Parasympathetic Nervous System and Receptors

Parasympathetic Nervous System (PNS)

• Includes both motor and sensory components.
• Primarily involved in "rest and digest" functions.
• The neurotransmitter acetylcholine (ACh) is central to its operation.
• Key receptors include muscarinic (m1, m2, m3 ) receptors.

Parasympathetic Receptors (m + ACh)

• m1 receptors occur in salivary glands, stomach, and mediate motion sickness.
• m2 receptors decrease heart rate and contractile force, and AV node velocity.
• m3 receptors cause smooth muscle contraction, broncho constriction, and increase endo/exocrine function, vasodilation, and bladder contraction.
• ACh's primary, skeletal muscle function is as a neurotransmitter.
• Direct cholinergic drugs increase ACh by binding to the receptor.
• Indirect cholinergic drugs inhibit acetylcholinesterase (AChE).
• Anticholinergic drugs block parasympathetic impulses, inducing a sympathetic response.
• Muscarinic antagonists compete with ACh to bind to receptors.
• Cholinergic drugs cause side effects like bradycardia, defecation, drowsiness, difficulty breathing, salivation, sweating, memory issues, urination, and blurred vision; atropine serves as an antidote.

Cholinergic Drugs

• Indirectly increase acetylcholine (ACh) in the synapse by inhibiting acetylcholinesterase (AChE).
  • Physostigmine (Antilirium) is used for myasthenia gravis by increasing ACh receptors in muscle and acts as antidote for deadly nightshade poisoning
  • Neostigmine (Prostigmin) is also used for myasthenia gravis.
  • Pyridostigmine (Regonol) is used for myasthenia gravis.
  • Donepezil (Aricept) increases ACh in the synapse and is used in Alzheimer's disease (AD) when ACh function is reduced.
  • Rivastigmine (Exelon) increases ACh in the synapse and is used for Alzheimer's disease (AD).
• Directly bind to ACh receptors, activating the parasympathetic response
  • Bethanechol (Urecholine) stimulates urination.
  • Pilocarpine (Isopto Carpine) stimulates urination.

Anticholinergic Drugs

• These compete with ACh and bind to the receptor, and cause sympathetic by parasympathetic response:
  • Atropine (Atro-Pen) decreases tone of the anal sphincter.
    • can cause dry mouth/eyes, dilated pupils, increased heart rate, relaxed bronchi, constipation and sexual dysfunction
    • It only affects muscarinic receptors, not nicotinic ones, slows GI tract function, and can reverse cholinergic storm.
  • Benztropine (Cogentin) is used to treat Parkinson's disease (PD) and manage tremors.
  • Ipratropium (Atrovent) used for asthma and COPD.
  • Oxybutynin (Ditropan, Oxytrol) treats incontinence.
  • Propanimeline (Pro-Banthine) is prescribed for IBS and peptic ulcer disease.
  • Scopolamine (Transderm-Scop) can alleviate motion sickness and irritable bowel syndrome (IBS).

Sympathetic Nervous System

• (SNS) uses norepinephrine (NE), epinephrine (E), and dopamine (DA) as neurotransmitters.
• α1 receptors constrict vascular and smooth muscle, and dilate pupils.
• α2 receptors inhibit insulin and glucagon, and activate platelets.
• β1 receptors increase heart rate, AV node conduction, contractile force, and amylase production.
• B2 receptors cause smooth muscle relaxation, bronchial dilation, and decreased GI motility.
• β3 receptors increase lipolysis and relax the bladder.
• The sympathetic system's uses include treating nasal congestion and hypotension, as well as dilating pupils.

Adrenergic Drugs

• Albuterol (Proventil, Ventolin) acts on β2 receptors to treat asthma and COPD.
• Isoproterenol (Isuprel) acts on β1 and β2 receptors to treat asthma, dysrhythmias and heart failure.
• Phenylephrine (Neo-Synephrine) acts on α1 receptors to treat hypotension and nasal congestion.
• Pseudoephedrine (Sudafed) acts on α and β receptors to treat nasal congestion,.

Drugs Mechanism

• After NE is released into the synapse, it acts on adrenergic (α, β) receptors.
• Excess NE is reuptaken into the cell to be recycled, while COMT and MAO break down NE in the synapse and cell, respectively.

Aderenergic Drugs (Sympathomimetics)

• Direct-acting drugs include NE, E, and DA, and indirect-acting drugs cause the release, reuptake or destruction of NE.
• Aderenergic blocking works on receptors, α receptors affect smooth muscle, and β receptors affect heart rate, contractive force, and AV node velocity.

