or types of receptors which drug acts on

2. The normal response to activation of receptors

3. What the drug in question DOES to the receptor (increase or decrease)

Isoproterenol: Old-school drug for heart problems

• Acts on Beta1 and Beta 2 receptors

• Normal Response

  • Beta 1 increase HR + Cardiac Contraction

  • Beta 2: Bronchial dilation + glucose elevation

• What drug does

  • Cause activation of both receptors

Peripheral Nervous System Division

• Somatic motor system: Muscles under voluntary control

• Parasympathetic Nervous system/ AUTONOMIC: relaxed/normal body

• Sympathetic Nervous system/ AUTONOMIC: Action, F or F

Functions of Parasympathetic: (9)

THINK ABOUT: CHOLINERGIC

• Constrict pupils

• Stimulate saliva

• Slow heartbeat

• Constrict airways

• Stimulate stomach activity

• Inhibit glucose release, stimulate gallbladder

• Stimulate intestinal activity

• Contract bladder

• Promote erection

Overall function:

• Digest food

• Excrete waste

• Control vision

• CONSERVE ENERGY

Functions of Sympathetic (10) opposite of parasymp

THINK ABOUT ANDGRENGERIC

• Dilate pupils

• Inhibit salivation

• Increase heartbeat

• Relax airway

• Inhibit stomach

• Stimulate glucose release, inhibit gallbladder

• Inhibit intestinal activity

• Secrete epinephrine and norepinephrine

• Relax bladder

• Promote ejaculation and vaginal contraction

Sympathetic main function

• Regulate cardiovascular

• Regulate body temp

• Fight or flight

Overview of autonomic nervous system

Dont have to think about

• Regulate heart rate

• Regulate secretory glands (salivary, gastric, sweat, bronchial)

• Regulate smooth muscles (bronchi, blood vessels, urogenital, GI tract

Sympathetic Homeostatic Objectives

1. Maintain blood flow to brain

2. Redistribute blood flow during exercise

3. Compensate for blood loss, through vasoconstriction

Regulate body temp

Regulate cardiovascular

NOT JUST FOR F OR F

PNS and SNS Innervation

Structures under autonomic control INNERVATED BY BOTH PNS and SNS

• Dual innervation = maintain homeostasis

• Some times complementary (works together)

  • PNS cause erection

  • SNS cause ejaculation

SOME ONLY INNERVATED BY ONE

• EX. Blood vessels only innervated by sympathetic (KNOW THIS)

  • Drugs affect blood vessels ONLY ACT ON SNS

Feedback regulation for single innervation + Baroreceptor reflex

Main elements:  Think about thermostat

• Sensor

• Effector

• Neurons connecting sensor to effector

Blood vessel BARORECEPTOR REFLEX (KNOW THIS)

• MOST important feedback loop of ANS (regulates BP change)

• Located in carotid sinus of aortic arch

• If change in BP, detected by baroreceptor and send info to brain

• Brain sends impulse along nerve to ANS 

  • Decreased BP = vasoconstriction

  • Increased BP = vasodilation

Autonomic Tone vs Predominant Tone

Autonomic: Balance between PNS and SNS

Predominant: only one division provides basal control

• Most organs predominant = PNS

• Vascular system: predominant = SNS

Anatomic Considerations

• PNS: 2 neurons in pathway from spinal cord to organ innervated by parasymp nerve

• Neurons go from spinal cord to parasymp ganglia = (Pre ganglionic neurons)

• Neurons from ganglionic to effector = (post ganglionic neuron)

  • Same for SNS

• Spinal cord -(preganglionic neuron)-parasymp ganglia - (postganglionc neruon)- organ

Somatic Motor System: one neuron in pathway from spinal cord to skeletal muscle innervated by motor neuron (voluntary control)

Ganglion

• Junction/Synapse between 2 neurons = GANGLION

Peripheral Nervous System Neurotransmitters

• Acetylcholine: Most peripheral NS junctions (present everywhere (PNS, SNS, Somatic motor)

