Drugs Affecting The Autonomic Nervous System

WK 2 – May 17WK 3 – May 24WK 4 – May 31

The Nervous System

• Broken down into two major divisions:• The Central Nervous System, which includes

the brain and spinal cord (CNS) and the Peripheral Nervous System (PNS), which includes everything else except possibly the neurons that governs the function of the gastrointestinal system. It is separate from the ANS since it has its own independent reflex activity.

PNS

• Efferent signals – go toward the effector organs (viscerea, muscles, glands) as the info EXITS the brain

• Afferent signals – from sensors to the brain and spinal cord

• Afferent informs what is going on in the body or environment

• Efferent nerves allow us to act on that information

Second way PNS is broken down

• Autonomic nervous system – involuntary – generally unconscious - gets info from internal receptors and outputs info to smooth muscles and glands

• Somatic nervous system – voluntary – input from sense organs=output to skeletal muscles.

• Breathing IS affected by conscious effort so it is NOT included in the ANS

Efferent ANS

• Sympathetic (fight or flight) suppresses immune, digestive, reproductive systems; higher mind analytical problem solving ability and relies on pre-programmed responses. MAIN TRANSMITTER IS NOREPINEPHRINE

• Adrenergic system

Efferent ANS

• Parasympathetic – safety response• Maintains homeostasis; puts the brakes on

sympathetic (stress response) functions; supports immune, digestive and reproductive systems; supports higher mind and problem solving functions

• MAIN TRANSMITTER IS ACETYCHOLINE• Cholinergic system – the degeneration of this

system is associated with Alzheimers

Sample quiz question

• In the sympathetic division, the main neurotransmitter is:

• A. acetylcholine• B. histamine• C. norepinephrine• D. serotonin

Cholinergic Agonists

• Act by stimulating the postsynaptic membrane and have a much longer duration of effect than acetylcholine

• Cholinergic effects with oral dosages may be cumulative so use the lowest effective dose for elderly

• Used to tx bladder retention, muscular weakness such as myasthenia gravis, Sjogren’s syndrome and Alzheimer’s disease

Cholinergic agonists side effects

• Diaphorisis, HA, urinary urgency, n/v/d, hypotension, salivation, flushing, abdominal pain and cramps, bronchospasm/panting, heart palpitations, tremors, tachycardia

• In TCM, look at qi, blood and/or qi deficiency, heat or phlegm

• Patients with asthma , hyperthyroid or coronary insufficiency should avoid these agents

Sample question

• Cholinergic drugs are used to treat Alzheimer’s disease. A reversible cholinsterase inhibitor increases cholinergic activity by inhibiting the enzymes which degrade acetylcholine. Acetylcholine is important in the brain for laying down new memory and cognitive function. A drug which is used to treat Alzheimer’s disease is:

Sample test question

• A. cimetadine/Tagamet• B. donepezil/Aricept• C. etomidate/Amidate• D. eszopicione/Lunesta• The above drug is minimally effective for

increasing memory and has no effect on dementia. It also carries a high risk for: a. Parkinsons b. diabetes c. kidney disease d. cardiovascular side effects

Anticholinesterases (reversible)

• Act by preventing the breakdown of acetylcholine in the synaptic cleft. Effects last longer- makes it seem there is more Ach than there actually is

• Reversible type – therapeutic• Irreversible type – used in insecticides and

possible nerve agents in chemical warfare• Neostigmine and pyridostigmine are used for

myasthenia gravis caused by an autoimmune reaction to membrane receptors

Anticholinesterases - reversible

• Donepezil, galantamine, tacrine, and rivastigmine are used to treat Alzheimer’s

• Donepezil used occasionally for ADHD• Also used as a prophylaxis to biochemical

weapons such as cholinesterase inhibitor poisons

• S&S within a few hours “SLUDGE” factor

Adverse reactions

• HA, urinary urgency, nausea, diaphoris, miosis, hypotension, salivation, flushing, abdominal pain and cramps, bronchospasm and diarrhea