Adrenergic Blocking Drugs

• Atenolol (Tenormin) and bisoprolol (Zebeta) act on β1 receptors to treat hypertension and angina/heart failure.
• Metoprolol (Lopressor, Toprol) acts on β1 receptors to treat hypertension, acute myocardial infarction, angina, and heart failure.
• Cartelol (Cartrol) acts on both β1 and β2 receptors to treat hypertension and glaucoma.
• Propanolol (Inderal, Innopran XL acts on both β1 and β2 receptors to treat hypertension, dysrhythmia, and heart failure.
• Carvedilol (Coreg) acts on α and β receptors to treat hypertension and heart failure.
• Prazosin (Minipress acts on α1 receptors to treat hypertension.
• Tamsulosin (Flomax acts on α1 receptors to treat urinary issues from BPH.

Anxiety

• Situational anxiety occurs due to stressful motivators, while Generalized Anxiety Disorder (GAD) excessively impacts daily living.
• Panic disorder is marked by immediate fearfulness, terror, and a perception of impending doom
• Phobias feature fearful feelings attached to situations or objects.
• Social anxiety involves persistent, unreasonable fear of being judged, ridiculed, or embarrassed.
• Obsessive-compulsive disorder (OCD) involves recurrent intrusive thoughts or repetitive behaviors that interfere with activities/relationships.
• Post-traumatic stress disorder (PTSD) involves extreme situational anxiety that arises from reexperiencing a prior event.

Limbic System

• Located in the middle of the brain, and it handles emotions, learning, and memory.
• It connects to the hypothalamus and then the reticular formation.
  • The hypothalamus triggers an unconscious response to stress.
  • The reticular formation (RF) modulates alertness/arousal and drowsiness..
• Reticular activating system (RAS) routes signals from the brainstem to thalamus, impacting alertness, focus, and the sleep wake cycle.

Anxiety Treatment

• Determining and eliminating the underlying stressor is the first step to reduce angiolytics.
  • Benzodiazepines and barbiturates are also options
  • SSRIs/SNRIs, TCAs, and MAOIs can be used.
  • Beta-blockers are another viable course of action.
  • SSRIs are often used that reuptake of serotonin to keep 5-HT in the synapse longer:
    • escitalopram (Lexapro), fluoxetine (Prozac), and Scrtaline (Zoloft).
    • Can cause weight gain and sexual dysfunction.
  • SNRIs effect NE + DA + ５-HT reuptake.
    • Duloxetine (Cymbalta) is an example.

Benzodiazepines

• They positively modulate the effects of GABA by enhancing its binding to the GABAA receptor, leading to increased chloride ion conductance, hyperpolarization, and inhibition of neuronal firing, resulting in anxiolytic and sedative effects.
  • alprazolam (Xanax)
  • diazepam (Valium)
  • lorazepam (Ativan)
• Barbituates can also be used but have increased risk of side effects

Insomnia

• Short-term insomnia is often stress-related, while long-term insomnia lasts over 730 days and can be caused by PTSD, head injuries, chronic pain, or depression/mania.
• Narcolepsy is characterized by falling asleep at any time.
• The drug Motafinil (Provigil) enhances wakefulness.
• Other treatments limit caffeine and alcohol intake, increasing time from dinner to bed, decreasing screen time, adjusting the temperature.

Insomnia - Non-Pharmacologic & Anxiolytics

• Non-pharmacologic

  • Limiting caffeine & alcohol
  • Increasing time from dinner to bed
  • Decreased screen time and room temperature

• Anxiolytics

  • Barbiturates
  • CNS depressants
  • Melatonin receptor
  • Orexin receptor

GABA & Glutamate

• GABA is inhibitory, while glutamate is excitatory.
• GABA influx of Cl- into the cell, causing the cell to have a more negative charge that makes it harder to reach action potential threshold.

CNS Depressants

• Eszopiclone (Lunesta).
• Zalepion (Sonata) for people who wake up at 2-3am due to its ability to positively modulate GABA receptors.
• Zolpidem (Ambien) used for short-term insomnia, but it should not be combined with alcohol or given to lactating women (insomnia).
• Other insomnia prescriptions target melatonin receptors (ramelteon (Rozerem)) or orexin (Surorexant (Bel Somnia)).

Seizures

• Partial seizures include simple seizures that involve auditory and/or visual effects, and complex seizures that involve seeing lights, confusion, drowsiness, and patients taking off clothes.
• Generalized seizures include absent seizures that last a few seconds, and last few seconds in children, can also cause confusion.
  • Atonic seizures that cause a lack of muscle control, and tonic clonic seizures that involve muscle contraction by muscle relaxation tonic.

Seizures- Causes

• Febrile is caused by a fever by high fever in children.
• Myoclonic large jerking movements from limbs.
• Status epilepticus continues seizure activity that leads to long-term incidents and it requires immediate medical attention.

