Autonomic Pharmacology Flashcards
What drugs are part of the Direct-Acting Cholinoceptor Agonists: Choline Esters class?
Acetylcholine
Methacholine
Carbachol
Bethanechol
Mnemonic: Ace Met Beth in his Car and Ester on a date
Characteristics of Choline Esters
All have cationic quaternary ammonium –> makes them insoluble in lipids
(Poor GI absorption/Poor CNS distribution)
Which two Choline Esters are insusceptible to Cholinesterase?
Carbachol
Bethanechol
Mnemonic: Beth avoids AchE in her Car
What is the action of Choline Esters similar to?
M2 or M3 Activation
Acetylcholine
- Class
- Muscarinic Effects
- Nicotinic Effects
Class: ***Prototype*** Choline Ester (Direct-Acting Cholinoceptor Agonist)
Muscarinic:
Cardiovascular-
Low Doses: Vasodilation –> reflex tachycardia
High Doses (M2 Effects): Bradycardia ; Decreased A-V conduction; (-) Inotropy
Bronchial constriction, increased bronchial secretion
Salivary excretion, tears, sweat
Urinary bladder contraction
Eye short-lasting miosis
Nicotinic: NOT COMMONLY SEEN, since Ach does not penetrate the fat surrounding skeletal muscle and autonomic ganglia
Acetylcholine
- Clinical Uses (2)
Use:
Eye Surgery (short-lasting MIOSIS)
PROVOCATION TEST in Coronary Angiography (Dx: Coronary Vasospasm)
Methacholine (Provocholine)
- Class/About
- Clinical Uses
Class: Choline Ester (Direct-Acting Cholinoceptor Agonist)
Similar to Ach in action, but has longer half life
Use:
- Methacholine Challenge (inhaled) –> Bronchiolar Hypersensitivity (excessive BronchoCONSTRICTION)
- Belladonna alkaloid poisoning (SubQ) –> Dose would NOT elicit normal MUSCARINIC effects in someone with this
Carbachol
- Class
- Effects
- Clinical Uses
Class: Choline Ester (Direct-Acting Cholinoceptor Agonist)
Effects:
Therapeutic Doses: Activate both NICOTINIC and MUSCARINIC cholinoceptors (Nicotinic effects - Autonomic Ganglia, Adrenal Medulla, Skeletal muscle)
High Doses: Muscarinic effects - May include CARDIAC ARREST
Use:
Glaucoma (contracts Ciliary muscle, enlarges canal of Schlemm, increases drainage of Aq. Hum., Decreases Intraocular Pressure)
Bethanechol (Urecholine)
- Class
- Effects
- Clinical Uses
Class: Quaternary Choline Ester (Direct-Acting Cholinoceptor Agonist)
Effects: Acts Predominantly on M3 (NO nicotinic effects)
Genitourinary: increased detrusor tone, decreases outlet resistance of internal sphincter
Gastrointestinal: increased motility and secretion
Weak effects on M2 - minimal cardiac effects
Clinical Uses:
Gastric Atony after vagotomy to reduce reflux (INCREASES lower esophageal sphincter tone)
Gastric Emptying Abnormalities
Urinary RETENTION (in the ABSENCE of obstruction)
Mnemonic: Beth think Bladder
What drugs are part of the Direct-Acting Cholinoceptor Agonists: Muscarinic Alkaloids class?
Muscarine
Pilocarpaine
Mnemonic: Al has a Pile of Muscles
Muscarine
- Class
- Properties
Class: Muscarinic Alkaloid (Direct-Acting Cholinoceptor Agonist) Quaternary Ammonium Compound
Properties: No Nicotinic Activity; 100x more potent than Ach and has a longer duration of action than Ach, as it is not broken down by AchE because it is not a choline ester)
Muscarine Poisoning
- Cause
- Symptoms
Cause: Mushrooms (e.g. Amanita Muscaria)
Sx: A very WET PICTURE
- Salivation, sweat, tear flow
- Abdominal pain, nausea, diarrhea, blurred vision, dyspnea
- Severe Cases: cardiac/respiratory failure and Death
***Symptoms normally subside within 2 hours***
Pilocarpine (Isopto Carpine, Salagen)
- Class
- Effects
- Clinical Use
Class: Muscarinic Alkaloid (Direct-Acting Cholinoceptor Agonist) Tertiary Amine
Effects: Produces Ophthalmic (M3) Effects similar to Ach (applied Topically)
Contracts iris sphincter muscles –> Miosis
Frees entrance to Canal of Schlemm –> Narrow-angle Glaucoma
Enhances tone of trabecular network –> Wide-angle Glaucoma
Contracts the ciliary muscle (Lens becomes more spherical) –> Accomodation__/LOSS of FAR vision
Uses:
GLAUCOMA (***Drug of choice***), Xerostomia (dry mouth - given orally), tests the AUTONOMIC STATE (similar to Methacholine Challenge)
What drugs are part of the Direct-Acting Cholinoceptor Agonists: Nicotinic Alkaloids class?
