Pharmacology Lecture: Drugs & Toxins - PDF

8.1 Drug & Toxin Absorption Bloodstream -​ Drugs and toxins must be introduced into the bloodstream to interact with the brain and body -​ The bloodstream will transport the substance around the whole body -​ Will only interact with certain tissues -​ Ligands binding...

8.1 Drug & Toxin Absorption Bloodstream -​ Drugs and toxins must be introduced into the bloodstream to interact with the brain and body -​ The bloodstream will transport the substance around the whole body -​ Will only interact with certain tissues -​ Ligands binding to receptors -​ Primary cause of side effects -​ Drug designed to interact with the brain region -​ Activates the same receptors in another part of the brain or body -​ Ex. antihistamine, opioids, etc. Substance Breakdown -​ Once a substance enters the bloodstream, it will start to be broken down by the body -​ The substance’s effect is dependent on: -​ Dose -​ Route of administration Dose -​ The effectiveness of the substance is directly related to its concentration -​ More of the substance, greater the effect on the body -​ Effective and fatal doses greatly vary between substances Dose - Opioids -​ Diverse class of analgesics -​ Pain killers  -​ A slight difference to the structure greatly influences how effective each opioid is at pain suppression Substance Breakdown -​ Most direct path from administration to the target tissue will have the most significant effect -​ Has the least amount of time to be broken down Routes of Administration -​ Ingestion (Least effective) -​ Absorption -​ Intramuscular injection -​ Inhalation -​ Intravenous injection (Most effective) Substance Effectiveness -​ The effect a drug or toxin has on the body is determined by the dose and route of administration -​ Few structures in the body have additional protective to filter out some drugs and toxins Blood-Brain Barrier (BBB) -​ Astrocytes tightly wrap around blood vesicles in the brain -​ Materials must pass through the astrocytes before reaching the neurons -​ Allow in good stuff -​ Glucose -​ Oxygen (O2) -​ Water  -​ Amino acids -​ More -​ Blocks bad stuff -​ Waste -​ Toxins -​ More -​ Small and uncharged substances can still slip through the BBB to interact with the CNS -​ Drugs and toxins that interact with the brain are able to pass through the BBB -​ Pharmaceutical companies take advantage of this fact -​ Design medications to pass through or to be blocked -​ Example: -​ Diphenhydramine (Benadryl) -​ Loratadine (Claritin) Benadryl -​ Diphenhydramine -​ Allergy medicine -​ Reduced allergy symptoms -​ Such as excessive mucus production -​ Antihistamine Antihistamines -​ Mucus producing cells in our sinuses are regulated by histamine receptors -​ When histamine binds to histamine receptors, mucus is produced  -​ Antihistamines are antagonists -​ Molecules that bind to a receptor but do not activate the receptor -​ Prevents histamine from binding and activating the receptors -​ Antihistamines will block receptors on mucus producing cells in the sinus -​ Reducing mucus production -​ Giving relief from allergy symptoms Histamine in the Brain -​ The same molecule is reused in different organs for different functions -​ Histamine is a NT that activates receptors in our brain that keep us awake Benadryl -​ Benadryl is a small molecule that can pass through the BBB -​ Antihistamines in the brain will block histamine receptors -​ Resulting in drowsiness and exhaustion Claritin -​ Loratadine -​ Allergy medicine -​ Antihistamine -​ Similar ligand -​ Different molecule structure, larger and slightly charged -​ Different structure prevents it from passing through the BBB -​ Antihistamine is unable to access the brain -​ Prevents drowsy side effects BBB Summary -​ Substance must get past the BBB to interact with the brain -​ Small substances are able to get through 8.2 Botox NMJ Introduction -​ The first drugs and toxins we will cover primarily act on the neuromuscular junction (NMJ) -​ Location of communication from the nervous system to the muscles -​ Skeletal muscles are made of many parallel muscle fibers -​ Muscle fibers contract when stimulated by axons -​ PNS neurons of the somatic efferent division have axons that synapse with each muscle fiber Neuromuscular Junction (NMJ) -​ Presynaptic -​ Axon -​ Functions are identical to neuron-to-neuron synapses -​ Releases acetylcholine (ACh) -​ Postsynaptic -​ Muscle fiber -​ Contracts when ACh binds to ACh