• Norepi: released by postganglionic of SNS

• Epinephrine: released by adrenal medulla

LOOK at Picture

Peripheral NS Transmitters Cntd (picture expalantion) (6 things)

1. ALL preganglionic neurons of paraS + symp release acetylcholine

2. ALL postganglionic of parasymp release acetylcholine

3. Most postganglionic of symp release norepienprhine

4. Postganglionic of symp for sweat glands release acetylcholine

5. Epinephrine is principial transmitter released by adrenal medulla

6. ALL motor neurons to skeletal muscles release acetylcholine

Receptors of Peripheral Nervous

Cholinergic: mediated by acetylcholine

• Nicotinic N

• Nicotinic M

• Muscarinic

Adrenergic: mediated by epinephrine and norepinephrine

• Alpha 1

• Alpha 2

• Beta 1

• Beta 2

• Dopamine

Receptor selectivity

LOOK AT PICTURE, Subtypes of receptors allow for MORE specialization

Receptors of Peripheral NS (ALL OF THE ONES IWTH PICTURES = IMPROATN)

1. Nicotinic N receptors are located on cell bodies of ALL POSTGANGLIONIC NEURONS of parasymp and symp

2. Nicotinic N also located on ADRENAL MEDULLA cells

3. Nictonic M located on skeletal muscle

4. Muscarnic receptors

   1. On ALL ORGANS regulated by parasymp nervous (organs innervated by postganglionic parasymp)

   2. On Sweat glands (think sweaty = musky)

5. Adrenergic (Alpha, Beta, or both)

   1. Located on ALL ORGANS regulated by SYMPATHETIC (except sweat glands)

   2. ALSO located on organs regualted by epinephrine from adrenal medulla

Functions of Cholinergic Receptor Subtypes

Nicotinic N (neuronal)

• Promotes ganglia transmission by producing acetylcholine

• Promotes epi release

Nicotinic M (muscle)

• Contraction of skeletal muscle

Muscarinic

• Activates parasymp NS 

• Activates sympathetic sweat glands

Andrenergic Receptor Subtypes

Alpha1: (ALL MAJOR SNS Stuff)

• Vasoconstriction of arterials: skin, veins, mucous membranes, etc.

• Ejaculation

• Contraction: bladder + prostate

• Pupil dilation

Alpha 2 (less clinically significant)

• Located in presynaptic junction

Beta1: (1/2)

• HEART

• Increase HR, contraction force

• Velocity of conduction in AV node

Beta1 (2/2)

• KIDNEY

• Renin release (to increase blood pressure)

Beta 2

• Bronchial dilation

• Relax uterine muscle

• Vasodilation

• Glycogenolysis (glycogen broken down into glucose for energy)

Dopamine

• Dilates renal blood vessels

Receptor specificity of Adrenergic neurotransmitters/ CATECHOLAMINES (know this)

Adrenergic neurotransmitter = CATECHOLAMINES

• Epinephrine can activate ALL alpha + beta but NOT dopamine

• Norepi can activate alpha 1, alpha 2, beta 1, but NOT beta 2 or dop

• Dopamine activate alpha 1, beta 1, dopamine

ONLY DOPAMINE CAN ACTIVATE DOPAMINE

Terminology (sympathetic and parasymp)

Sympathetic

• Adrenergic

• Anticholinergic

• Sympathomimetic

• Parasympatholytic

• Cholinergic Blocker

Parasympathetic

• Cholinergic

• Antiandrenergic

• Sympatholytic

• Parasympathomimetic

• Adrenergic blocker

• Beta adrenergic blocker (beta blocker)

• sympathetic inhibitor

Agonist = stimulate

Antagonist = inhibit

Cholinergic/ Parasympatheic NS drugs

• Influence cholinergic receptors (most act directly)

  • Mimic or block acetylcholine

• SOME influence cholinesterase (enzyme which breaks down acetylcholine)

• Extensive toxicology of cholinergic drugs (nicotine, insecticides, chemical warfare)