Nicotine
Succinylcholine
Mnemonic: Nicotine Succs
Nicotine
- Class
- Action on NM
Class: ***Prototype***Nicotinic Alkaloid (Direct-Acting Cholinoceptor Agonist)
NM Action:
Skeletal Muscle Contraction
Fasciculations, spasm
Depolarizing Blockade –> Paralysis (Similar to Succinylcholine under neuromuscular blocking drugs)
Nicotine
- Action on NN
NN Action: Stimulate both sympathetic and parasympathetic post-ganglion neurons
Cardiac: increased heart rate (sympathetic > parasymp)
Vascular: mostly sympathetic innervation –> peripheral vasoconstriction
GI: increased gut motility/secretion
Carotid Bodies: increased respiratory rate
Medullary Emetic Chemoreceptors: nausea and vomiting
Nicotine
- Clinical Indications
Smoking cessation
-Stimulates the hypothalamus to secrete more cortisol
What are some Contraindications (3) and Drug Interactions (3) to consider when administering Direct-Acting Cholinoceptor Agonists?
Contraindications:
Peptic Ulcers (Increased Gastric Acid secretion)
GI Tract Disorders
Asthma (Bronchoconstriction)
Drug Interactions: Drugs having antimuscarinic properties can block the effects of muscarinic agonists
(e.g. Quinidine (antiarrhythmics), Procainamide (antiarrhythmics), Tricyclic Antidepressants
What drugs are part of the Indirect-Acting Cholinesterase Inhibitors/Cholinomimetics: Reversible class?
Edrophonium
Neostigmine
Physostigmine
Donepezil
Tacrine
Mnemonic: Ed and Don Physically Tackled Neo
Edrophonium
- Class
- Characteristics
- Clinical Uses
Class: Indirect-Acting Cholinesterase Inhibitors/Cholinomimetic: Reversible
Characteristics: Short-acting
Uses: Diagnosis of MYASTHENIA GRAVIS (MG) ; If Edrophonium IMPROVES the symptoms, then it confirms diagnosis of MG vs. Cholinergic crisis, neurasthenic/infectious/endocrine/congenital/neoplastic/degenerative neuromuscular disorders
Neostigmine, Pyridostigmine
- Class
- Characteristics
- Clinical Uses
Class: Indirect-Acting Cholinesterase Inhibitors/Cholinomimetic: Reversible
Chracteristics: Quaternary amines (NO CNS ENTRY), Intermediate Acting
Uses: Ileus (Abdominal Distension), Urinary Retention (Non-obstructive), Myasthenia, Reversal of non-depolarizing NM Blockers
Mnemonic: Neostigmine has Neo (No) CNS action
Physostigmine
- Class
- Characteristics
- Clinical Uses
Class: Indirect-Acting Cholinesterase Inhibitors/Cholinomimetics: Reversible
Characteristics: Tertiary Amine (ENTERS CNS), Intermediate Acting
Uses: Glaucoma (2nd line due to blocked accomodation and causation of myopia); antidote to Atropine Overdose
Mnemonic: Physostigmine physically enters the CNS
Donepezil, Tacrine
- Class
- Characteristics
- Clinical Uses
Class: Indirect-Acting Cholinesterase Inhibitors/Cholinomimetics: Reversible
Characteristics: Lipid-soluble (ENTERS CNS)
Use: Treats Alzheimer Disease (increases cholinergic neurotransmitters in the CNS)
Organophosphates
- Class
- Characteristics
- Clinical Uses
Class: Indirect-Acting Cholinesterase Inhibitors/Cholinomimetics: IRr__eversible
Characteristics: Lipid-soluble (CNS ENTRY), Long-acting IRREVERSIBLE inhibitors of AchE
Uses: Glaucoma (echothiophosphate), Insecticides (malathion, parathion), Nerve Gas (sarin)
Symptoms of AchE Inhibitor/Cholinomimetic Toxicity
D - Diarrhea
U - Uncontrolled urination (contraction of detrusor)
M - Miosis (constriction of sphincter)
B - Bronchiolar constriction
B - Bradycardia (decreased contractility)
E - Excitement, convulsion, coma
L - Lacrimation (tears)
S - Sweating
S - Salivation
How is AchE Inhibitor/Cholinomimetic Toxicity managed clinically?
Symptomatic
Airway control/oxygen delivery
Cardiovascular support
Antidote: Atropine (muscarinic receptor antagonist)
-Relieves tracheobronchial/salivary secretion, bronchoconstriction, bradycardia, peripheral ganglionic and central actions of anti-AchE
Regeration of AchE: Praladoxim (2-PAM)
- Reverses phosphorylation of AchE (by AchE inhibitors)
- Does not work for neostigmine, physostigmine, or rapidly-aged phosphorylated AchEs
What drugs are part of the Cholinoceptor-Blocking Drugs: Muscarinic Receptor Antagonist (Antimuscarinic) class?