receptors Botulinum Toxin -​ Commonly known by commercial name: Botox -​ Neurotoxin poison  -​ Produced by bacteria found in mishandled meat -​ “Sausage Poisoning” Botulinum Toxin/Botox Mechanism of Action -​ Breaks down the SNARE complex -​ Prevents the SNARE from operating Botulinum Toxin Effects -​ PNS axon is unable to release NTs without intact SNARE complexes -​ Muscle fiber will not receive NTs when the axon is stimulated -​ Muscle fiber is permanently paralyzed Botulinum Toxin Uses -​ It is both! -​ Depends on: -​ Dose -​ Route of administration -​ Ingestion of a high dose of botulinum toxin will allow the toxin to enter the bloodstream and circulate to NMJs across the whole body -​ Resulting in -​ Botulism -​ Possible Death -​ Local injection of a low dose of botulinum toxin to a specific muscle will not spread to the bloodstream -​ Only the injected muscle will be affected  -​ Resulting in: -​ Localized muscle paralytic Botox Uses -​ Cosmetic -​ Paralyzes small face muscles -​ Prevents wrinkles in skin when muscles contract -​ Tension Headache Treatment -​ Weakens overly constricted muscles around base of skull -​ Relieving tension causing headache -​ Strabismus treatment -​ Aka “lazy eye” -​ Caused by muscles of the eye unevenly pulling on the eye -​ Pulling one eye more to one side than the other -​ Muscles on tenser side are weakened to even tension across the eye 8.3 Reuptake Inhibitors Substances in the Brain -​ Botox primarily acts on only synapses in the PNS -​ Cannot pass the BBB -​ Substances that pass through the BBB are able to access the brain to influence synaptic transmission Reuptake Inhibitors -​ Multiple commonly prescribed medications influence synaptic transmission by modulating the activity of NT reuptake proteins SSRI -​ Selective serotonin reuptake inhibitors (SSRI) -​ Medication commonly prescribed as treatment for: -​ Major Depression Disorder -​ Generalized Anxiety Disorder -​ The synapse will take longer to clear all 5-HT out from the cleft -​ Still have: -​ Some functioning 5-HT uptake proteins -​ Degradation proteins -​ Diffusion -​ SSRI increases the amount of time 5-HT is in the synaptic cleft -​ Giving 5-HT more opportunities to bind and unbind from 5-HT receptors -​ Resulting in increased postsynaptic activation Serotonin Hypothesis -​ Working theory of why SSRIs helped people with depression and anxiety -​ Belief that those people had decreased 5-HT signaling -​ Currently being reevaluated SSRI - Mysteries -​ While the initial mechanism of SSRIs are very well understood, it is unclear how increased 5-HT signaling helps some people with depression and anxiety disorders -​ SSRIs do not work for everyone -​ Beneficial behavioral outcomes typically take ~3 weeks to manifest -​ Even though 5-HT levels increase within hours of first dose  -​ Beneficial outcomes might be due to presynaptic changes following prolonged increase of 5-HT signaling -​ Currently being investigated -​ 5-HT is most likely a part of the puzzle, but not the “magic bullet” that it was first thought to be 5HTT KO Experiment - Paradoxical Finding -​ Researchers knocked out (KO) a 5-HT transporter (5HTT) which is a reuptake protein -​ Expected to reduce anxiety because they thought 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 is an illegal recreational drug that inhibits the reuptake of -​ Dopamine (DA) -​ Norepinephrine (NE) -​ Serotonin (5-HT) -​ Near identical mechanism of action as SSRIs -​ Stimulant drug that causes one to experience -​ Hyperactivity -​ Euphoria -​ Emotional dysregulation SSRI vs Cocaine -​ The drugs have different behavioral effects because they influence the signaling of different NTs -​ The increase DA and NE will result in hyperactivity, euphoria, and other symptoms -​ Neural activity is dependent on the activity of the receptors in the brain -​ Modulating different NT signaling in the brain will affect those receptors, thus having different effects on behavior Methylphenidate -​ Commonly know by commercial name: Ritalin -​ Commonly prescribed to treat attention-deficit hyperactivity disorder (ADHD) -​ Same activity component as cocaine -​ Unclear how and why the increase of DA and NE signaling has a beneficial outcome for some people with ADHD Reuptake Inhibitors -​ Amazing tool for supporting people with a range of neurological disorders -​ Thought to be a “magic bullet” but in reality, seems to be helping a part of a bigger picture -​ Hot bed of research !