Pharmacology: Cholinergic And Adrenergic Drugs

Front 1

Discuss sympathomimetics in general:

example clinical uses-- (5)

Back 1

*Imitate the effects of the sympathetic nervous system, activating alpha or beta receptors or both.

*Most agents directly stimulate receptors rather than increasing amounts of available endogenous catecholamines (i.e., norepinephrine)

*Example Clinical Uses:
Nasal congestion (Alpha-1)
Bronchospasm (Beta-2)
Anaphylaxis (Beta-2 and Alpha-1)
Cardiovascular collapse (Alpha-1 and Beta-1)
Overactive bladder (Beta-3...new drug)

Front 2

Epinephrine, Norepinephrine and Dopamine:

can you give them orally?

Back 2

*Endogenous catecholamines

*Cannot be given orally (rapidly inactivated in the GI mucosa and liver by COMT (catechol-O-methyltransferase) and MAO (monoamine oxidase)

Front 3

Epinephrine:

what receptors does it activate?

Back 3

*Potent agonist for Alpha-1, Beta-1 and Beta-2 receptors
Systemic (intravenous) administration, causes:
1) Significant direct cardiac effects (Beta-1): increase in chronotropic (increase SA firing-->HR), dromotropic (increase AV conduction) and inotropic (increase contractility) effects on the heart.
2) Blood pressure effects (Alpha-1-->increase) at higher doses; some Beta-2 (decrease) at lower doses.
3) Bronchodilation (Beta-2).

*Other effects based on receptor stimulation should be anticipated-- the effects will be systemic, beyond your target therapy.

Front 4

Norepinephrine:

what receptors does it activate?

What do you do if you accidentally inject NE outside of a blood vessel?

Back 4

*Potent agonist for Alpha-1 receptors; Beta-1 agonism

*With systemic IV administration, causes significant increase in BLOOD PRESSURE (NO Beta-2 effects to counteract) and significant increase in INOTROPY. Your HR might not actually increase (multiple receptor effects)!

*Clinical Pearl:
IV administration of any Alpha-1 agonist can cause significant NECROSIS if extravasation occurs. Prevention of this adverse effect by CAREFUL TECHNIQUE is essential. Phentolamine (an Alpha blocker) is administered locally if extravasation occurs.

Front 5

Dopamine:

Back 5

*Precursor of NE but also direct agonist for Beta-1 and Alpha-1 receptors. Additionally stimulates dopamine D-1 receptors in mesenteric, renal, and coronary vasculature causing VASODILATION.

*Dose-related effects:
Low (1-2 mcg/kg/min): renal/mesenteric vasodilation.
Medium (5-10 mcg/kg/min): increased heart rate, inotropy.
High (10-20 mcg/kg/min) increased vasoCONSTRICTION, HR, inotropy.

*Clinical Pearl:
Low dose dopamine has limited effects on improving renal function; At high dose, increased vascular resistance predominates over any vasodilatory effects

Front 6

Other Representative Sympathomimetics:

Isoproterenol and Dobutamine--

what receptors do they stimulate?

Back 6

Uses:
*Intravenous: cardiogenic shock with primary increase in
contractility (rather than increase in peripheral resistance); Increase heart rate with isoproterenol.

*Inhaled Isoproterenol: previous use for asthma patients but newer agents are selective for Beta-2 receptors and do not cause the same cardiac side effects.

*Note: Although both increase contractility, in patients with cardiogenic shock, dobutamine less likely to cause reflex tachycardia than isoproterenol.

Front 7

Other Representative Sympathomimetics:

Ephedrine, Phenylpropanolamine, and Pseudoephedrine:

what receptors do they stimulate?

Back 7

*Considerations:
All these agents cause significant Alpha-1 stimulation (vasoconstriction) and can significantly raise BP increasing risk of stroke.

*Ephedrine is banned by the FDA- beware of herbal products containing like compounds.

*Phenylpropanolamine (PPA)was commonly used as an
OTC decongestant and appetite suppressant. PPA is now banned by the FDA because of blood pressure/stroke risk.

*Pseudoephedrine is sold OTC behind the counter due to its use as a precursor for methamphetamine.