Atropine
Ipratropium
Benztropine
Mnemonic: Ipray for a Benz and Atrophy
Atropine
- Class
- Characteristics
Class: ***Prototype*** Muscarinic Receptor Antagonists (Antimuscarinic)
Characteristics: Tertiary Amine (ENTERS CNS), Competes with Ach & M at receptors ; DOES NOT DISTINGUISH between M1, M2, M3 receptors
Atropine
- Pharacologic Effects (in order of increasing dose)
Decreased secretions (salivary, bronchiolar, sweat)
Mydriasis and Cycloplegia
Hyperthermia
Tachycardia
Sedation
Urinary retention and constipation
Behavioral excitation and hallucinations
***Note: completely counteracts vasodilation caused by choline esters
DOES NOT affect blood pressure when given ALONE
Atropine
- Clinical Uses
Uses:
Antispasmodic (relaxes)
Antisecretory (dries)
Management of AchE inhibitor overdose
Antidiarrheal (dries)
Ophthalmology
Prevents vagal reaction (pericardiocentesis) by increasing heart rate
Treatment of acute intoxication: Symptomatic, Physostigmine
Ipratropium (Atrovent)
- Class
- Characteristics
- Clinical Uses
Class: Non-selective Muscarinic Receptor Antagonist (Antimuscarinic)
Characteristics: Mainly acts on M3 in Bronchial smooth muscle/glands when inhaled ; Quaternary amine (NO CNS ENTRY)
- Decreases bronchoconstriction
- Decreases bronchial constriction
Uses: ***1ST LINE THERAPY*** for COPD ; also used for asthma (2nd line therapy)
Benztropine (Cogentin)
- Class
- Characteristics
- Clinical Uses
Class: Muscarinic Receptor Antagonists (Antimuscarinic)
Characteristics: Tertiary Amine (CNS ENTRY) ; Acts on Muscarinic receptors in the BRAIN and PARASYMPATHETIC EFFECTOR SITES
- Re-establishes Dopaminergic-Cholinergic Balance** in patients with **Parkinson’s Disease (PD: decreased dopaminergic –> cholinergic goes unchecked)
- Decreases GI/GU secretions (Dries) and motility
- Increases heart rate
Uses: Parkinson’s Disease (2nd or 3rd line therapy to antipsychotic)
What drugs are part of the Cholinoceptor-Blocking Drugs: Nicotinic Receptor Antagonists (NN & NM)/GANGLION BLOCKING AGENTS class?
Hexamethonium
Mecamylamine
Mnemonic: Mecca Hex
Hexamethonium and Mecamylamine
- Class
- Characteristics
- Clinical Uses
Class: ***GANGLION BLOCKING AGENTS*** Nicotinic Receptor Antagonists (Antinicotinic NN & NM)
Characteristics: Reduce predominant autonimic tone
-Prevent baroreceptor reflex changes in Heart Rate
***Most are no longer available due to TOXICITIES***
What are the effects of Ganglion Blocking Agents on Arterioles, Veins, Heart, Iris, Ciliary Muscle, GI Tract, Bladder, Salivary Glands, Sweat Glands?
Arterioles (SANS) –> Vasodilation, hypotension
Veins (SANS) –> Dilation, decreased venous return, decreased CO
Heart (PANS) –> Tachycardia
Iris (PANS) –> Mydriasis
Ciliary Muscle (PANS) –> Cycloplegia (paralysis –> loss of accomodation)
GI Tract (PANS) –> Decreased tone/motility - constipation
Bladder (PANS) –> Urinary retention
Salivary Glands (PANS) –> Xerostomia
Sweat Glands (SANS) –> Anhidrosis
What drugs are in the Cholinoceptor-Blocking: Neuromuscular Blocking Drugs (Antinicotinic NM) class?
D-tubocurarine (Non-depolarizing)
Succinylcholine (Depolarizing)
What are some important properties of Neuromuscular Blocking Drugs? Clinical Uses?
- They all structurally resemble Ach
- Interfere with transmission at the neuromuscular endplate
- Interefere by preventing channel opening** (Non-depolarizing) or channel **closing (Depolarizing)
- Highly ionized, Quaternary Amines (NO CNS ENTRY)
Clinical Uses: Facilitation of Tracheal Intubation ; optimize surgical conditions while ensuring adequate ventilation
D-Tubocurarine
- Class
- Mechniasm of Action
Class: Non-Depolarizing Neuromuscular (NM) Blocking Drug
MoA:
Small Doses: Prevent opening of Na+ channel by binding to receptor and competing with Ach
Large Doses: enter channel pores
-Block pre-junctional Na+ channels –> Decreased Ach release
Succinylcholine (Anectine)
- Class
- Mechanism of Action
Class: Depolarizing Neuromuscular (NM) Blocking Drug
MoA:
Phase 1 Blockade: Binding to NM receptors –> persistant depolarization –> paralysis
-Augmented by AchE inhibitors
Phase 2 Blockade: End plate is finally repolarized, however, is DESENSITIZED and will not depolarize easily again
What are some clinical uses of Neuromuscular Blockers (i.e. D-tubocurarine and Succinylcholine)?
-
Decrease neuromuscular transmission during anesthsia
- Larger muscles are more resistant than smaller muscles
- Diaphragm responds last (recovery is in reverse order) - Tracheal Intubation
- Control of Ventilation
- Treatment of Convulsions
- Decreased manifestations of seizures
- No effect on central processes that occur during convulsion
What are some side effects of Neuromuscular Blockers?