• Red flags – any SOB• No major interactions but can slow down GI

motility and reduce absorption• In TCM, helps to disperse qi

ANTIMUSCARINIC AGENTS

• AKA muscarinic receptor antagonists• Act by binding to post-synaptic receptor sites

and preventing binding of Ach to these receptors

• Atropine – antispasmotic that relaxes the GI tract and the bladder. Also used in the eye for diagnostic procedures

Antimuscarinic agents

• Benztropine, biperiden, procyclidine, and trihexyphenidyl are used to treat Parkinsons

• Dicyclomine is used As a antispasmotic for IBS• Glycopyrrolate – inhibits salivation and

secretions in respiratory tract. Adjunct tx of peptic ulcers

• Homatropine – combined with hydrochodone is used as an antitussive – relieves or prevents coughing

Cont

• Hyoscyamine – peptic ulcers, IBS, neurogenic bladder/bowel, spasmotic GI tract, Parkinsons and to dry up rhinitis

• Methscopolamine – allergic reactions such as rhinitis, skin reactions, lung congestion and vasomotor rhinitis

• Propantheline – peptic ulcers, IBS, pancreatitis and bladder spasms

Cont

• Darifenacin, oxybutynin, solifenacin, tolterodine, and trospium treat overactive bladder and incontinence

• Scopalamine – motion sickness and spasms of the GI/GU tract

• Trimethobenzamide – antiemetic• Adverse effects – blurred vision, confusion,

drowsiness, mydriasis, constipation, dry mouth, tach,HA, restlessness, urinary ret

Cont

• Atropine – contraindicated for narrow angle glaucoma pts

• Red flags – ventricular tachycardia or atrial fibrillation

• INTERACTIONS• Scopolamine may have the following herb

interactions: fu ling, ren shen, yuan zhi, shi chang pu, dang gui

Direct-acting ADRENERGIC AGONISTS

• Many of these agents are used to treat asthma and are inhaled for maximum effect

• Adrenergic neurons are similar in function to cholinergic neurons in that they both have mechanisms for releasing a neurotransmitter, breaking down that neurochemical in the synaptic cleft, and reabsorbing and recycling the chemical

Cont

• Catecholamines- neurotransmitter family that includes epinephrine, norepinbephrine, and dopamine

• Two major families of adrenergic receptors:• Alpha and Beta – each family has subtypes

ADRENERGIC RECEPTORS

• a1 – vasoconstriction, increased peripheral resistance, increased bp, increased closure of internal sphincter of the bladder – smooth muscle contraction and increase in peripheral vascular resistance – thus ^ bp

• a2 – inhibition of norephinephrine release and inhibition of insulin release. Work paradoxically on the CV control centers, decreasing sympathetic activity, thus decreased bp.

AR cont/Adrenergic Agonists

• a2 – because of its localized vasoconstriction, you can use these agents as nasal decongestants

• Common drugs include but are not limited to: albuterol, clonidine, guanabenz, methyldopa, midodrine, terbutaline, tizanidine

• Common side effects- cardiac arrhythmias, hyperactivity, HA, insomnia, n/v, tachy, tremors

AA cont

• a2 side effects – dry mouth, sedation, sexual dysfunction, brady down, dermatitis if using a patch

• NOTE – most B2 selective adrenergic agonists work on pulmonary receptors because the agent is inhaled.

• NOTE – B2 agonists may cause hyperglycemia in some diabetic patients

AA cont

• RED FLAGS – B2 agonists may initiate arrhythmias and cardiac infarctions

• The FDA has issued a warning regarding the use of long acting B2 agonists (LABA), including salmeterol and formoterol. Recent studies show more asthma related deaths in patients who use regular asthmas treatments when combined with LABAs than with regular treatment alone. No LABAs for asthma attacks

AA cont

• Interactions with herbs• a1 – Gan Cao• Clonidine – Gan Cao, Ma Huang• Midodrine – Ma Huang• Phenylephrine – San Qi, Xi Yang Shen• Sympathomimetic Drugs – Chen Pi, Ma Huang,

Qing Pi, Rou Cong Rong, Zhi Ke, Zhi Shi

DIRECT ACTING ADRENERGIC AGONISTS SUMMARY

• Can treat asthma, hypo and hypertension, muscle spasms

• Side effects – cardiac arrhythmias, hyperactivity, HA, insomnia, n/v, dry mouth, sedation or somnolence, tachycardia, bradycardia

• Study page 349!!!!

