Drugs and Toxins: Effects, Pathways and Side Effects

Drug & Toxin Absorption

Bloodstream

• Drugs and toxins must be introduced into the bloodstream to effectively interact with the brain and body
• The circulatory system transports substances throughout the body
• Interaction is limited to specific tissues, involving ligands binding to receptors
• Side effects are primarily caused by drugs designed to interact with the brain, which can also activate the same receptors elsewhere in the body (antihistamines, opioids)

Substance Breakdown

• Substances entering the circulation begin to be broken down
• Effects depends on the dose and the route of administration

Dose

• Substance effectiveness is directly related to its concentration
• The more substance, the greater the effect
• Effective and fatal doses vary greatly among substances

Dose - Opioids

• Opioids represent a diverse class of analgesics, serving as pain killers
• A slight structural difference can significantly alter an opioid's effectiveness in pain suppression

Substance Breakdown

• The most direct route of administration to the target tissue yields the most significant effect
• The more direct the route, the less time for breakdown

Routes of Administration

• Ingestion (least effective)
• Absorption
• Intramuscular injection
• Inhalation
• Intravenous injection (most effective)

Substance Effectiveness

• How a drug or toxin impacts the body is determined by the dose and administration route
• Few bodily structures offer extra protection to filter out drugs and toxins

Blood-Brain Barrier (BBB)

• Astrocytes tightly encircle blood vessels in the brain, forming the BBB
• Materials must pass through astrocytes to reach neurons
• Allows passage of essential substances (glucose, oxygen, water, amino acids)
• Blocks harmful substances (waste, toxins)
• Small, uncharged substances can bypass the BBB and interact with the CNS
• Drugs/toxins interacting with the brain must pass through the BBB
• Pharmaceutical companies design drugs either to cross or be blocked by it

Benadryl

• An antihistamine containing diphenhydramine that is used as an allergy medicine
• It alleviates allergy symptoms like excessive mucus production

Antihistamines

• Histamine receptors regulate mucus-producing cells in the sinuses, inducing mucus production upon binding
• Antihistamines act as antagonists, binding to receptors without activating them
• They prevent histamine from binding, reducing mucus production and allergy symptoms

Histamine in the Brain

• Histamine functions differently across organs
• In the brain, it is a neurotransmitter that activates receptors to maintain wakefulness

Benadryl

• Benadryl's small molecular structure enables it to cross the BBB and block histamine receptors in the brain
• This can leads to drowsiness and exhaustion

Claritin

• An allergy medicine containing loratadine
• Has a similar ligand structure to Benadryl, but is larger and slightly charged
• Its different structure prevents passage through the BBB
• This prevents drowsy side effects

BBB Summary

• Substances must pass the BBB to interact with the brain
• Small substances can usually pass through

Botox

• Drugs and toxins primarily act on the neuromuscular junction (NMJ)
• The NMJ is the site where the nervous system communicates with muscles
• Skeletal muscles are composed of parallel fibers that contract when stimulated by axons
• PNS neurons in the somatic efferent division have axons synapsing with muscle fibers

Neuromuscular Junction (NMJ)

• Presynaptic
  • Axon
  • Functions like neuron-to-neuron synapses, releasing acetylcholine (ACh)
• Postsynaptic
  • Muscle fiber
  • Contracts when ACh binds to ACh receptors

Botulinum Toxin

• Commonly known as Botox
• A neurotoxin poison
• Generated by bacteria in mishandled meat
• Also known as "Sausage Poisoning"

Botulinum Toxin/Botox Mechanism of Action

• Breaks down the SNARE complex
• Prevents SNARE from operating

Botulinum Toxin Effects

• PNS axon is unable to release NTs without intact SNARE complexes
• If no intact SNARE complex, the muscle fiber will not receive NT stimulation from the axon
• Permanently paralyzes muscle fiber

Botulinum Toxin Uses

• Has both harmful and helpful uses
• Depends on dose and route of administration
• High doses of botulinum toxin that enter the bloodstream can circulate through NMJs
• Resulting in botulism and possible death
• Low doses of botulinum toxin injected directly into a specific muscle will not spread to the bloodstream
• Results in paralysis limited to the injected muscle

Botox Uses

• Cosmetic applications, to paralyze small facial muscles and reduce wrinkles when muscles contract
• Tension headache treatment to weaken constricted muscles around the skull base and relieve tension
• Strabismus (lazy eye) treatment is another use of botox by weakening muscles on the tenser side to even out tension

Reuptake Inhibitors

• Botox primarily affects synapses in the PNS and can't cross the BBB
• Substances crossing the BBB can affect brain synaptic transmission

Reuptake Inhibitors

• Commonly prescribed, medications influence synaptic transmission by adjusting NT reuptake proteins

SSRI

• Selective serotonin reuptake inhibitors (SSRI)
• Commonly prescribed treatment for major depression and generalized anxiety disorders
• Synapse takes longer to clear 5-HT entirely from the cleft
• Still have:
  • Some functioning 5-HT uptake proteins
  • Degradation proteins
  • Diffusion
• SSRIs increases the amount of time 5-HT remains in the synaptic cleft
• Providing more opportunities to bind and unbind from 5-HT receptors
• Resulting in increased postsynaptic activation

Serotonin Hypothesis

• Served as the working theory for how SSRIs helped with depression and anxiety
• Belief that those people had decreased 5-HT signaling
• Experiencing reevaluation

SSRI - Mysteries

• It is still unclear how increased 5-HT signaling helps with depression and anxiety disorders
• SSRIs are not effective for everyone
• Beneficial changes usually take ~3 weeks to appear
• 5-HT levels can increase within hours of the first dose

• Beneficial results are thought to be from presynaptic changes after prolonged 5-HT increase
• Current investigation
• 5-HT likely a contributing factor, though not a "magic bullet" as thought

5HTT KO Experiment - Paradoxical Finding

• Researchers knocked out (KO) a 5-HT transporter (5HTT) which is a reuptake protein
• Expected that reducing anxiety because KOing reuptake would increase 5-HT signaling
• Surprised to see they actually killed off 5-HT producing cells

Reuptake Inhibitors

• SSRIs are not the only substance that influences synaptic signaling by decreasing the effectives of reuptake proteins

Cocaine

• Cocaine, an illegal recreational drug, is used for inhibiting the reuptake of dopamine (DA)
• Cocaine, an illegal recreational drug, is used for inhibiting the reuptake of Norepinephrine (NE)
• Cocaine, an illegal recreational drug, is used for inhibiting the reuptake of Serotonin (5-HT)
• Follows a similar mechanism of action as SSRIs, but leads the user to experience
  • Hyperactivity, euphoria, and emotional dysregulation

SSRI vs Cocaine

• Drugs have different behavioral/mental effects due to signaling various NTs
• Increasing DA and NE leads to hyperactivity, euphoria, and other symptoms
• Neural activity relies on the activity of brain receptors
• Modulating different NT signaling impacts receptors, with behavioral effects

Methylphenidate

• Commonly called Ritalin
• Commonly prescribed for attention-deficit hyperactivity disorder (ADHD)
• Shares an activity component with cocaine
• The exact reason and mechanisms of increasing DA and NE are beneficial for some ADHD people

Reuptake Inhibitors

• Amazing support tool for a range of neurological disorders
• Though considered a “magic bullet”, it seems to be helping as a part of a bigger picture
• Hot bed of research!

Explore the effects, pathways, and side effects of drugs and toxins in the body, emphasizing their interaction with the bloodstream and brain. Understand the role of ligands, antihistamines, and blood-brain barrier astrocytes with a focus on drug specificity and unintended consequences.