-
Cardiovascular: Hypotension (Histamine release due to Tubocurarine) –> prevented with ANTIHISTAMINES
- High doses –> Ganglion blockade –> severe HYPOtension - Hyperkalemia (response to Succinylcholine from patients with burns, nerve damage, or neuromuscular disease)
- Increased Intraocular Pressure (due to Succinylcholine ; only contraindicated if anterior chamber is OPEN due to trauma)
- Increased Gastric Pressure (can cause aspiration/regurgitation in heavily-muscled patients)
- Muscle Pain (heavily-muscled and largely-dosed patients)
What drugs are part of the Selective Direct Acting Adrenergic Agonist class?
Phenylephrine (a1)
Clonidine (a2)
Terbutaline (B2)
Fenoldopam (D1)
Mnemonic: You can Find Old Pam playing the Pine TPC
Phenylephrine (Neo-Synephrine)
- Class
- Mechanism of Action
- Clinical Uses
Class: alpha 1 - Selective Adrenergic Receptor Agonist
MoA:
- Activate alpha adrenergic receptors on vascular smooth muscle –> increased blood pressure and increased TPR
- Activate Beta receptors only at HIGH concentrations
Use:
- Antihypotensive
- Paroxysmal Atrial Tachycardia
- Nasal Decongestant
- Mydriatic
Clonidine (Catapres)
- Class
- Mechanism of Action
- Clinical Uses
Class: alpha 2 - Selective Adrenergic Receptor Agonist
MoA: Activate Central alpha 2 receptors –> Decreased Central sympathetic outflow –> Decreased Blood Pressure
Uses: Systemic Hypertension
a-methyldopa (Aldomet)
- Class
- Mechanism of Action
- Clinical Uses
Class: alpha 2 - Selective Adrenergic Receptor Agonist
MoA: Activate Central alpha 2 receptors –> Decreased Central sympathetic outflow –> Decreased Blood Pressure
Uses: Systemic Hypertension
Apraclonidine (Lodipine)
- Class
- Mechanism of Action
- Clinical Uses
Class: alpha 2 - Selective Adrengergic Receptor Agonist
MoA: Decreased aqueous humor production –> Decreased Intraocular pressure
Use: GLAUCOMA
Brimonidine (Alphagan)
- Class
- Mechanism of Action
- Clinical Uses
Class: alpha 2 - Selective Adrengergic Receptor Agonist
MoA: Decreased aqueous humor production –> Decreased Intraocular pressure
Use: GLAUCOMA
What are some adverse effects of alpha 2 - Selective Adrenergic Receptor Agonists?
Dry Mouth
Sedation
Hypotension
Metaproterenol (Metaprel)
- Class
- Mechanism of Action
- Clinical Uses
Class: Beta 2 - Selective Adrenergic Receptor Agonists
MoA:
***Resistant to methylation by COMT***
-Beta 2-Selective (LESS selective than Albuterol or Terbutaline)
Uses: Long-term treatment of obstructive airway diseases - ASTHMA** ; treats **Acute Bronchospasm
Terbutaline (Bricanyl)
- Class
- Mechanism of Action
- Clinical Uses
Class: Beta 2 - Selective Adrenergic Receptor Agonists
MoA: ***NOT a substrate for COMT methylation***
-Beta 2-Selective
Uses:
- Long-term treatment of obstructive airway diseases
- Acute Bronchospasm
- Emergency treatment of Status Asthmaticus (IV use)
Albuterol (Ventolin, Salbutamol)
- Class
- Mechanism of Action
- Clinical Uses
Class: Beta 2 - Selective Adrenergic Recptor Agonist
MoA:
- Beta 2 - Selective (Same as Terbutaline)
- Treats Acute Bronchospasm
Uses:
(Same as Terbutaline)
-Delays PRETERM LABOR
Ritodrine (Yutopar)
- Class
- Mechanism of Action
- Clinical Uses
Class: Beta 2 - Selective Adrenergic Receptor Agonist
MoA:
-Beta 2 - Selective Agonist
Uses:
- Designed specificall for use as a _***UTERINE RELAXANT***_
- Arrests Premature Labor
- Prolongs Pregnancy
What are some adverse effects of Beta 2 - Selective Adrenergic Receptor Agonists?
Caused by a result of excessive activation of Beta receptors
-
Tachycardia (especially those with CAD or arrhythmia)
- Risk for adverse CV events INCREASED with use of MAO inhibitors, as they allow buildup of Beta 2 agonists in plasma ; wait 2 weeks between MAO use and Beta 2 administration) - Increased glucose, lactate, and free fatty acids
- Decreased plasma K+ (potassium) (especially in patients with cardiac disease –> taking Digoxin and diuretics)
How can Beta 2 - Selective Adrenergic Receptor Agonist adverse effects be reduced?
By using INHALATION THERAPY rather than parenteral or oral
Fenoldopam (Corlopam)
- Class
- Mechanism of Action
- Clinical Uses
- Side Effects
Class: D1 - Selective Adrenergic Receptor Agonist
MoA:
- Mainl a D1 Receptor Agonist
- Some stimulation of alpha 2 (a2) adrenoceptors –> feedback inhibition of Norepinephrine release
- Leads to renal, peripheral, and coronary vasoDILATION
Use:
_***HYPERTENSIVE CRISIS***_ (Given IV)
Side Effect: Hypotension
What drugs are in the Non-Selective Direct Acting Adrenergic Agonist class?