Epilepsy and Drug Targets

• Epilepsy occurs when there are recurrent Seizures
• Drug targets for epilepsy involve:
  • Blocking Na+ channels.
  • Enhancing GABA.
  • Delaying Ca++ influx.
• All of which help reduce brain activity.

Barbiturates & Benzodiazepines

• Barbiturates enhance GABA

  • takes weeks to work but no longer used
  • Phenobarbital (Luminal) used for seizure activity

• Benzodiazepines boost GABA and well tolerated

  • tolerance builds in months
  • diazepam (Valium) used for general seizure activity
  • lorazepam (Ativan) used for tonic activity

Seizure Drugs

• Drugs that boost GABA:
  • Gabapentin (Gralise)
  • Pregabalin (Lyrica)
  • Topiramate (Topamax).
• Drugs that inactivate Na+ receptors include phenytoin (Dilantin) and increase influx into cells, first line of defence for most seizures
  • Carbamazepine (Tegretol) is prescribed for tonic clonic and partial seizures.
  • Valproic acid (Depakene) enhances GABA.
• Succinimides that delay Ca++ influx, like ethosuximide (Zarontin), treat absence seizures.

Depression

• Major depression as having 5+ of the following 9 symptoms, almost every day, for a period of 2 or more weeks.
  • Sleep
  • Interest
  • Guilt
  • Energy
  • Concentration
  • Appetite
  • Psychomotor
  • Suicidal

Depression Causes

• Include disease (PTSD and AD), pharmacological effects (L-DOPA, corticosteroids, oral contraceptives), and other issues (thyroid problems, B-vitamin deficiency).
• Serotonin syndrome impacts synthesis, uptake, and metabolism, causing mental changes, restlessness, tremors, etc.

Depression Non-Drug Therapies

• Behavioral therapy help to understand life and work reward system.
• Interpersonal therapy focuses altered relationships skills.
• Electroconvulsive therapy is highly effective but can cause more side effects than drug therapy.

Depression Drug Therapies

• Drugs that reduce NE breakdown by decreasing reuptake of NE & 5-HT:
  • SSRIs target 5-HT uptake into the presynaptic terminal
    • escitalopram (Lexapro)
    • fluoxetine (Prozac)
    • Scrtaline (Zoloft)
  • SNRIs target 5-HT + NE uptake, increasing DA at synapse.
    • duloxetine (Cymbalta)
  • Bupropion (Wellbutrin) inhibits DA+/+ NE transport.
  • TCAs target 5-HT and NE that increase levels of NE.

Bipolar Disorder

• Alternation between mania and depression, with potential for abnormal neurotransmitter function.

Drugs Treat Bipolar

• Mood stabilizers such as lithium (Eskalith).
  • Constantly monitors blood levels
• Atypical Drugs :
  • Aripiprazole (Abilify): less PD like symptoms along with small weight loss
  • risperidone (Risperdal) reduces symptoms.

ADHD

• Usually occurring in children and effecting learning through play and social cues.
• Treated with stimulants, mainly drugs acting on reuptake of NE.

ADHD - Drugs

• CNS Stimulants

• insomnia, nervousness, anorexia, and weight loss

• d-L-amphetamine (Adderal) mainly focuses on receptors

• memylphenidate (Ritalin) mainly focuses on blocking the drug

• non-Stimulants

• Datomexctine (Strattera): NE release - improved focus, & hyperactivity

Psychosis

• Dopamine activity in basal activity
• causes overactive pathways that creates synchronicity in motor activity

Psychosis Drugs

• Phenomiazines (Excitement blocking)

• chlorpromazine

• prochlorperazine (compazine)

• Non Phenothiazines

  • EPS
  • haloperidol

• Atypical is type 2 diabeetus

• risperidone (Risperdal)

Alzheimer's

• Loss in neurofibulary's

• progressive loss of memories and confusion

• Treatmemt: main focus to increase cortex that can contain :

  -Donepezil -mementine decreases glutamate with positive effects of decreasing AD

• Combination with both for better effect

Multiple Sclerosis

• autoimmune
• female dominated
• remission during pregnancy

Treatment

• Interferon: mainly targets t cells that modulates system

  -Glatiramec: myelin reduces attack

• Fingolimod; decreases flares

• Palfampridine slows down speed and walking

Muscle Spasms

• Tonic : Single contraction
• Clonidine: Repeating contractions

Pain

• Is a defense of an action by the body
• Noriceptor : tissue

Adjuvant Analgesics

• Used for intractable pain

Opiods Moderate Levels

• targets mu and kappa receptors
• Patient is self-medicating

Anesthesia

• numbing medicine

• sodium and channel blocks

• Lidocaine* has few effects to side effects

    1-general: Loss of conisness
  

Anesthetic

• pre-op for anxiety
• post op for pain Zofran-cmesis neuromuscular blockers Succing- choline: at NMJ