Pharmacology – Exam 3

Autonomic Drugs

Examples of Autonomic Drugs in Dentistry

Epinephrine	Most Important
	Agonist Action	1) vascular smooth muscle			Post-synapse a-1 adrenergic receptors Blood vessel constriction
		2) bronchodilation			b-2 adrenergic receptors (lungs) Valuable in tx for anaphylactic bronchospasms
		3) á heat rate and contractility			b-1 adrenergic receptors (heart) á cardiac output tx for hypotenstion from anaphylactic shock
	Antagonist Action	Antagonize allergic mediators			Counter effect of mediators during anaphylactic reactions
b-2 Adrenergic	Selective for b-2 adrenergic receptors on bronchial smooth muscle Bronchodilators Used in Conjunction with Inhaled Steroids Examples à albuterol, terbutaline, salmeterol, metaproterenol Found in dental emergency kits as inhalers for tx of acute bronchospasms
Anticholinergics	Muscarinic (M1, M3) receptor Antagonist			Useful in producing short-term xerostomia
	Muscarinic M-2 receptor agonist			Injectable atropine Cardiac M-2 receptor antagonist Inhibits Vagus influence on HR Tx for bradycardia
	Examples à Atropine, Propantheline
Cholinomimetics	Stimulates parasympathetic nervous system
	Pilocarpine		Acts directly on multiple muscarinic receptors Used to stimulate salivary flow Approved for Sjorgen’s Disease
	Physostigmine		Acts to inhibit acetylcholinesterase â metabolism of acetylcholine á action at muscarinic receptors á salivary flow Approved for Sjorgen’s Disease
	Cevimeline		Muscarinic receptor agonist á salivary secretions Indicated for treating xerostomia (Sjorgen’s Disease)

Blocker/Antagonist à terms are used interchangeably

Inhibitor à used less frequently, but similar in meaning

Below is the list of terms to know from lecture one. They have been reorganized with adrenergic-related terms

at the top, and cholinergic-related terms at the bottom.

Autonomic Agent	Prototype	Action
Catecholamine	Norepinephrine Epinephrine
Indirect Acting Sympathomimetic	Tyramine Ephedrine Amphetamine	Displace NE in synaptic terminal NE diffuses into synapse w/o calcium use
Sympatholytic		Block action of sympathetic nervous system response
Sympathomimetic		Mimic action of sympathetic nervous system response
Uptake-1 Inhibitor	Imipramine	Block re-uptake of norepinephrine á NE concentration in synapse
MAO Inhibitor	Pargyline	Prevents metabolism of catecholamines Results in á NE concentration in tissue No change in neuroeffector organ response to sympathetic stimulation
COMT Inhibitor	Pyrogallol
Adrenergic receptor agonist	Norepinephrine	á Sympathetic action Stimulates all receptors Less effect on b2-receptors
Adrenergic receptor agonist	Epinephrine	Equal effect on all adrenergic subtypes
Alpha Adrenergic Blocker	Phentolamine	Both a1 and a2
Alpha-blocker	(same as above)
Alpha-1 Adrenergic Receptor Blocker	Prazosin (Minipres)	Vasodilation
Antiadrenergic	(same as above)
Alpha-1 receptor agonist	Phenylephrine	Vasoconstriction
Alpha-1, Beta-1, Beta-2 blocking agent		Anti-hypertensive
Alpha-2 receptor agonist	Clonidine	Vasodilation, â BP Action is largely on presynaptic end Negative feedback turns of release of NE
Central Acting Alpha-2 receptor agonist
Alpha-2 receptor antagonist	Yohimbine	Very selective No therapeutic role Enhances male sex
Beta-1 Adrenergic receptor blocker	Metoprolol Atenolol	Specific for b1 on heart Tx of cardiovascular disorders
Cardioselective beta-blocker	(same as above)
Beta Receptor Agonist	Isoproterenol	Equally effective for all b-adrenergic Does not stimulate alphas
Beta-1 receptor agonist	Dobutamine	Cardioselective Effects on the heart only
Beta-2 receptor agonist	Albuterol, Terbutaline	Bronchodilator
Beta-2 bronchodilator	(same as above)
Beta-adrenergic Receptor Antagonist	Propanolol	Block both b1 and b2 receptors Slow HR, â contractility Tx of Hypertension, Arrhythmia
Beta-blocker	(same as above)
Non-selective Beta-blocker	(same as above)