Front 8

Other Representative Sympathomimetics:

Terbutaline, Albuterol, and Salmeterol--

what receptors do they stimulate?

Back 8

*Uses:

*Inhalation: As bronchodilators in the treatment of airways disease such as asthma and COPD. Drugs differ with regards to onset of action and duration of effect.

*Example: Salmeterol cannot be used for acute management of asthma because of its slow onset.

*Oral: less frequently used dosage form due to increase risk of adverse effects.

Front 9

Sympathomimetics: Adverse Events from ß1 overstimulation: 4

Back 9

*Tachycardia, increased myocardial oxygen demand, arrhythmias, cardiac damage.

*Clinical Pearl: Although Beta-1 agonists such as dobutamine can be used in the short-term management of decompensated heart failure, intermittent infusions to treat chronic heart failure increase overall mortality.

Front 10

Sympathomimetics: Adverse Events Due to Beta-2 over-stimulation: 4

Back 10

*Skeletal muscle tremors, tachycardia, arrhythmias, hypokalemia.

*Clinical Pearl: While less common with inhaled administration (rather than oral) of Beta-2 agonists, these side effects may still occur.

Front 11

Sympathomimetics: Adverse Events Due to Alpha-1 over-stimulation: 4

Back 11

*Severely elevated blood pressure, increasing myocardial oxygen demand, predisposing to stroke and cardiac damage

*CNS effects--agitation, headaches.

Front 12

Alpha Sympatholytics (Alpha Blockers): Alpha-1 receptor selective agents:

how do they work?

uses? 2

Back 12

*Bind to alpha receptors and block the effects of endogenous agonists.

*Alpha-1 receptor selective agents:
-Representative: prazosin, terazosin, doxazosin
-Uses:
Hypertension: decreases vascular resistance
Benign prostatic hyperplasia (BPH): improves urinary flow.

*Caution: Orthostatic hypotension; syncope with first use or an increase in dose.

Front 13

Tamsulosin is an Alpha-1 selective blocking agent. It is very effective for the treatment of benign prostatic hyperplasia but is not effective as an antihypertensive agent. Why is this true?

Back 13

There are SUBTYPES of alpha-1 receptors.

Alpha-1a is the one Tamsulosin impacts. It doesn't act on the other subtypes, so it doesn't work for HTN.

Front 14

Alpha Sympatholytics (Alpha Blockers): Combined Alpha-1 and Alpha-2 receptor blockers--

use?

adverse effects?

Caveat?

Back 14

*Representative: phentolamine, phenoxybenzamine

*Use: pheochromocytoma

*Adverse effects: Significant hypotension causing reflex stimulation of the heart resulting in tachycardia, arrhythmias and myocardial ischemia.

*Caveat to sympatholytics: central acting Alpha-2 agonists (e.g., clonidine) reduce CNS efferent sympathetic outflow, reducing blood pressure as well.

Front 15

Beta Sympatholytics (Beta-Blockers):

how do they work?

How are they distinguished among each other? 5 traits

Back 15

*Bind to beta receptors and block the effects of endogenous agonists.

*Beta Blockers are distinguished by the following properties:
-Likelihood to block only Beta-1 receptors (Selectivity)
-Ability to act as a beta-agonist (Intrinsic Sympathomimetic Activity; ISA)
-Ability to cause concurrent Alpha-1 blockade (vasodilating effect)
-Metabolism and Elimination (Pharmacokinetics, esmolol is short acting, nadolol long acting)
-Likelihood to cross into CNS (Lipophilicity)

Front 16

Beta Sympatholytics (Beta-Blockers): Discuss Selectivity considerations--

Back 16

*Property is useful when needing to avoid risk of BRONCHOCONSTRICTION.

*Clinical Pearl: Selectivity is dose-related; maximum doses lose selectivity.

Front 17

Beta Sympatholytics (Beta-Blockers): DISCUSS ones with ISA--

Back 17

*Partial beta-agonism that occurs at times of low sympathetic tone (e.g., during sleep).

*Property is useful when patients with HTN treated with beta-blockers have excessively low heart rates at night.

*Property NOT USEFUL in patients with ischemic heart disease, where overall benefit related to lowered heart rate.