Isoproterenol (B1 B2)
Dobutamine (B1 a1 B2)
Epinephrine (B1 B2 a1)
Norepinephrine (a1 B1)
Dopamine (D1 D2 a)
Isoproterenol (Isuprel)
- Class
- Effects
- Clinical Uses
Class: B1 B2 Agonists
***No effect on alpha (a) receptors***
Effects:
-Cardiovascular: Decreased TPR, Increased Heart Rate (arrhythmias), Increased Myocardial Contractility
-Bronchodilation (STRONG)
Uses:
- Bradycardia (Treated via Reflex Tachycardia from B1 receptors)
- A-V block
-TORSADES de POINTES (Ventricular Fib)
-Pacemaker Placement
Dobutamine (Dobutrex)
- Class
- Effects
Class: B1, a1, B2 Receptor Agonist
***Mainly acts on Beta 1 (B1) at Therapeutic Doses (considered Selective)
-Directly interacts with a and B receptors; DOES NOT release NE from sympathetic nerve endings
Effects:
Cardiovascular: Positive inotropic effect on heart ( >Isoproterenol)
- Positive Chronotropic effect (Increased SA node automaticity and A-V conduction)
- TPR is NOT AFFECTED (Due to a1-B2 Balance)
Dobutamine (Dobutrex)
- Adverse Effects
- Clinical Uses
AE:
- Excessive increases in blood pressure and heart rate
- Increased ventricular response rate in patients with A-Fib
- Ventricular ectopic activity
- May increase the size of Myocardial Infarct
- Tolerance
Uses:
- Short-term treatment of Cardiac Failure (post cardiac surgery, CHF, MI) –> ***Increases Contraction WITHOUT increasing the Heart Rate
- Longer-term efficacy is uncertain
- Stress Tests (pts with CAD)
Epinephrine (Adrenaline)
- Class
- Effects
- Clinical Uses
Class: a and B receptor Agonist
***Beta (B) has higher affinity** for **Epinephrine so B goes First dosewise
Effects (IV):
-Small Doses: B1 –> Increased Pulse Pressure, Heart Rate, Stroke Volume, and Cardiac Output
B2 –> Decreased Total Peripheral Resistance
-Moderate Doses: B1 –> (Same as above)
B2 –> (Same as above) + Decreased Diastolic Blood Pressure
a1 –> Increased TPR and Blood Pressure ***Counteracts B2***
-High Doses: a1, B1, and B2 are all same as above, except that alpha 1 (a1) predominates** which –> **REFLEX BRADYCARDIA (Potentially)
Uses: Subcutaneously causes slow absorption, vasoCONSTRICTION for SUTURING
What is the Epinephrine Reversal Phenomenon and How does it work?
If you block a or B receptors prior to administration of Epinephrine, the response will be much more pronounced
a receptor antagonism (e.g. Phentolamine) –> Increased vasoDILATION –> Decreased TPR –> Decreased Mean Arterial Pressure
***Opposite with B receptor antagonism
What are the Vascular Effects of Epinephrine** and where are the **main sites of action?
Main Sites of Action: Smaller ARTERIOLES and Precapillary SPHINCTERS
Leads to a General redistribution of blood flow
- Cutaneous Flow Decreases
- Skeletal Muscle Flow Increases
- Cerebral Circulation shows little or no vasoconstriction (@ thereapeutic doses)
- Renal Blood Flow Decreases, GFR <->, Filtration Fraction Increases, Renin Secretion Increases (Beta 1 (B1))
- Pulmonary Blood Flow: both PAP and PVP Increase
- Coronary Blood Flow Increases (Increased relative diastole, aortic pressure, and metabolic stimulation)
What are the Cardiac Effects of Epinephrine?
Powerful Cardiac Stimulant: B1
- Increased Heart Rate, Shortened Systole, Diastole <->
- Increased Inotropy (Contraction), Lusitropy (Relaxation; active process),and chronotropy (Heart Rate) –> Increased Myocardial Oxygen Consumption
- Increased Automaticity –> Arrhythmias (potentially)
- ECG Changes
What are the Smooth Muscle effects of Epinephrine?
***Vascular smooth muscle is most affected
-Most important during Cardiac Arrest
GI Smooth Muscle: Relaxation
What are the Toxic/Adverse Effects of Epinephrine? Contraindications?
AE:
- Throbbing headache, tremor, palpitations
- Cerebral Hemorrhage (LARGE doses, rapid IV)
- Arrhythmias
- Angina (in pts with CAD)
***Contraindications: Patients using NON-SELECTIVE BETA BLOCKERS***
What are the Therapeutic Uses of Epinephrine?