Anticholinergic	Atropine, Propantheline	Muscarinic receptor antagonist Produces short term xerostomia (M1, M3) Tx for bradycardia (M2)
Anticholinesterase	Physostigmine	Inhibition of neurotransmitter metabolism Has the effect of a cholinergic agonist Enhances magnitude and duration of cholinergic effect
Belladona Alkaloid	Atropine	(see Anticholinergic)
Cholinergic Agonist	Acetylcholine
Cholinomimetic	Pilocarpine	Acts directly on multiple muscarinic receptors Stimulate salivary production/flow
Parasympatholytic		Block action of parasympathetic nervous system response
Parasympathomimetic	Pilocarpine	Mimic action of parasympathetic nervous system response
Muscarinic Receptor Agonist	Pilocarpine	Acts directly on multiple muscarinic receptors Stimulates salivary flow and production
Muscarinic Receptor Agonist	Cevimeline	á secretion of salivary glands tx for xerostomia, Sjorgen’s disease
Muscarinic Receptor Antagonist	Atropine	(see Anticholinergic)
Nicotinic ganglionic cholinergic agonist	Nicotine
Ganglionic Blocker	Trimethaphan	These are no longer used
Neuromuscular Blocker	Pancuronium	Curare derivatives Block NMJ, relaxes muscle Must be an anesthesiologist

Adrenergic Receptors
Alpha-1			Alpha-2			Beta
a1A	a1B	a1D	a2A	a2B	a2C	b1	b2	b3

Alpha-1 receptors are prominent on arterial vasculature à epinephrine induces vasoconstriction
Norepinephrine and epinephrine coexist in the adrenal medulla
Synthesis assisted by phenethanolamine-N-methyltransferase
Cytoplasmic accumulation in storage granules in chromaffin cells
Norepinephrine à accounts for approximately 20% of catecholamines
Epinephrine à accounts for approximately 80% of catecholamines

Cholinergic Receptors
Nicotinic			Muscarinic
Ganglionic	Skeletal Muscle	Neuronal CNS	M1	M3	M5	M2	M4

Acetylcholine elicits various responses based on differences among receptors
Drugs that work on muscarinic do not work on nicotinic even though both utilize acetylcholine.
Muscarinic à response of autonomic effector cells of peripheral visceral organs
          Atropine has similar affinity for all muscarinic receptors
          M1 à found in autonomic ganglia (modulate direct neurotransmission through nicotinic receptors)
          M2 à found in the heart
          M3 à located in glands and smooth muscles
Nicotinic à parasympathetic and sympathetic ganglia, skeletal muscle
          These are activated by nicotine, or nicotine-like agents
          The difference between the two receptor types is in the agent that blocks them
                   Trimethaphan blocks autonomic ganglia nicotinic receptors
                   Pancuronium blocks skeletal muscle nicotinic receptors