INDIRECT ACTING ADRENERGIC AGONISTS AND OTHER

STIMULANTS• These agents work by causing the presynaptic

neuron to release norepinephrine into the synaptic cleft and physiological activation of the postsynaptic membrane receptors.

• Drugs and function:• Amphetamines – used primarily as an obesity

drug – also illegal as a recreational drug

Cont

Dextroamphetamine – obesity, narcolepsy, ADHD

• Methamphetamine – obesity, ADHD, illegal recreational drug

• Methylphenidate – ADHD and narcolepsy• Modafinil – narcolepsy, sleep apnea, ADHD,

and fatigue associated with MS and other disorders. Mechanism of action is unknown

Cont

• Common side effects – HA, chills, palpitations, fatigue, depression, arrhythmias, angina, hyper/hypotension, excessive sweating, dry mouth, metallic taste, n/v, anorexia, diarrhea, abdominal cramping

• Overdosage – restlessness, irritability, insomnia, dizziness, tremors, etc and homicidal/suicidal thoughts. Dependence/tolerance occur with chronic use

Red Flags

• Cardiac collapse, convulsions, coma, cerebral hemorrhaging, and death. Have also been linked with precipitating an initial psychotic break in schizophrenics

• INTERACTIONS• Contraindicated for glaucoma, advanced

arteriosclerosis, symptomatic CVD, moderate to severe hypertension or hyperthyroidism

Interactions

• Should not be given if pt is in an agitated state or has a history of drug abuse

• Should not be used within the first 14 days of initiating monoamine oxidase inhibitor (MAOI) therapy as can cause a hypertensive crisis.

• Interactions may occur with concurrent use of anticonvulsant medications

Interactions

• Methylphenidate may inhibit the metabolism of coumarin, anticoagulants, anticonvulsants, and some antidepressants

• Herbs that may interact with sympathomimetic drugs:

• Chen pi, Ma Huang, Rou Cong Rong, Zhi Ke, Zhi Shi

MIXED ACTION ADRENERGIC AGONISTS

• These agents are called mixed agents because they have several different effects. Primarily, they have both direct and indirect agonist effect in that they promote the release of norepenephrine from the presynaptic neuron as well as direct effects on the postsynaptic membrane receptors. Both a and B receptors are stimulated.

Main drugs

• Ephedrine can be used as a bronchodilator for asthma but not so much today (Primatene tablets)

• Epinephrine (Adrenalin, Epi Pen, Jr. Epi Pen, Twinject) – used as an inhaled agent for asthma, bronchospasms and OTC nasal decongestants

ADVERSE EFFECTS

• Ephedrine – insomnia and potential hyperten sion

• Pseudoephedrine – HA, insomnia, nausea, dry mouth

• May reduce the antihypertensive effects of reserpine, veratrum alkaloids, methyldopa and mecamylamine

• Effects may be increased if used with MAOI and B adrenergic blockers

HERB INTERACTION

• Ephedrine – Green tea, Ma Huang• Pseudoephedrine – Ma Huang• Sympathomimetic Drugs – used to treat

cardiac arrest and low blood pressure, or even delay premature labor, among other things

• They mimic the effects of the sympathetic nervous system. Reacts with Chen Pi, Ma Huang, Qing Pi, Rou Cong Rong, Zhi Ke, Zhi Shi

ALPHA ADRENERGIC BLOCKING AGENTS

• Multi- functions including vasoconstriction, in creased peripheral vascular resistance, increased blood pressure, increased closure of the bladder’s internal sphincter. Alpha blockers prevent these effects by binding, either reversibly or irreversibly to the post-synaptic membrane alpha receptors. Most therapeutic effects are tied to alpha1 inhibitions.