Front 18

Beta Sympatholytics (Beta-Blockers): discuss ones that have concurrent alpha-1 blockade--

Back 18

*Property allows for broader scope of antihypertensive actions.

*Patients treated with beta-blockers for other cardiovascular disease may experience a relatively greater reduction in blood pressure.

Front 19

Beta Sympatholytics (Beta-Blockers): discuss PK considerations--

Back 19

*Primary difference is degree of metabolism and renal elimination of unchanged drug.

*Limited relationship of pharmacokinetic half-life and duration of pharmacodynamic effect/ dosing for indications.

Front 20

Chart of representative Beta-Blockers:

Back 20

*commonly used: metoprolol, atenolol

*timolol is used for the eyes.
*esmolol for the AV node.
*carvedilol and metroprolol succinate for heart failure.

Front 21

Cardiovascular Indications for Beta-Blockers (Beta-1 blockade):

Discuss HTN and ischemic heart disease--

Back 21

*Hypertension
Commonly used antihypertensive (primary effect to reduce cardiac output); may be less desirable as first line therapy.

*Ischemic Heart Disease
-Chronic Angina Pectoris: reduces cardiac workload; decreases symptoms.
-Acute Coronary Syndromes: decreases workload and ischemia; decreases mortality if given long-term.

Front 22

Cardiovascular Indications for Beta-Blockers (Beta-1 blockade)

Discuss systolic heart failure as an indication--
How do the drugs help?
Dosing considerations?

Back 22

*Decreases long-term mortality by blocking effects of high circulating levels of norepinephrine. Results in reduced mortality from both cardiac arrest and progressive heart failure.

*Clinical Pearl: In patients with systolic HF, doses MUST be titrated very slowly to avoid an exacerbation of heart failure symptoms (i.e., initiate with 1/10 of target dose, increasing every 2 weeks).

*carvedilol and metroprolol succinate are the ones.

Front 23

Cardiovascular Indications for Beta-Blockers (Beta-1 blockade)

Discuss arrhythmias and prevention of SCD as indications--
mechanism:

Caveat drug?

Back 23

*Mechanism of benefit is from blocking effects of sympathetic nervous system (not direct membrane-stabilizing effects).

*Prevention of sudden death (e.g., ventricular fibrillation) in patients with systolic heart failure and patients with myocardial infarction.

*Treatment of supraventricular arrhythmias by causing Beta-1 blockade of the AV node (SA node).

*Caveat: Sotalol is an Class III antiarrhythmic that also has significant beta-blocking properties.

Front 24

Some Other Uses of Beta-Blockers:

Back 24

*Glaucoma
-Instillation of beta-blockers (e.g., ophthalmic TIMOLOL) decreases intraocular pressure.
-Clinical Pearl: Case reports have demonstrated that ophthalmic preparations may have enough systemic absorption to cause adverse beta-blocking effects (such as acute worsening of heart failure symptoms).

*Thyroid Storm
*Performance anxiety (“stage fright”)
*Migraine prophylaxis

Front 25

Adverse Effects of Beta-Blockers:
3 categories

Back 25

*May be dependent/modified by characteristics of beta-blocker (e.g., Beta-1 selectivity)

*Direct Cardiac Effects:
-Acute decompensation of systolic heart failure especially with large doses.
-Symptomatic AV nodal block/ sinus bradycardia.

*Bronchoconstriction:
-More likely to occur with NON-SELECTIVE beta-blockers but be careful with higher doses of Beta-1 selective drugs. Should generally avoid in patients with asthma.

*Dyslipidemias:
-Decreased HDL; may be less likely with ISA-containing beta-blockers.

Front 26

Adverse Effects of Beta-Blockers

Back 26

*Decreased recognition of hypoglycemia in DM:
-Most important in patients with hard to control insulin-dependent diabetes.
-If patients have cardiac conditions requiring beta-blockade, DM is usually NOT a contraindication.

*Peripheral vasoconstriction:
-More likely to occur with non-selective beta-blockers (ß2 receptors).

*CNS side effects:
-Nightmares; sedation (propanolol).
-May be less common with use of beta-blockers having lower lipid solubility.

Front 27

Beta-Blockers: Important Considerations when discontinuing beta blockers:

Back 27

*Patients should not abruptly discontinue their beta-blockers on their own: can increase risk of ischemic events.