Mechanisms of Pharmacological Agents in the Peripheral Nervous System

Action	Mechanism	Example
Ganglion Blockade Inhibition of Neurotransmitter synthesis Inhibition of Neurotransmitter release	Either no longer used or obsolete
Promotion of Neurotransmitter release	Activation of nicotinic ganglionic cholinergic receptors	Nicotine
Promotion of Neurotransmitter release	«Release of cytoplasmic stores of norepinephrine	«Amphetamine
Inhibition of Neurotransmitter storage	Blockade of norepinephrine accumulation in cytoplasmic granules	Reserpine (obsolete)
Inhibition of Neuronal uptake	«Blockade of amine uptake pump	«Imipramine
Inhibition of Neurotransmitter Met.	Inhibition of enzymes in metabolic pathway	· Parygline (MAOI) · Pyrogallol (COMTI) · Physostigmine (inhibits acetylcholinesterase)
Stimulation of Autonomic Receptors	Stimulation of a- and b-receptors	· Phenylephrine (activates a-1 receptors) · Isoproterenol (activates b-receptors)
Blockade of Autonomic Receptors	Blockade of a- and b-receptors	· Prazosin (blocks a-1 receptors) · Propanolol (blocks b-receptors) · Atropine (blocks muscarinic receptors)

Uptake Inhibitors

Imipramine (as well as cocaine)

Block amine uptake pump

á synaptic concentrations of norepinephrine causing enhanced/facilitated adrenergic responses

Amitriptaline (Elavil) à belongs to Imipramine class

Antidepressant in CNS

Some respiratory effect because of blocking re-uptake of norepi on presynaptic bulb

Significant atropine-like effects

Indirect Acting Sympathomimetics

Mimic action of sympathetic nervous system stimulation

Cause indirect release of norepinephrine

à Tyramine, Ephedrine, Amphetamine

Enter synaptic terminal and displace norepinephrine which then diffuses into synapse (no calcium required)

Neurotransmitter Breakdown Inhibition

The major enzymes involve in the breakdown of catecholamines are monoamine oxidase and catechol-O-methyltransferase

MAO Inhibitor à pargyline

COMT Inhibitor à pyrogallol

Hydrolysis of acetylcholine is catalyzed by acetylcholinesterase, which results in terminating the cholinergic effect

Inhibition is by physostigmine à enhances magnitude and duration of cholinergic effects

Direct Acting Muscarinic Agonists

Receptor	Agonist	Role	Substrate for Cholinesterase
Muscarinic	Muscarine		No
	Pilocarpine	Use in dentistry
	Bethanechol	Limited
	Methacholine	Limited	Yes
Nicotinic	Nicotine		No
Both Types	Acetylcholine	No therapeutic role	Yes
Both Types	Carbachol	Limited	No

Pilocarpine

Approved for the relief of radiation therapy induced xerostomia
Limited role in tx of xerostomia brought on by other medications
A direct acting cholinomimetic
Brand name is Salagen®

Contraindications

Hypersensitivity to pilocarpine (as with any drug)

Uncontrolled asthma (or even mildly controlled asthma)

Acute iritis (the drug induces undesirable miosis)

Narrow angle glaucoma (the drug induces undesirable miosis)

Warnings

Cardiovascular à rhythm changes

Ocular à visual blurring, decreased acuity

Pulmonary à bronchospasm, bronchitis

Precautions

Patients taking beta-blockers

Anticholinergic drugs (atropine) can antagonize pilocarpine actions

Adverse Reactions à sweating (most common), nausea, rhinitis, diarrhea, chills, flushing, urinary infrequency, dizziness, asthenia

Prescribing pilocarpine for xerostomia (when salivary glands are functional and NOT with xerostomia producing medications)

Rx à Pilocarpine HCl 5 mg

Disp à 90 tablets

Sig à take 1 tablet tid

Often suggested for treatment of xerostomia in association with Sjorgen’s Syndrome

Symptoms	· Parched mouth · Accelerated or unusual dental decay · Swollen salivary glands · Alteration in taste · Difficulty chewing and swallowing dry foods · Burning and cracking of lips and corners of mouth
Signs	Dry, parchment-like mucosa Caries at incisal surface or gingival line Premature loss of teeth Loss of filiform papillae of tongue Angular cheilitis Reduction of infralingual salivary pooling Parotid and/or submandibular enlargement
Treatment	Moisture Replacement	Ocular, oral Punctual occlusion Moisture chamber glasses
	Moisture Stimulation	Physical Pharmacological à pilocarpine, cevimeline
	Systemic Therapy	NSAIDs Corticosteroids Immunomodulatory agents Cytotoxic agents