- Hypersensitivity Reactions (including Anaphylaxis)
- Cardiac Arrest
- Local Anesthetics
- Post-extubation croup, viral croup (Dilates Bronchiole Smooth Muscle)
Norepinephrine
- Class
- Properties
Class: a1 >> B1 >>>>>> B2 Receptor Agonist
***Potent alpha (a) agonist ( <epinephrine><u>LITTLE ACTION</u> on <strong>B2 receptors</strong></epinephrine>
Norepinephrine
- Cardiovascular Effects
- Increase Systolic and Diastolic Blood Pressure, as well as Pulse Pressure
- Increase Coronary Flow (Coronary dilation/elevated BP)
- <-> / Decrease Cardiac Output
- ***Increase Total Peripheral Resistnace (TPR)***
- Decrease Renal Blood Flow
- Decrease Splanchnic and Hepatic Blood Flow
Norepinephrine
- Toxicity/Adverse Effects
- Therapeutic Uses
AE: Similar to those of Epinephrine (e.g. Restlessness, Throbbing Headache, Tremor, Palpitations, Cerebral Hemorrhage (large doses/Rapid IV), Cardiac Arrhythmias, Angina (pts with CAD))
***Greater elevation of Blood Pressure (Treats HYPOtension)***
Leads to Reflex BRADYcardia
Uses:
-Treatment of Hypotension (dose titration needed)
Dopamine
- Class
- Properties
Class: D1, D2, B1, a1 Receptor Agonist
Properties:
- Immediate metabolic precursor of Norepinephrine and Epinephrine
- In CNS: Neurotransmitter important in regulation of movement
- In Periphery: Synthesized in the epithelial cells of the proximal tubule –> ***Local Diuretic/Natriuretic Effects***
- Substrate for both MAO and COMT (ineffective if given orally)
How do low doses (< 2 ug/kg/min) of Dopamine lead to Increased Urine Output via Presynaptic D2 Receptors?
Dopamine (low dose) –> Presynaptic D2 receptors (on peripheral circulation nerves) –> Decreased NE release and Decreased stimulation of VSMCs –> Vasodilation –> Increased GFR and Increased RBF –> Increased Na+ Filtered –> ***Na+ Diuresis***
How do low doses (< 2 ug/kg/min) of Dopamine Increase Urine Output via Vascular D1 Receptors?
Dopamine (low dose) –> Vascular D1 receptors (renal, mesenteric, coronary) –> Vasodilation –> Increased GFR, RBF (Renal Blood Flow) –> Increased Na+ Filtered –> ***Na+ Diuresis***
How does low dose (< 2 ug/kg/min) Dopamine cause Increaed Urine Output via Renal Tubular Cell D1 receptors?
Dopamine (low dose) –> Renal Tubular Cell D1 receptors –> Increased Proximal, Henle Loop [cAMP] –> Decreased Na+-K+-ATPase –> Decreased Na+ Reabsorption –> ***Na+ Diuresis***
Dopamine
- Cardiovascular Effects of Moderate Doses (2-5 ug/kg/min)
- Increased Inotropic Effect (B1) (Increased cardiac contractility, Tachycardia, Increases Systolic Blood Pressure/Pulse Pressure ; NO EFFECT on Diastolic Blood Pressure)
- Release of Norepinephrine from nerve terminals
- Little Effect on Total Peripheral Resistance
Dopamine
- Precautions, Adverse Reactions, Contraindications
- Hypovolemia should be corrected before use of Dopamine
- Tachycardia, Angina, Arrhythmias, Headache, Hypertension
- Extravasation –> Ischemic Necrosis and Sloughing
- MAO Inhibitor or Tricyclic Antidepressant –> AVOID Dopamine (or use with EXTREME CAUTION)
***Inhibit Degradation***
Dopamine
- Therapeutic Uses
Uses:
- Severe CHF, particularly in patients with oliguria (abnormally small amount of urine) and low/normal peripheral vascular resistance
- Cardiogenic/Septic Shock
- May acutely improve Cardiac and Renal Function in severely ill patients with chronic Heart Disease or Renal Failure
Ephedrine (Ephedrine, Ephedra)
- Class
- Characteristics
Class: ***The ONLY Mix-Acting Adrenergic Agonist***
Acts on a1, a2, B1, B2, and releasing agent
Characteristics:
- First orally active sympathomimetic drug
- Found in ma-huang
- High bioavailability and a relatively long duration of action
- A Mild CNS stimulant
- Pseudoephedrine** (ephedrine enantiomer) is a **Decongestant
What drugs are part Indirect-Acting Releasing Agents?
Amphetamine
Tyramine
Amphetamine
- Class
- Characteristics
Class: Indirectly Acting Sympathomimetic Amine Releasing Agent
Characteristics:
- Structurally related to Norepinephrine –> Transported into the terminal by NET1
- Displaces Norepinephrine –> Norepinephrine is then released Independent of Exocytosis and does NOT require the presence of Ca++
- Partially active by inhibiting NET 1 (decreasing reuptake of NE) and partially by inhibiting MAO (decreasing metabolization of NE)
Amphetamine
- Effects on the CNS
- ***Releases Biogenic Amines from storage sites in nerve terminals
- Stimulates the medullary respiratory center
- Stimulates cortex and reticular activating system –> this prevents Fatigue and delays the need for sleep
- Treats obesity (Decreased food intake)
Amphetamine
- Cardiovascular Responses
- Activates peripheral alpha (a) and beta (B) (like Norepinephrine)
- Increases Systolic/Diastolic Blood Pressure
- Increases Heart Rate
- Cardiac arrhythmias (may occur)
Amphetamine
- Effect on the Bladder Sphincter
Increased Bladder Sphincter Contraction
Treats: Enuresis and Incontinence
Tyramine
- Class
- Characteristics
- Adverse Effects
Class: Indirectly Acting Sympathomimetic Amine Releasing Agent
Characteristics:
- Used to synthesize Norepinephrine and Epinephrine via the alternate pathway
- Destroyed by MAO in the gut wall and liver
AE:
-Action is Increased by MAO inhibition –> Ingestion of Tyramine-rich foods ***FERMENTED CHEESE*** –> Sudden and Dangerous rise in Blood Pressure
What is the main drug in the alpha (a) Adrenoceptor Antagonist: a1 >>> a2 class?