Cont Mechanism of Action• Phenoxybenzamine irreversibly binds to alpha

receptors. Treats HPTN but has a slower onset and lasts longer

• Reduction of HPTN is cause by reducing total peripheral resistance – does this by causing vascular dialation

• See p. 351

ADVERSE REACTIONS

• Dizziness, orthostatic hypotension, nasal congestion, fatigue, ha, drowsiness, sodium and fluid retention

• This category also used to treat benign prostatic hyperplasia (BPH) allowing less constricted urine

• Tachycardia is a big red flag and do not use with the herb Gan Cao

BETA ADRENERGIC BLOCKING AGENTS

• Again, adrenergic means working on adrenaline (epinephrine) or noradrenaline (norepinephrine) as a neurotransmitter. Contrasts with cholinergic – acetycholine is used as the neurotransmitter

• Now, let’s look at Beta adrenergic blocking agents. To make it easy, please note that all beta adrenergic blocking agents end with the suffix - lol

Mechanism of action

• Beta adrenergic blocking agents work by competitively binding with postsynaptic adrenergic membrane receptors and preventing their normal activation by adrenergic neurotransmitters.

• There are two main types of beta receptors: B1 and B2

Cont

• B1 receptors are located primarily in the heart and normally increase HR, increase the contractility of the heart muscle, and can speed artioventricular node conduction. For people with heart disease, this is not a good thing.

• They are put on B1 blockers to block the normal functions of B1 receptors, reducing the amount of O2 required by the heart.

Continued

• This action of the beta blockers helps protect from hypoxia and infarction.

• In addition, this decreased HR and contractility reduces cardiac output and lowers BP

• B1 blockers are also found in the kidneys but play little or no clinical role

B2 receptors

• These receptors are found in the vascular smooth muscles of the arterioles (except the skin and brain) and normally cause vasodilation.

• Blocking B2 receptors will therefore vasoconstrict and increase peripheral resistance.

Continued

• Rather than counteracting the B1 induced reduction of blood pressure, it mediates it causing a gradual reduction in BP rather than a dramatic decrease.

• B2 blockers also cause bronchoconstriction and reduce glycogenolysis in the liver, Bronchoconstriction is particularly and explains some of the side effects and red flags for non-selective agonists.

Continued

• Non-selective B antagonists are also used in the treatment of migraines, glaucoma and hyperthyroidism. It is believed that these agents prevent migraine onset by reducing catecholamine induced vasodialation. In glaucoma, beta blockers can be applied locally to reduce secretions of aqueous humor and thus reduce intraocular pressure. For hyperthyroidism, reduces sympathetic stimulation.

Common beta blockers

• Acebutolol – hypertension and ventricular arrhythmia

• Atenolol – hypertension, angina and post myocardial infarction

• Betaxolol – HPTN• Bisoprolol – hypertension, CHF• Carteolol - can be used in the eye for

glaucoma and ocular HPTN

Continue

• Carvedilol – HPTN, CHF, post MI• Labetalol – HPTN emergencies• Metoprolol – HPTN, CHF• Nadolol – angina• Penbutolol – HTN• Pindolol – HTN, antidepressant augmentation• Propranolol – HTN, migraine, angina, arrythmia

RED FLAGS

• Cannot stop abruptly – can cause sudden death

• Can reduce glucagon secretions• Bradycardia• See further page 61• Interacts with several cardiac medications

Herbal interactions

• With antihypertensives – Chen Pi, Gan Cao, Ma Huang, Qing Pi, Sheng Ma, Zhi Ke, Zhi Shi

• Beta Adrenergic Blockers – Gan Cao, Ma Huang• Propranolol – Black pepper• SIDE EFFECTS OF DRUGS – hypertension,

migraines, hyperthyroidism, angina, MI, decreased libido, cold extremities, fatigue, insomnia, nightmares, depression, brady down

SIDE EFFECTS CONT

• Can induce CHF and asthma