Cevimeline (Evoxac®) à a direct acting cholinomimetic

Indication	Treatment of xerostomia Especially associated with Sjorgen’s Syndrome
Contraindication	Uncontrolled asthma Hypersensitivity to drug Acute iritis
Mechanism	Binds and activates M-3 receptor Promotes salivary secretion Some effects on M-2 (â HR, miosis of eye)
Adverse Reactions	Sweating (19%) Nausea (14%) Diarrhea (10%) Cervical palpations, eye pain, â visual acuity
Drug Interactions	á action with P-450 enzyme inhibitors (diltiazem, erythromycin, ketoconazole) â action with anticholinergics (atropine, scopolamine, tricyclic antidepressants)
Pharmacokinetics	Half life à 5 hours Peak effect at 1.5 – 2.0 hours Taken with or without food Metabolized in the liver
Dose	30 mg oral tablets, tid

Acetylcholinesterase Drugs

Treatment of Alzheimer’s Disease

There is a relative deficiency of acetylcholine in this disease

Mechanism is selective brain acetylcholinesterase action à increases brain Ach

Donepezil (Aricept) the most commonly prescribed

Diarrhea, nausea, vomiting, fatigue, anorexia, weight loss

Galatamine (Reminyl)

Diarrhea, nausea, vomiting, anorexia, weight loss

Rivastigmine (Exelon)

Diarrhea, nausea, vomiting, indigestion, weakness, weight loss

Tacrine (Cognex)

á liver transaminases, diarrhea, nausea, vomiting, dyspepsia, myalgia, anorexia, ataxia, weight loss

warning associated with monitoring of liver function

Similar GI effects occur with same frequency as placebo

All of the above medications should be used with caution in patients with active peptic ulcers, severe asthma, or bradycardia

Case Review

Patient was taking Mestinon à an anticholinesterase

Patient complained of hypersalivation, wheezing, shortness of breath, diarrhea (muscarinic), and muscle cramps (nicotinic)

Note that the muscarinic effects of Mestinon are similar to those that would be seen with Pilocarpine, a general muscarinic agonist

Mestinon (pyridostigmine bromide)

Description	Orally effective anticholinesterase Has both muscarinic and nicotinic effects
Indication	Treatment of myasthenia gravis
Actions	Inhibits break down of acetylcholine á transmission of nerve impulses The idea is to improve muscle strength
Contraindications	Intestinal or urinary obstruction Bronchial asthma
Adverse Reactions	Muscarinic à nausea, vomiting, diarrhea, á salivation, á bronchial secretions Nicotinic à skeletal muscle cramps, fasciculation
Use of Atropine	Care must be taken Used only to abolish muscarinic effects Masking of pyridostigmine effects may result in cholinergic crisis
Cholinergic Crisis	Excess anticholinesterase action Excessive cholinomimetic effect Immediate use of atropine
	Cardiac	Arrhythmias, AV Block, Bradycardia
	CNS	Confusion, Nausea, Tremors, Vomiting, Blurred Vision, â visual acuity
	GI Tract	Diarrhea, Stomach cramps
	Misc.	Excessive Sweating, Flushing, Redness, Lacrimation

Clinical Uses of Some Cholinergic Antagonists (block effect of acetylcholine)

Condition/Use	Drug
Motion Sickness	Scopolamine (a belladonna alkaloid; oral or transdermal patch)
Parkinson’s Disease	Primary à Benztropine Others à Trihexyphenidyl
Mydriatics and Cycloplegics	Atropine, Scopolamine, Homatropine, Cyclopentolate, Tropicamide
Antispasmodics	Primary à Oxybutynin Others à Dicyclomine, Methylatropine, Methylscopolamine, Glycopyrrolate, Trihexethyl, Isopropamide, Methantheline, Propantheline, Clidinium
Urinary Incontinence	Oxybutynin
Chronic Obstructive Pulmonary Disease	Ipratropium
Rapid-type Mushroom Poisoning	Atropine

