Pharmacology of Adrenergic Antagonists and Stimulants

Drugs Affecting the Nervous System

• Drugs affecting the nervous system are categorized into modules, with this material being Module 6.
• The nervous system is broken down into peripheral and central nervous systems.
• The peripheral nervous system is further divided into efferent and afferent divisions.
• The efferent division is also split into autonomic and somatic systems.
• The autonomic system affects internal organs, which include intestines and smooth/visceral muscles.
• The somatic system is involved in skeletal muscle movement.
• Autonomic pharmacology discusses drugs that affect the autonomic nervous system.
• The autonomic nervous system has two divisions: parasympathetic (PNS) and sympathetic (SNS).
• The parasympathetic nervous system's main function is "rest and digest."
• The sympathetic nervous system's function is "fight or flight."
• The sympathetic and parasympathetic nervous systems often have opposing actions on organs to maintain homeostasis.
• Key autonomic effector organs and their sympathetic and parasympathetic responses are detailed.
• The central nervous system involves the brain and spinal cord, affecting both.
• Many chemical signals are crucial to nervous system function, including norepinephrine, epinephrine, acetylcholine, dopamine, serotonin, histamine, glutamate, and γ-aminobutyric acid.
• Each chemical signal binds to a specific family of receptors.

Autonomic Pharmacology

• Two main types of neurotransmitters: cholinergic and adrenergic.
• Cholinergic transmission is mediated by acetylcholine (ACh).
  • ACh is the primary neurotransmitter in all autonomic ganglia and also at the synapses between parasympathetic postganglionic neurons and effector cells.
  • ACh is also the primary neurotransmitter in the somatic (voluntary) skeletal muscle neuromuscular junction.
• Adrenergic transmission uses norepinephrine (NE).
  • NE is the primary transmitter at sympathetic postganglionic neuron-effector cell synapses.
    • Exceptions exist, like fibers to sweat glands needing ACh
  • Dopamine may be a vasodilator transmitter in the renal blood vessels, but NE is a vasoconstrictor in other vessels.

Actions of sympathetic and parasympathetic nervous systems on effector organs

• Various effector organs (e.g., eye, heart, kidneys, bladder, GI system) are presented with their corresponding sympathetic and parasympathetic responses.
• Sympathetic responses are often characterized by an increase in activity, such as increased heart rate.
• Parasympathetic responses usually involve decreased activity; for example, decreased heart rate.

Fight or Flight Response vs. Rest and Digest

• Each response has a different system functioning.
• The sympathetic nervous system is responsible for a "fight or flight" response.
• The parasympathetic nervous system is the primary system for the "rest and digest" response.
• These systems have different overall functions and ways of responding to stimuli.

Sympathetic vs. Parasympathetic Nervous Systems

• These two systems maintain homeostasis through balanced activity.
• Sympathetic activity generally dominates during "fight or flight" responses.
• Parasympathetic activity is usually dominant during "rest and digest" states.

Neuron

• Neurons are the basic structural and functional units of the nervous system.
• Axons are the long, slender projections that transmit signals away from the neuron.
• Dendrites are short, branched projections that receive signals from other neurons and transmit them to the cell body where the signals are processed.
• The myelin sheath is an insulating layer that surrounds the axons and helps to speed up the transmission of signals.
• Neurotransmitters are chemical messengers that transmit signals between neurons.
• Neuron-transmitter mechanisms happen via synaptic signaling.

Types of Neurotransmitters

• There are many neurotransmitters in the nervous system impacting and related to drugs.
• Norepinephrine, epinephrine, acetylcholine, dopamine, serotonin, histamine, glutamate, and γ-aminobutyric acid are among the most involved in drug therapies.
• Each of these has receptors, the chemical signals bind to these receptors.

Cholinergic Transmission

• Acetylcholine (ACh) is the primary neurotransmitter for many functions in the nervous system.
• ACh, at all autonomic ganglia, plays a role in the synapses between parasympathetic postganglionic neurons and their effector cells.
• ACh acts at postganglionic sympathetic neurons to control thermoregulatory sweat glands.