Cholinergic vs Anticholinergic drugs

Cholinergic (parasymp)

• Mimic acetylcholine

• Stimulate cholinergic receptor

  • Direct stimulation with agonist

  • Release of acetylcholine

  • Inhibit acetylcholine breakdown/enzyme

• Anticholinergic

  • Block action of acetylcholine

Cholinergic Drug Types (6)

1. Direct acting agonists

2. Indirect acting agonists

3. Muscarinic antagonist

4. Nicotinic antagonist

5. Cholinesterase reactivator

6. Cholinergic toxicity antidote

Direct Acting Agonist (Cholinergic)

• Drug: Bethanechol (muscarinic), Pilocarpine, Cevimeline Nicotine

• Receptor: Muscarinic, Nicotinic M and N

• Action: Stimulate receptors directly

• Uses: Urinary retention, dry mouth(cevimeline), glaucoma(pilocarpine)= increase fluids to eye, GERD (relax lower esophagus), illeus (help stimualte bowel movement)

• Side effects: bradycardia, diarrhea, salivation, sweat

  • Can ALSO BE ADR if impact of these is serious

• Contraindications:

  • Asthma: precipitates bronchospasm (tightening of airway/bronchoconstriction)

  • Mechanical obstruction in GI or ureters (too much movement can cause perforation)

• Nurse implications; WATCH FOR CHOLINERGIC OVERDOSE

  • Extreme SLUDGE, use atropine as antidote

Indirect Acting Agonist (Cholinergic)// Cholinesterase inhibitors

• Drug: Neostigmine (revers), Pyridostigmine (revers), Donepezil

• Receptor: Acetylcholinesterase (AChE), inhibit ache allows action of acetylcholine to be prolonged NOT INCREASING ACH, just allowing more to be used

• Action Inhibit ACh breakdown, to increase ACH at synapse

• Uses: Myasthenia gravis (chronic autoimmune neuromuscular disease), Alzhemier’s for memory, reversal of NMJ block

• Other uses: Insecticides, chemical warfare

• Side Effects: SLUDGE (salivation, lacrimation, urination, dirrhea, GI upset, emesis) lacrimation = tear flow

• Contraindication: patients with bradycardia, urinary or GI obstruction (will make HR TOO slow or cause perforation with obstruciton)

Muscarinic Antagonist (Cholinergic)

• Drug: Atropine, Scopolamine(motion sickness), Ipratropium

• Receptor: Muscarinic

• Action: BLOCK M receptors

• Uses: Bradycardia, motion sickness blocks muscarninic in CNS, COPD/Asthma think BRONCHOSPASM, diarrhea,

• Side Effects: dry mouth, blurry vision, urinary retention, confusion

Nicotinic Antagonists (Cholinergic)

• Drugs: pancuronium, Succinylcholine (M)

• Receptor: Nicotinic M and N

• Action: BLOCK Nic N and M at NMJ, blocks acetylcholine from binding

• Use: Muscle relaxation during surgery, intubation

  • Does NOT cause patient to lose consciousness/go to sleep just paralysis of muscles

  • Can STILL FEEL PAIN

• Side effects: Respiratory paralysis (that’s why only use with intubation), hyperkalemia (depolarization of muscle receptors = efflux of K)

• Reversible: Use anticholinesterase inhibitor (neostigmine, etc.)

Cholinesterase Reactivator (Cholinergic)

• Pralidoxime (2PAM)

• Receptor: Enzyme- AChE

• Action: Reactivate AChe after organophosphate poisoning

• Use: Organophosphate toxicity WITH atropine (other antidote drug)

• Side effects: hypertension or muscle rigidity

Cholinergic Toxicity Antidote (Cholinergic)

• Atropine: ATROPINE IS SYMPOTHETIC AND OPPOSITE TO CHOLINERGIC hence why its an antidote

• Receptor: Muscarinic

• Action: Competitive antagonist at M receptor

• Use: antidote for organophosphate or mushroom poisoning

• Side effects: anticholinergic toxidrome if overdosed

Cholinergic Effects: SLUDGE

• Salivation

• Lacrimation (crying)