Atropine

Action	Anticholinergic, Antispasmodic, Antiarrhythmic Antidote for cholinergic crisis Antisialogogue (produce xerostomia)
Indications	Peptic ulcer Antisialogogue (produce xerostomia) Cardiac arrhythmias, Sinus Bradycardia Antidote for anticholinesterase, muscarine, organophosphate pesticide Ophthalmic use à mydriasis, cyclopegia
Contraindications	Hypersensitivity to belladonna alkaloids (e.g., scopolamine) Narrow angle glaucoma Parotitis Obstructive uropathy BPH (Benign Prostatic Hypertrophy) Intestinal atony, Parylitic ileus Obstructive diseases of GI tract Severe ulcerative colitis Tachycardia Myasthenia gravis
Side Effects	CNS	Headache, ataxia, dizziness, irritability Convulsions, confusion, hallucinations, delirium
	Cardiovascular	Ventricular tachycardia, palpitations, AV dissociation Atrial or ventricular fibrillation
	Eye	Mydriasis, blurred vision, photophobia á Intraoccular Pressure (IOP), â Tear production Conjunctivitis
	Oral and GI	Dry mouth, thirst, dysphagia, loss of taste Nausea, vomiting, constipation
	Urinary	Hesitancy and retention, dysuria, impotence
	Skin	Flushed dry skin, anhidrosis, rash, Urticaria
Use in Dentistry	To promote short-term xerostomic effect Sal-Tropine®, 0.4 mg (most common) Take 1 tablet 1 hour prior Duration of effect is approximately 4-6 hours Significant drying of eyes may occur (caution to contact lens wearers) Shield patients eyes from dental light Obtain physician consult for patients with cardiac disease, glaucoma Included in Dental Emergency Kits Precaution for life-threatening bradycardia Blocks the effect of the Vagus (which normally â HR) on the heart (which is also why it is contraindicated in tachycardia; inhibiting the Vagus will indirectly á heart rate; rate increase is NOT due to stimulation of SA node)

Propantheline

Action	Anticholinergic, Antispasmodic
Indications	Treatment of peptic ulcer, irritable bowel syndrome, pancreatitis Ureter and urinary bladder spasms Reduction of duodenal motility during diagnostic procedures Produce xerostomia (unlabelled use)
Contraindications	Pregnancy, narrow angle glaucoma, GI obstruction Myasthenia gravis Paralytic ileus, obstructive uropathy, toxic megacolon
Side Effects	Constipation, dysphagia, difficulty urinating Xerostomia Blurred vision, mydriasis, photophobia, drowsiness
Use in Dentistry	To promote short-term xerostomic effect Take one 15-30 mg tablet ½ hour prior Duration of effect is approximately 4-6 hours

An alternative to atropine or propantheline for inducing xerostomia is diphenhydramine (Benedryl®), an antihistamine

Patients are advised to purchase OTC

Take two 25-mg tablets 1 hour prior

Also may make the patient sleepy

An additional alternative is Tolerodine (Detrol®)

Normally used for overactive bladder with urinary incontinence and frequency

Has some xerostomic (23%) effect

Tolerodine is a competitive muscarinic antagonist (like atropine)

Some notes on Sympathomimetics…

Direct Acting (meaning they are agonists for alpha and/or beta receptors)

Agent	Route of Admin.	Notes
Epinephrine	IV, inhalation, topical	Nonselective
Isoproterenol	IV, inhalation	Obsolete Beta-Agonist NO effect on alphas
Dopamine	IV	Cardiac/ kidney
Phenylephrine Methoxamine	IV, IM	a-1 receptor agonist selective arterial constriction most potent of this type
Albuterol Metaproterenol Terbutaline Salmeterol	Oral, inhalation	b-2 receptor agonist selective direct acting bronchodilators management of asthma structural difference is in functional group a change only effects duration, not action
Dobutamine	IV	b-1 receptor agonist selective for heart