Adrenergic Transmission

• Norepinephrine is the primary neurotransmitter in sympathetic systems.
• NE plays a role at sympathetic postganglionic neurons in many pathways.
• NE has important roles including in sweat glands and vasodilation of skeletal muscles.

Motor Fiber

• ACh is released from preganglionic fibers;
• In sympathetic neurons, NE(or EPI) is released.

Receptor Organs

• The autonomic nervous system and neurotransmitters control various organs.
• Adrenergic and cholinergic responses differ considerably by organ.

Drugs Affecting the ANS

• Four main types of drugs are:
  • Adrenergic agonists (sympathomimetics)
  • Adrenergic antagonists (sympatholytics)
  • Cholinergic agonists (parasympathomimetics)
  • Cholinergic antagonists (parasympatholytics)
• Drugs affecting the ANS function in several therapeutic ways and areas.

Adrenergic Agonists (Sympathomimetic Drugs)

• Several sympathomimetics are widely used.
• Norepinephrine (Levophed) is an alpha agonist causing vasoconstriction in blood vessels.
• Epinephrine (Adrenaline) impacts both alpha and beta receptors, and is used in cardiac arrest, anaphylaxis, and asthma.
• Albuterol (Ventolin) is a beta2 agonist used for dilation of bronchi and asthma.
• Dopamine affects blood pressure and is used in emergency medicine and critical care.

Adrenergic Antagonists (Sympatholytic Drugs)

• Phentolamine (Regitine) is an alpha blocker, preventing vasoconstriction.
• This can be used in hypertensive crises and necrosis prevention due to extravasation of NE/EPI or dopamine.
• Several medications are categorized as adrenergic antagonists, and useful in several conditions.
• Beta blockers, non-selective or selective, block beta receptors, useful in cardiac disease.

Cholinergic Agonists (Parasympathomimetic Drugs)

• These drugs increase parasympathetic activity.
• Physostigmine (Antilirium) is a treatment for poisoning from atropine-type drugs.

Cholinergic Antagonists (Parasympatholytic Drugs)

• Atropine is a common cholinergic antagonist.
• It's used to treat bradycardia and has other effects on the pulmonary system, leading to bronchodilation and suppressing secretions.
• Atropine is the drug of choice for nerve agent and organophosphate poisoning.

Drugs Affecting CNS

• Several diverse drug types affect the central nervous system (CNS).
• Analgesics, anesthetics, anxiolytics, and sedative-hypnotics, CNS stimulants, antipsychotic drugs, antidepressants, and neurodegenerative drugs, all have important roles in CNS function.

Analgesics

• Analgesics decrease pain sensation.
• Opioid analgesics (e.g., morphine, codeine, fentanyl, hydrocodone), Act on mu and kappa receptors.
• Non-opioid analgesics include salicylates (e.g., aspirin) and nonsteroidal anti-inflammatory drugs (NSAIDs) (e.g., ibuprofen, naproxen).
• Acetaminophen is an analgesic but doesn't affect peripheral prostaglandin synthesis.

Opioids

• Opioids are derived from opium, mimicking the actions of endorphins.
• A prototype opioid, morphine, acts primarily on mu receptors.
• The effects of opioids vary by receptor type.

Actions at Opioid Receptors

• Opioids can trigger different actions at opioid receptors, depending on the drug type and the specific receptors it interacts with.
• Some agents are pure agonists or antagonists, or are mixed agonist-antagonists.

Morphine Sulfate

• Morphine Sulfate is an opioid used for pain relief in many areas, including moderate to severe pain.
• Appropriate use of morphine involves evaluating patients and closely monitoring their responses.
• Adverse reactions are presented.

Fentanyl Citrate (Sublimaze)

• Fentanyl is a powerful opioid analgesic.
• It is used in various medical situations requiring strong pain relief.
• It's used for acute pain, as well as sedation, and in some surgical procedures.
• Risks and benefits need to be carefully considered regarding its use.

Ondansetron (Zofran)

• Ondansetron is an antiemetic used to prevent/treat nausea and vomiting.
• It acts by blocking serotonin receptors in the brain.
• Important considerations are presented, as well as relevant adverse effects.

Non-opioid Analgesics

• Salicylates (like aspirin)
• NSAIDs (like ibuprofen, naproxen, and diclofenac) have different mechanisms and therapeutic uses.