Prazosin
Also, Terazosin and Doxazosin
What is the main drug in the alpha (a) Adrenoceptor Antagonist a1 > a2 class?
Phenoxybenzamine
Which drug(s) are part of the alpha (a) Adrenoceptor Antagonist a1 = a2 class?
Phentolamine
Which drug(s) are part of the alpha (a) Adrenoceptor Antagonist a2 > a1 class?
Yohimbine
Rauwoscine
Torazoline
What determines the effecs of Reversible alpha receptor antagonists? Irreversible?
Reversible: effects are determined by the half-life of the inhibitor/antagonist
Irreversible: effects are determined by the rate of production of new receptors
What are the effects of alpha receptor antagonists?
- Decrease blood pressure –> orthostatic hypotension
- Tachycardia (Transient, Reflex Tachycardia)
- Reverse the pressor effects of a and B agonists
- Miosis (M3 is unopposed, conracts sphincter)
- Nasal Stuffiness
- Decreased resistance to urine flow
What are the therapeutic uses of alpha receptor antagonists?
- Pheochromocytoma (Rare –> Releases Norepinephrine)
- Hypertensive emergency
- Chronic hypertension
- Peripheral vascular disease (Small doses)
- Urinary obstruction
- Erectile dysfunction (promotes ejaculation)
Phenoxybenzamine (Dibenzyline)
- Class
- Mechanism
- Effects
Class: alpha (a) receptor antagonist
MoA: Irreversibly blocks a1 and a2 (LONG duration of action)
- Also blocks H1, Acetylcholine, and Serotonin (5-HT) receptors
- Indirect Baroreflex activation
Effects:
-Decreases Blood Pressure but Heart Rate Rises due to Baroreflex Activation
Phenoxybenzamine (Dibenzyline)
- Clinical Uses
- Toxicity
Uses:
- Treats Pheochromocytoma
- Treats High Catecholamine states
Toxicity:
Half life is >1 day
-Orthostatic hypotension, Tachycardia, Myocardial Ischemia (increased heart rate can exacerbate this), Problems with ejaculation (due to alpha 1a blockade)
Prazosin (Minipress)
- Class
- Mechanism
- Effects
- Clinical Uses
- Toxicity
- Similar drugs
Class: alpha (a) adrenoceptor antagonist
MoA: Blocks alpha 1 (a1) but NOT alpha 2 (a2)
-Relaxes arterial, venous, and prostate smooth muscle
Effects:
-Decreases blood pressure
Uses:
-Treats Hypertension and Benign Prostatic Hyperplasia
Toxicity:
-Larger depressor effect with first dose may cause Orthostatic Hypotension (watch for Tachycardia)
Similar Drugs: Doxazosin and Terazosin
Tamsulosin (Flomax)
- Class
- Mechanism
- Effects
- Clinical Uses
- Toxicity
Class: alpha (a) adrenoceptor antagonist
MoA: slightly selective for alpha 1A (PROSTATE)
Effects:
-alpha 1a (a1A) blockade may relax prostatic smooth muscle more than vascular smooth muscle
Uses:
-Treats _***BENIGN PROSTATIC HYPERPLASIA***_
Toxicity: Orthostatic Hypostension is less common with this subtype
Yohimbine
- Class
- Mechanism
- Effects
- Use
- Toxicity
Class: alpha (a) adrenoceptor antagonist
MoA: Blocks alpha 2 (a2) (has CNS activity) and increases norepinephrine release
Effects: INCREASES Blood Pressure and Heart Rate
Uses: Treats ***Erectile Dysfunction***
-Hypotension, as well, but not as much
Toxicity:
- Anxiety
- Excess pressor effect if NET1 is blocked
Labetalol
- Class
- Mechanism
- Effects
- Use
- Toxicity
Class: Beta (B) and alpha 1 (a1) adrenoceptor antagonist
Moa: ***Blocks BOTH (B > a1)***
Effects:
Decreases Blood Pressure w/ limited heart rate increase
Uses:
***Used in High Sympathetic States*** (e.g. Hypertensive Crisis, Hypertension, Pheochromocytoma)
-Good because it will not/very limited reflex Tachycardia
Toxicity:
***LESS Tachycardia***
What are the drugs in the B1 = B2 Non-Selective 1st Generation Beta (B) Adrenoceptor Antagonists class?
Propranolol
Nadolol
Timolol
Pindolol* (ISA)
Mnemonic: These drugs are Not Sharp like a PiNTiP
What are the drugs in the B1 >>> B2 Selective 2nd Generation Beta (B) Adrenoceptor Antagonist class?