Indirect Acting (meaning they indirectly á release of catecholamines from presynaptic end)

Agent	Route of Admin.	Notes
Amphetamine	Oral, exchange resin
Ephedrine	Oral (most common) SC, IV, IM, topical	3-6 hour half life
Phenylpropanolamine		No longer available due to toxicity
Pseudoephedrine	Oral	Common decongestant

Comparative Effect on Barostatic Reflex (sympathetic response to change in blood pressure) of two drugs

Phenyleprhine

(Vasoconstrictor)

Histamine

(Vasodilator)

Effect on Blood Pressure

Pressor effect

á BP

Depressor Effect

â BP

Sympathetic Reflex

â in nerve activity

result = â HR

á in nerve activity

result = á HR

Vagus Reflex

á in nerve activity

result = â HR

â in nerve activity

result = á HR

Remember that HR is under dual control from sympathetic (b-1) and Vagus activity.

As BP increases, the barostatic reflex will elicit a drop in heart rate to compensate

This is accomplished by decreasing b-1 activity and increase Vagus activity

As BP decreases, the barostatic reflex will elicit an increase in heart rate to compensate

This is accomplished by increasing b-1 activity and decreasing the inhibitory effect of the Vagus

Select Sympathomimetics Effect on Heart Rate

Agent	Activted Receptors	Blood Pressure	Heart Rate
Agent	Activted Receptors	Blood Pressure	Direct	Reflex*	Overall
Norepineprhine	a, b-1	á	á	â	Either
Epinephrine	a, b-1, b-2	á	á	â	Either
Phenylephrine	a-1	á	No effect	â	â
Isoproterenol	b-1, b-2	â	á	á	áá
Dobutamine	b-1	No direct effect	á	None	á

* Reflex refers to barostatic reflex, see above

(a positive chronotropic effect refers to an increase in heart rate)

Methamphetamine is another sympathomimetic

Also known as speed

Legally prescribed for narcolepsy

Effect of Selective Antagonists on Muscle Action

Receptor	Antagonist	Antagonist + Propranolol (beta-blocker)	Antagonist + Phentolamine (alpha-blocker)
a-1 arterial contraction	Norepinephrine	No change in contraction from antagonist alone	Blocks NE effect Competitive Inhibition Much more NE required to achieve similar contraction
b-2 bronchodilation	Isoproterenol	Blocks Isopro. Effect Competitive Inhibition Much more Isopro. required to achieve similar dilation (relaxation)	No change in dilation (relaxation) from antagonist alone
b-1 heart rate	Norepinephrine	Blocks NE effect Competitive Inhibition Much more NE required to achieve similar contractility	No change in contractility from antagonist alone

Epinephrine Allergy

Patients may complain of allergies to epinephrine

There are no documented allergies to epinephrine

Patients may actually be experiencing a sulfite allergy (sulfites are in the carpules to stabilize epinephrine)

ADA Guidelines with regard to epinephrine

Patients with cardiovascular disease à monitor vital signs, and stay below 40 mg of epinephrine

One carpule of 1:100,000 epinephrine is equivalent to 18 mg

Compare that 40 mg limit to stress induced catecholamine release

The adrenal medulla releases 7 mg/min of epinephrine and 1.5 mg/min of norepinephrine under normal conditions

The adrenal medulla releases 280 mg/min of epinephrine and 56 mg/min of norepinephrine under “stressful” conditions

à Stress causes a 40 fold increase in blood epinephrine levels (meaning improper pain control)

Retraction cord is contraindicated in patients with cardiovascular disease because it contains 80 milligrams (not micrograms) epi

Norepinephrine vs. Epinephrine

Both are effective in inducing vasoconstriction

Epinephrine has little or no effect on carotid and cerebral blood flow (a good thing)

Norepinephrine may induce vasoconstriction of cerebral blood vessels (a bad thing)