NSAID Properties

• Specific NSAIDS have different properties.
• The properties are antipyretic, anti-inflammatory, and analgesic.

CNS Stimulants

• Amphetamines are used for their effects on neurotransmitter release and have several side effects.
• Methylphenidate (Ritalin) is used for attention deficit disorder to increase focus and concentration.
• Methylxanthines (like caffeine and theophylline) act by blocking adenosine receptors.

Anesthetics

• General anesthetics include nitrous oxide and others which act to impact consciousness and loss of sensation.
• Local anesthetics like lidocaine affect areas around injections.

Anti-anxiety & Hypnotic Medications

• These drugs are used for sedation, hypnotism, anxiety reduction, and insomnia relief.
• Two primary classes are barbiturates and benzodiazepines (e.g., diazepam, lorazepam, midazolam, alprazolam).

Mechanism of Action of Anti-Anxiety/Sedative-Hypnotics

• Both barbiturates and benzodiazepines influence/enhance the actions of GABA receptors in the CNS, but do so in different ways.
• GABA is a crucial inhibitory neurotransmitter in the brain.

Benzodiazepines vs. Barbiturates

• Considerations like safety, degree of CNS effect, and abuse potential distinguish these drug types.

Anti-seizure Medications

• Multiple chemical classes lower the frequency of action potentials associated with seizures, useful and essential for a variety of seizure types and conditions.

Psychotherapeutic Medications

• Psychotherapeutic medications treat dysfunction related to neurotransmitter imbalances, typically involving monoamines like norepinephrine, dopamine, and serotonin.
• These medications aim to restore neurotransmitter balance impacting various pathways, symptoms, and conditions.

Antipsychotic Drugs (Neuroleptics)

• Antipsychotic medications are used to address conditions like schizophrenia and other conditions where dopamine release is thought to be too high.
• These medications often lower dopamine activity. Classes include phenothiazines and butyrophenones (e.g., chlorpromazine, haloperidol).

Antipsychotic MOA (Mechanism of Action)

• Antipsychotics often work through receptor antagonism, particularly affecting dopamine receptors in the brain.
• They also, depending on the type of antagonist, may affect muscarinic cholinergic receptors, histaminergic receptors, and adrenergic receptors.

Antipsychotic Side Effects

• Side effects related to antipsychotic use tend to be immediate.
  • Extrapyramidal symptoms (EPS)
  • Anticholinergic effects (dry mouth, blurred vision, constipation, etc.)
  • Orthostatic hypotension (a sudden drop in blood pressure)
  • Sedation
  • Reduced seizure threshold

Antidepressants

• Antidepressants address imbalances in monoamines (norepinephrine, dopamine, serotonin). Treatments often involve increasing neurotransmitter synthesis within presynaptic nerve endings, boosting neurotransmitter release from these endings, and/or inhibiting reuptake of neurotransmitters by presynaptic endings.

Tricyclic Antidepressants (TCAs)

• TCAs block the reuptake of norepinephrine (NE) and serotonin (5-HT).
• They have similar side effects to phenothiazines, including orthostatic hypotension, sedation, and anticholinergic effects; they can also present cardiac toxicity.

TCA Side Effects

• Orthostatic hypotension, sedation, and anticholinergic effects are among the key side effects of TCAs.
• Cardiac effects, including ventricular arrhythmias, can be serious.

Selective Serotonin Reuptake Inhibitors (SSRIs)

• SSRIs block only serotonin reuptake, unlike TCAs which impact norepinephrine as well.
• They tend to have fewer side effects than TCAs, including no orthostatic hypotension, anticholinergic effects, and cardiac toxicity.

Monoamine Oxidase Inhibitors (MAOIs)

• MAOIs inhibit the enzyme monoamine oxidase, which inactivates monoamines.
• This action can elevate neurotransmitters within the brain.
• Importantly, MAOIs interact with tyramine. This interaction can cause significant side effects, a critical aspect of treatment or patient education.

MAOI Side Effects

• CNS stimulation (anxiety, agitation); orthostatic hypotension; hypertensive crisis (from tyramine consumption).