Atenolol
Metoprolol
Esmolol
Betaxolol
Acebutolol* (ISA)
Mnemonic: Slimey AMEBA
***Selectivity is lost at HIGH DOSES***
What are the drugs in the B1 = B2 >or= a1 > a2 Vasodilatory 3rd Generation Mixed a-B Antagonist class?
Labetalol
Carvedilol
What are the Cardiovascular Effects of Beta Receptor Antagonists? Clincal uses?
Effects:
- Decreased inotropic/chronotropic effect –> Decreased Blood Pressure in hypertensive (***no effect on normotensive individual; thefore used for GLAUCOMA)
- Decreased myocardial oxygen consumption
- Decreased renin release
Uses:
- Treats Hypertension
- Glaucoma (blocks B1 and B2 in Ciliary Epithelium
- Arrhythmias
- Ischemic Heart Disease
What are the Respiratory Effects of Beta Receptor Antagonists?
-Beta 2 (B2) Blockade –> Increased airway resistance –> undesiable in asthma and COPD
***No Beta Blocker is completely free of B2-blocking effect***
What are the effects of Beta Receptor Antagonists in the Eye?
Decreased aqueous humor production –> Decreased intraocular pressure
What are the Metabolic Effects of Beta Recptor Antagonists?
Inhibits lipolysis
May decrease glucagon release
Increases VLDL
Decreases HDL
_***BAD EFFECTS ON CHOLESTEROL***_
What are the Therapeutic Uses of Beta Receptor Antagonists?
Treat:
- Hypertension
- Ischemic Heart Disease
- Arrhythmias
- Heart Failure - especially 3rd Degree and onward (caused by reduction in myocardial contraction –> reflex INCREASE in circulating catecholamines (e.g. Norepinephrine/Epinephrine) and INCREASED plasma renin activity –> OVERACTIVATION of B1 receptors in Heart and subsequent downregulation of adrenergic receptors)
***Treated with really low doses of B1-selective antagonists
- Glaucoma
- Hyperthyroidism (Symptomatic; treats increased heart rate)
- Neurologic Diseases (e.g. migraines, anxiety, etc.)
What are the 3 important Clinical Considerations for choosing Beta Blockers? (List them in order of clinical consideration)
1. Cardioselectivity (e.g. AMEBA group) - DO NOT use Non-Selective in pts with Asthma/COPD (due to B2 blocking effect –> Bronchiole CONSTRICTION); Use Selective** and keep the **Dose Low
2. Intrinsic Sympathomimetic Activity (ISA)
-e.g. Pindolol and Acebutolol (allows use of Beta blocker without dropping the Heart Rate)
3. Lipid Solubility
What are the four factors to consider related to lipid solubility when using Beta blockers?
1. Plasma Levels and Duration of Action (fat tissue)
- Lipophilic Beta-Blockers: (e.g. propranolol/metoprolol) produce lower plasma concentration and have less predictable plasma concentration because they are metabolized by the liver
- Hydrophilic Beta Blockers: longer biological action (allow once-a-day dosing)
2. CNS
-Hydrophilic Beta-Blockers enter the brain much less than Lipophilic
3. Kidney
-Hydrophilic are effected by kidney functions; Lipophilic are not
4. Age
-Older = lower liver function –> higher plasma concentrations of lipophilic Beta Blockers –> higher incidence of side effects
What are the Adverse Effects of Beta Receptor Antagonists?
- Fatigue
- Worsening PVD (Due to B2 blockade –> Vasoconstriction in microvasculature)
- Worsening Bronchospasm
- Decreased Sexual Functions (Common)
- Increased Diabetes incidence
- _***Masked Symptoms of HYPOGLYCEMIA***_
Pay attention to this, especiall in patients with advanced diabetes, due to downregulation of neuro contorls of glycemia
Signs = drop in blood sugar with faster heart rate, agitation, palpitations, ***SWEATING***
***If you block beta receptors, these go away, except Sweating***
What are the effects of Choline Esters (Direct-Acting Cholinoceptor Agonists)?
Cardiovascular –> Hypotension, Bradycardia, SLOWED conduction/PROLONGED refractory period
GI–> INCREASED motility, acid secretion, NVD
GU –> INCONTINENCE
Eye –> Miosis (pupillary CONSTRICTION via sphincter muscle)
Respiratory –> BronchoCONSTRICTION
Glands –> INCREASED SECRETION
What drugs are not effected by prior treatment with Reserpine** or **Guanethidine and actually potentiated by these drugs, as well as Cocaine?
DIRECT-ACTING ADRENERGIC AGONISTS
Both Selective (e.g. Phenylephrine, Clonidine, Terbutaline, Fenoldopam)
and Non-Selective (e.g. Isoproterenol, Dobutamine, Epinephrine, Norepinephrine, Dopamine)
What drugs are reduced by prior treatment with Reserpine** or **Guanethidine?
Ephedrine (a mix-acting Adrenergic Agonist)
What drugs are abolished by prior treatment with Reserpine** or **Guanethidine?
INDIRECT-ACTING
Including Releasing Agents (e.g. Amphetamine and Tyramine)
Uptake Inhibitors (e.g. Cocaine)
and MAO/COMT Inhibitors (e.g. Pargyline and Entacapone)