NE is thus not as safe as E for obtaining localized vasoconstriction

Epinephrine and Hypertension

There is much debate on the role epinephrine may play in the hypertensive patient

Most advise caution

Some say epinephrine is contraindicated in the hypertensive patient

Others say it is acceptable with proper precautions and monitoring

Virtually all agree against the use of retraction cord in the hypertensive patient

Epinephrine Contraindications

Active, untreated hyperthyroid conditions (Grave’s Disease)

Epinephrine increases vascular constrictor effects of thyroid hormone

á vasoconstriction, á HR

Uncontrolled Diabetes Mellitus

Epinephrine is absolutely contraindicated

Promotes hyperglycemia (has action opposite to insulin)

Epinephrine Indications

Topical application à hemostatic effect on capillary bleeding

Effectiveness is limited to bleeding from arterioles and capillaries

It will not control venous oozing or bleeding from larger vessels

After it is metabolized (2-3 minutes), bleeding will resume with a rebound effect

Levonordefrin

Synthetic catecholamine vasoconstrictor

a-1 receptor activity à 75%

b-1, b-2 receptor activity à 25%

One-sixth as potent as epinephrine

Typical solution strength à 1:20K

Cardiac effects are the same as epinephrine, but to a lesser degree

Metabolized by COMT and MAO

Is this a safe alternative? No, not really

Beta-adrenergic Receptor Blocker Indications

angina pectoris
tachyarrhythmias
hypertension
aortic stenosis (with angina and palpations)
myocardial infarction (acute phase)
pheochromocytoma
vascular headache (prophylaxis only à propanolol)
anxiety (cardiac manifestations)
essential tremor (propanolol only; reduces skeletal muscle tremors)
thyrotoxicosis
open-angle glaucoma (timolol)
UNAPPROVED FOR panic syndrome (may have cardiac manifestations)

Commonly Prescribed Beta-blockers

Agent	Brand Name	Notes
Propanolol	Inderal	Non-selective
Metoprolol	Lopressor; Toprol	Cardioselective
Atenolol	Tenormin	Cardioselective
Pindolol	Visken
Sotolol	Betapace	For certain types of arrhythmias
Timolol	Timoptic	Eye drops Open-angle glaucoma
Esmolol	Breviblock
Carteolol	Cartrol	Tx for early signs of congestive hear failure

Cardioselective à minimal to no respiratory effects on b-2

Beta-adrenergic Receptor Blocker Contraindications

Absolute

Cardiac failure (acute)

Cardiogenic shock (acute MI)

2^nd/3^rd degree AV block

Sinus bradycardia (HR < 45 beats/min)

Systolic hypotension (systolic < 100 mmHg)

Relative

Asthma à cardioselectives are NOT any safer

Emphysema

Non-allergenic bronchitis

Congestive heart failure

Diabetes Mellitus

Hepatic function impairment

Mental Depression (lipophilic agents cross blood-brain barrier)

Renal Function impairment

Raynaud’s syndrome (not so much with beta-selective)

Dental Issues with Beta-blockers (each of the following is in relation to patients taking beta-blockers)

Non-selective beta-blockers attenuate/block normal b-2 vasodilating effects of epinephrine

Examples à propanolol, nadolol, timolol

Unmaksing of a-1 Receptor (remember that epinephrine also acts on a-1; if a non-selective beta-blocker inhibits the beta receptors, then the effect of epinephrine on the a-1 will be exaggerated à “unmasked”)

Epinephrine injections (local anesthetic or alone as emergency response) may cause a rise in arterial BP
There may also be an exaggerated vasoconstrictor effect with tissue blanching, ischemia, and possible necrosis