*Up-regulation of beta-receptors during chronic therapy is a possible mechanism.

*In patients admitted to the hospital with decompensated heart failure, beta-blockers are continued or re-instituted as soon as possible.

*In those patients requiring IV beta-agonists (NE, dopamine) for acute heart failure, higher doses may be needed in patients receiving chronic beta-blockade.

Front 28

Parasympathomimetics (Cholinergic Drugs):

How do they increase the effect of the PNS?

Back 28

Direct action: Stimulate muscarinic receptors

Indirect action: Inhibit acetylcholinesterase

Front 29

Diagram showing direct and indirect acting Parasympathomimetics (cholinergics):

Back 29

Front 30

Direct acting muscarinic agonists (examples):

Back 30

*Choline esters:
Carbachol
Bethanechol
Methacholine
Acetylcholine ( cannot be used clinically- rapidly hydrolysed)

*Alkaloids:
Pilocarpine

Front 31

Clinical Use of Direct-Acting Muscarinic Agonists- Examples: 3 conditions; list drugs for each

Back 31

*Glaucoma
-Reduce intraocular pressure through increasing outflow of aqueous humor (e.g., pilocarpine)

*Xerostomia
-Inceases salivary secretion (e.g., pilocarpine; cevimeline)

*Gastric atony /Urinary retention
-Improve gastrointestinal and urinary function in patients without obstruction (e.g., bethanechol)

Front 32

Indirect acting parasympathomimetics (examples):

Back 32

*Edrophonium
-Short-lived binding (MINUTES) to the active site

*Physostigmine, neostigmine, pyridostigmine
-Medium duration of action (MINUTES to HOURS) due to covalent bonding

*Organophosphates used as insecticides or as topical treatments (e.g., parathion, malathion) and nerve gases (e.g., sarin, soman)
-Long duration of action (DAYS) due to covalent phosphorylated active site
-Can undergo aging, whereby the bond becomes more stable over time

*Newer Acetylcholinesterase Inhibitors that cross the BBB (alzheimer's): tacrine, donepezil, rivastigmine, galantamine

Front 33

Clinical Use of Indirect-Acting Parasympathetic Agonists:

Back 33

*Conditions benefited by direct-acting agents
-Glaucoma, xerostomia, gastric atony/urinary retention

*Myasthenia gravis
-Increase acetylcholine at neuromuscular junctions
-neostigmine, pyridostigmine

*Alzheimer’s disease
-tacrine, donepezil, rivastigmine, galantamine

*Others
-Prophylaxis against nerve gas poisoning (physostigmine; temporary)
-Antimuscarinic poisoning with atropine and others

Front 34

Adverse Effects of Direct-Acting and Indirect-Acting Muscarinic Agonists:

Back 34

*Just extensions of pharmacologic effects.

*Cardiovascular:
-Bradycardia
-Hypotension

*Bronchial/Pulmonary:
-Bronchoconstriction
-Glandular hypersecretion

*Gastrointestinal:
-Distress
-Increased acid secretion

Front 35

Organophosphate Insecticide Poisoning: signs and symptoms--

Back 35

*Signs and Symptoms (nicotinic and muscarinic)

-Cardiovascular: hypotension, severe bradycardia, and arrhythmias.

-Pulmonary: respiratory distress and failure.

-GI: nausea, vomiting, abdominal cramps, diarrhea, incontinence.

-Eyes: miosis, reduced vision, ocular pain.

-CNS: confusion, seizures, central respiratory failure, coma.

Front 36

Organophosphate Insecticide Poisoning: management--

Back 36

*Decontamination

*Atropine for muscarinic side effects (also, it can cross the BBB at high doses).

*Pralidoxime (2-PAM) = cholinesterase reactivator- doesn’t enter CNS and efficacy is time dependent due to aging of the bond.

*Respiratory support

Front 37

Antimuscarinic Drugs:
Actions--

Direct effects--

Back 37

*Actions
-Block effects of exogenous and endogenous muscarinic agonists.