• Urination

• Defecation

• GI Distress (cramps)

• Emesis (vomiting)

THINK: REST AND DIGEST

Anticholinergic Effects

• Flush Skin/ Red skin

• Dry mouth,eyes, skin

• Dilated pupils

• Confusion

• Fever

• Urinary retention

THINK FIGHT OR FLIGHT
Cant see, cant pee, cant spit, cant shit

Muscarinic Agonists (CHOLINERGIC EFFECTS)

• Heart: Bradycardia

• Exocrine glands: increase sweat, salivation, bronchial secretion, secretion of gastric acid

• Smooth Muscle

  • Lung contraction

  • GI tract increase motility

  • Bladder contraction

  • Vascular relaxation/dilation

  • Pupillary constriction (dont need wide view)

Reversible vs irreversible cholinesterase inhibitors/ indirect cholinergic agonists

Irreversible

• SAME action as reversible

• Longer acting

• Used PRIMARILY FOR GLAUCOMA (very low concentration is poisonous in moderate to high dose) because you want it to tstay for a long time DUH

• Common in insecticides

Myasthenia Gravis (MG) Treatment

• MGL autoimmune disorder leading to weakness of voluntary skeletal muscles

• Drug type: acetylcholinesterase inhibitor/ indirect cholinergic agonist

  • Direct are LESS specific for MG, often activate muscarninc and NOT nicotninc M whihc is necessary here

• Drugs: Pyridostigmine

• DOSING is INDVIDIUALIZED

  • Have patient keep record of symptoms and drug affect to determine dose

  • Do proper assessment after drug: muscle strength, side effects, fatigue onset, etc.

• Pt teaching

  • Overdose (SLUDGE)

  • Myasthenia crisis

MG ADRs

• Cholinergic Crisis: Overdose

  • Acetylcholine accumulates at all muscarinic and neuromuscular junctions

  • Skeletal muscle paralysis + respiratory distress due to paralysis

  • SLUDGE symptoms (due to overstimulation)

  • Antidote = ATROPINE (anticholinergic)

• Myasthenia Crisis: Underdose

  • Too little medication

  • EXTREME muscle weakness

  • Dangerous due to respiratory distress

  • Antidote: Cholinesterase inhibitor (neostigmine)

Nondepolarizing vs Depolarizing Nicotinic antagonist

• Nondepolarizing:

  • Prevent acetylcholine from binding at NMJ receptors so that no muscle contraction occurs

• Depolarizing:

  • Binds to nicotinic M receptor, mimcs acetylcholine

  • Depolarizes, causes muscle contractions to depolarize = nerve blockage

  • Short acting

END RESULT IS SAME FOR BOTH

Nicotinic antagonist Nursing Implications

• Patient is STILL ABLE TO FEEL, but cant talk, breathe, or move

• Make sure to TALK WITH THE PATIENT

Sympathetic Nervous System Drugs

Mechanism of Adrenergic Receptor Activation

• Direct receptor binding

• Promotion of NE (norepinephrine) release = more available in synapse

• Inhibition of NE reuptake = more available because NOT taken up and removed

• Inhibit of NE inactivation = more available

Adrenergic Agonist

Alpha adrenergic: Vasoconstriction

Beta adrenergic

• Beta 1: increased heart

• Beta 2: bronchodilation of lungs and peripheral blood vessels

Dopaminergic: Dilation of kidney vasculature

Adrenergic Drugs Classes

1. Direct Acting Agonists

2. Indirect Acting Agonist

3. Mixed acting agonist

4. a1 agonists

5. a2 agonist

6. b1 agonist

7. b2 agonist

8. Non selective a blocker

9. Selective a1 blocker

10. Nonselective b blocker

11. B1 selective blocker

12. Mixed a/b blocker

Direct Acting Agonist (Adrenergic)