Management Strategies for Patients taking Non-selective Beta-blockers

Recommended and preferred if hemostasis is not a concern	Use a local anesthetic without vasoconstrictor (4% prilocaine, 3% mepivicaine)
Recommended if available	Use a local anesthetic with a lower concentration of epinephrine (4% prilocaine with 1:200K epinephrine)
Recommended	Use the minimum amount of local anesthetic containing 1:100K epi à administer in increments of one-half to one carp. à monitor pts BP and HR à repeat in additional increments if necessary à inform pt of possible longer duration of effect
NOT Recommended	Use of a local anesthetic with another vasoconstrictor (levonordefrin, norepinephrine, phenylephrine) Alter the beta-blocker medication à discontinue (physician only) à change to a cardioselective such as metopronol or atenolol

Patient, physician and dentist must not permit sudden withdrawal of any beta-blocker
Abrupt withdrawal in therapy can result in a cardiovascular event (MI or stroke)
When regulation of beta receptors ceases, the patient is extremely susceptible to endogenous epi and norepi effects
Younger patients respond with very low doses of beta-blockers
Older (geriatric) patients have a much lower response to beta-blockers
          not the drug of choice for this population
          P-450 pathway metabolism of propanolol, metoprolol and others is diminished
          may run the risk of drug accumulation à excess slowing of heart and cold extremities
Emergency injection of epinephrine à no, or minimal response
          bronchodilation (b-2) will be minimum or absent
          cardiac stimulation (b-1) will be blunted [cardiac stimulation refers to á HR and á C.O.]
          exaggerated vasoconstrictor effect [unmasking of a-1 receptror]

Beta-blockers in Type I Diabetes and Hypoglycemia

Beta-adrenergic blockade may mask acute hypoglycemia in these patients
Hypoglycemic attacks may be accompanied by precipitous elevation of BP

Case Review

Type I diabetic patient for prophy and SRP

Pt is taking Inderal (propanolol) for recurrent migraine, and an estrogen-containing oral contraceptive

Halfway through the appointment she becomes dizzy, and is near syncope

Pt is most likely hypoglycemic

Common Alpha-blockers

Hypertension and BPH

Terazosin

Doxazosin (more vasodilation; causes hypotension)

Prazosin (Minipres) à Hypertension only

BPH Only

Tamsulosin (Flomax)

Obsolete Agents

Very limited use, even in emergency situations

Phentolamine (competitive, reversible)

Phenoxybenzamine (non-competitive)

(BPH = benign prostatic hypertrophy)

Epinephrine Reversal

Injections of epinephrine without a-blocker à elevated BP (pressor) with little or no change on HR (depressor)

Injections of epi with a-blocker à little or no change on BP (now depressor) with elevated HR (now pressor)

Blockage of a-receptors causes reversal of epinephrine effect on b-receptor

Effect on BP goes from normal, PRESSOR to DEPRESSOR

Effect on HR goes from normal DEPRESSOR to PRESSOR

Case Review

1) Pt is taking prazosin (for hypertension) and propanolol (for cardiac arrhythmia)

Concerns with epinephrine?
à there may be no noticeable effect of epinephrine as alpha and beta are blocked by meds

2) Pt is taking terazosin (alpha blocker) for BPH or Hypertension

during procedures the duration of anesthesia is significantly shorter than usual

vasoconstriction of epinephrine is inhibited (no a-1 response)

anesthetic is metabolized much quicker

BPH à Benign Prostatic Hypertrophy

distribution of activated a-receptors in prostate constricts pathway along urethra

alpha-blockers prevent/alleviate this condition

Labetalol

Action

Blocks a-1, and b-1 and b-2

Alpha to Beta blockade ratio = 1:3

Predominant effect on beta

Alpha Effect) inhibits vasoconstriction

Beta Effect) â HR, â bronchodilation

Indication

Management of hypertension

Contradindication

Asthma, cardiac failure, severe bradycardia, prolonged hypotension

Incidence of Xerostomia with Adrenergic Blocking Drugs

Alpha Blockers	Doxazosin	1.4%
Alpha Blockers	Terazosin	~1%
Beta Blockers	Metoprolol	1%
	Nadolol	0.1 – 0.5%
	Propanolol	Dry mouth not listed as adverse reaction
	Atenolol
	Labetalol (a and b)