*Direct effects:
-Cardiac: increased heart rate, conduction velocity through AV node, block of reflex bradycardia.
-Lungs: bronchodilation, reduced bronchial secretions.
-GI/GU: inhibit tone, inhibit gastric acid secretion.
-Eyes: mydriasis, cycloplegia.
-CNS: excitation or depression.
-Other: anhydrosis and xerostomia.

Front 38

Antimuscarinic Drugs: Examples and Uses--

Back 38

*Alkaloids (atropine, scopolamine).

*Usual doses of atropine have little CNS effects; scopolamine has better permeation of blood-brain barrier at therapeutic doses (used for motion sickness).

*Intravenous atropine is used for significant bradycardia.

*Anti-muscarinic effects of atropine are dose related.

Front 39

Antimuscarinic Drugs: Examples and Uses of Tertiary Amine Derivatives--

Back 39

*Characterized by good CNS penetration/eye penetration.

*Benztropine and trihexylphenidyl:
-Parkinson’s Disease (improve effects of relative cholinergic excess).
-Treatment of extrapyramidal side effects (relative reduction in dopamine) of antipsychotics.

*Dicyclomine, oxybutynin: Antispasmodics for G/U. Helps alleviate patients peeing/pooping their pants.

*Homatropine, cyclopentolate: Topical mydriatic agents (get your eyes dilated).

Front 40

Antimuscarinic Drugs: Examples and Uses of Quaternary Ammonium Derivatives--

Back 40

*Bronchodilators administered by aerosol; Low systemic absorption; do not cross blood-brain barrier.

Frequently used in combination with beta-agonists like albuterol.

Front 41

An 85 year old man with Alzheimer's Disease is given donepezil. Which of the following should you anticipate as an adverse effect of the drug?

Constipation
Urinary incontinence
Dry eyes
Sinus tachycardia

Back 41

Urinary incontinence

****Names of drugs will be on the exam****

Front 42

A 6 year old child comes home from school with a note from the school nurse indicating that she has head lice. Her mother receives a prescription buys a bottle of malathion, an organophosphate. She mistakenly gives her child the malathion orally instead of using it as a topical application.

What symptoms who you expect this child to exhibit and why?

Back 42

salivation
lacrimation
respiratory failure
bradycardia
hypotension
GI activity

**Keeps talking about Katsung textbook** table 8.1

Front 43

Nonadrenergic-Noncholinergic (NANC) Neurotransmitters:
potential roles:
examples:
importance:

Back 43

*Potential Roles:
Cotransmitters
Neuromodulators
Primary Transmitters

*Examples
-Peptides: Neuropeptide-Y (NPY), Vasoactive Intestinal Peptide (VIP), substance P, enkephalins.
-Purines: ATP, adenosine.
-Small molecules: Nitric Oxide (NO).

*Importance: may have useful drugs based on these in the future.

Front 44

Indications for using beta blockers:

Back 44

HTN
Ischemic heart disease
Systolic heart failure
Arrhythmias and SCD
Thyroid storm
Performance anxiety
Migraine prophylaxis

Front 45

Which of the following is correct regarding SNS/PNS:
1) NE is more potent than E in stimulating ß1.
2) NE is more potent than E in stimulating ß2.
3) Destruction in the synaptic cleft by MAO is the primary means of terminating NE's effects on tgt organs.
4) Reserpine causes a reduction in BP by decreasing DA and NE's reuptake.
5) Removal from the synaptic cleft through reuptake by M4 receptors is the 1˚ means of terminating ACh's effects on tgt tissues.

Back 45

1) False. They're equal
2) Way false.
3) False. Transport back into neuron is 1˚ mechanism.
4) That's true.
5) False. AChe is main mechanism. Presynaptic receptors are for inhibition of further release of ACh, not for reuptake.

Front 46

A 45 y/o F has allergic rxn to peanuts (bronchoconstriction and BP 80/60). Which of the following receptors is most logical for stimulation in therapy?
1) M2 and M3
2) ß1 and ß2
3) alpha1 and ß1
4) alpha 1 and ß2

Back 46

1) M2 and M3: agonism here --> bradycardia, not much vasculature effect from cholinergic drugs. So False.
2) ß1 and ß2: NO.
3) alpha1 and ß1: NO.
4) alpha 1 and ß2: YES --> vasoconstriction to raise BP from alpha 1, and bronchodilation from ß2.