• Drugs: Epinephrine, NE, Dobutamine, Albuterol, Dopamine

• Receptor: A or B receptors

  • EPI = A1,A2,B1,B2

  • Albuterol = B2

  • Isoproterenol = B1B2

• Action: Directly stimulate adrenergic receptors

• Clinical use: anaphylaxis (Epi: blood flow, airway, and heart rate help), cardiac arrest, asthma, shock

• Side effects: hypertension, tachycardia, arrythmias, tremors

Indirect Acting Agonists (Adrenergic)

• Drugs: Amphetamines, Tyramine, Cocaine

• Receptor: Increase NE release or block reuptake

• Action: Increase synaptic NE 

• Uses: ADHD, narcolepsy, nasal decongestion, local anesthesia. adjunct

• Side Effects: Anxiety, increased BP/HR, insomnia, addiction (for some)

Mixed Acting Agonist (Adrenergic)

• Drug: Ephedrine

• Receptor: Direct and indirect

• Action: stimulate receptors and promote NE release

• Use: Hypotension, nasal congestion

• Side effects: Insomnia, tachycardia, CNS stimulation

A1 Agonist (Adrenergic)

• Drug: Phenylephrine

• Receptor: A1

• Action: Vasoconstriction + Increase BP

• Use: Nasal decongestion, hypotension, hemostasis (STOP BLEEDING, vasoconstriction at injury sitei)

• Side effects: Reflex bradycardia, hypertension

• ADR: Necrosis: If IV line is employed with this med and it seeps out it will cause tissue death due to vasoconstriction

• Bradycardia

A2 Agonist (Adrenergic) Centrally acting

• Drug: Clonidine, Methyldopa

• Receptor: A2(central)

• Action: Decrease sympathetic outflow from CNS = decrease BP

• Uses: Hypertension, ADHD, withdrawal symptoms

• Side effects: Sedation, rebound hypertension (if you discontinue drug abruptly blood pressure can skyrocket) , dry mouth

B1 Agonist (Adrenergic)

• Drug: Dobutamine

• Receptor: B1

• Action: Increase heart rate + contractility

• Use: Acute heart failure, cardiogenic shock, AV heart block to enhance AV conduction impulse, cardiac arrest

• Side effects: Tachycardia, arrythmia, angina, pectoris (increase cardiac oxygen demand

B2 Agonist (Adrenergic)

• Drug: Albuterol, Salmeterol

• Target: B2

• Action: Bronchodilation, smooth muscle relaxation

• Use: Asthma, COPD, premature labor (tocolysis), Gluconeogenesis= make glucose

• Side Effects: Tremor, tachycardia, hypokalemia, gluconeogenesis = hyperglycemia (BE CAREFUL WITH DIABETICS)

Nonselective A blockers (Adrenergic)

Drugs: Phentolamine, Phenoxybenzamine

Receptor: A1 and A2 (get it, non selective)

Action: Blocks A receptors = vasodilation

Use: Pheochromocytoma, extravasation reversal

Side effects: Orthostatic hypotension, Reflex tachycardia

Selective A1 Blockers (Adrenergic)

Drug: Prazosin, Terazosin

Receptor: A1

Action: Vasodilation of arteries and veins

Use: Hypertension, BPH (benign prostatic hyperplasia) = due to dialating ureter allowing for urination, pheochromocytoma (tumor causes hypertension)

Side Effects: First dose + orthostatic hypotension, dizziness, reflex tachycardia, nasal congestion, inhibit ejaculation

B Blockers (Non selective) (Adrenergic)

• Drugs: Propranolol, Nadolol

• Receptor: B1 and B2

• Action: Decrease HR + contractility, bronchoconstriction

• Use: Hypertension, angina pectoris, migraine prophylaxis, AFIB (heart rate fast + irregular), stage freight or anxiety (IN LOW DOSES)

• Side Effects: Bradycardia, bronchospasm (AVOID WITH ASTHMA), fatigue, high blood sugar due to inhibit of glycogenolysis ? what

NURS IMPL:

• Caution with diabetics and asthmatics

• Monitor for adverse reactions

• Monitor vitals: Cant give when BP and HR is TOO LOW

• Can also give orthostatic hypotension

B1 Selective Blockers (Adrenergic) also called CARDIOSELECTIVE

• Drug: metoprolol, Atenolol

• Receptor: B1

• Action: Cardioselectivity: Decrease HR and contractility

• Use: Hypertension, heart failure, post MI

• Side Effects: Bradycardia, fatigue, masks hypoglycemia symptoms

Mixed A/B Blockers (Adrenergic)

• Drugs: Labetalol, Carvedilol

• Target: a1, b1, b2 NOT a2 because a2 decreaess SNS form CNS so it would do opopsite

• Action: Decrease HR and vasodilation

• Use: Hypertensive emergencies, heart failure

• Side effects: Hypotension, dizziness, fatigue

Catecholamines

Catecholamines

• Norepinephrine and Epinephrine

  • Do NOT cross the blood brain barrier (unlike Non catecholamines)

• B1 Adrenergic Receptor = stimulate cardiac activity

• B2 Adrenergic Receptor = Lungs, smooth muscle and bronchial relaxation

THINK: 1 heart, and 2 lungs

Dopamine Receptor Activation: Clinical Consequences

• Activation of peripheral dopamine receptors = DILATION OF KIDNEY VASCULATURE

• Dopamine

  • Dopamine receptors: dilates renal blood vessels, increase renal perfusion, prevents renal failure

  • GIVE DOPAMINE FOR RENAL FAILURE

  • Urine output SHOULD increase

• For SEPSIS/Shock, give higher doses of dopamine to get organs moving and increase HR and BP

Catecholamines vs Non catecholamines

• Cat:

  • CANNOT be used orally, destroyed by MAO and COMT enzymes

  • Brief active period

  • CANNOT cross BBB (due to being polar)

  • Drugs:

    • Epi

    • NE

    • Isoproterenol

    • Dobutamine

    • Dopamine

• Noncat

  • CAN be given PO

  • Metabolized slowly by MAO = longer half life

  • More able to cross BBB

  • Drugs:

    • Ephedrine

    • Phenylephrine

    • Albuterol

TAKE A LOOK AT PICTURE

Albuterol Specific (Direct agonist)

• Beta 2 receptor acting

• NON-CAT

• Use; Asthma

• Side effects: minimal at therapeutic dose, tachycardia, tremor

Isoproterenol (Direct agonist)

• Receptor: B1 and B2

• CAT

• Use: bradycardia, heart block, asthma (albuterol is better), anesthesia

• Side effects: tachy, angina (chest pain due to low blodo to heart), hyperglycemia

Epinephrine: Adrenalin, Epipen (Direct agonist)

• ALL ALPHA AND BETA

• CAT

• Vasoconstriciton

• Uss: Asystole/heartblock, anaphylactic shock

• Side effects: Hypertensive crisis, dysrhythmia, angina pectoris, necrosis from escaped med, hyperglycemia

Treatment of Anaphylactic Shock

• Epinephrine can reverse most sever manifestations

  • A1 = vasoconstriction

  • B1 = Increased heart rate

  • B2 = open airways

DOPAMINE, DOBUTAMINE, EPHEDRINE 

Have to look these up?, really just know general class stuff

Adrenergic Antagonist/ Blockers: Selective vs Nonselective

Alpha:

• Nonselective: produce A1, A2 blockade

  • Phentolamine

• Selective

  • Produce a1 blockade + prazosin

Beta:

• Nonselective: Blocks B1 and B2

  • Propranolol

• Cardio selective: Blocks B1

  • Metoprolol

Adrenergic Neuron Blocking Drugs: IS THIS SAME AS Mixed AB block?

• Drug: Reserpine

• Action: Decrease release of NE from ALL postganglionic sympathetic neurons

• Decrease activation of ALL adrenergic receptors: Combo alpha and beta

• Use: Hypertension

• ADR: Depression, bradycardia, hypotension