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Local Anesthetics

• Cocaine is considered the best local anesthetic
• Procaine and lidocaine were later synthesized
• Procaine and lidocaine retained the nerve-blocking properties of cocaine, but without the damaging effects on the central nervous system (CNS)

Chemical Structure

• Common to all local anesthetics:
• An aromatic ring that imparts lipophilicity
• A central connecting group that can be an amide or ester
• An ionizable amino group that can either be protonated or not
• When protonated, it carries a positive charge, making it less likely to cross the membrane
• The un-ionized form can cross the membrane more easily
• The distance between the aromatic ring and side chain is constant
• Local anesthetics bind to the same receptors
• Lipid solubility determines a drug's potency

Mechanism of Action

• Local anesthetics are weak bases, so at low pH, there is high protonation
• Equilibrium favors the unprotonated form outside the cell, while the protonated form is favored inside the cell
• Mechanism of action involves blocking Na+ channels
• This prevents the generation of action potentials
• The protonated form facilitates the blockage of channels
• Lower pK results in a more rapid onset of action because it promotes the unprotonated form, facilitating membrane crossing

Considerations

• Inflammation and increased blood flow/vasodilation are contraindications with surgery
• Increased likelihood of local anesthetic spreading in these conditions
• If it reaches the heart, it can cause arrhythmia.
• If it reaches the CNS, it can disrupt neural functions

Effects of Local Anesthetics (LAs) on Nerves

• In myelinated nerves, there is no effect due to saltatory conduction
• Non-myelinated nerves have signal propagation channel by channel
• Blocking even one Na+ channel can cause complete blockage
• Excitable cells with long action potentials, especially those in the heart, are more susceptible to blockage
• Vasoconstrictors like adrenaline can prevent vasodilation
• Vasoconstrictors have longer duration of action and allow a higher dose to be given, keeping the drug localized
• Cocaine is an exception, as it has vasoconstrictor properties

Effects of LAs on Heart

• Reduction of myocardial excitability which leads to a decrease in pacemaker activity
• Myocardial depression leading to hypotension

Effects of LAs on CNS

• Inhibition of an inhibitory neuron, resulting in stimulation
• General depression leading to cardiovascular collapse

Other Effects

• Allergic reactions are another effect

Routes of Administration

• Superficial: applied to the nose and mouth
• Infiltration: injected near nerve terminations
• Field block: subcutaneous injections
• Nerve block: injection close to peripheral nerves
• Spinal root: injection into the subarachnoid space
• Epidural root: injection into the epidural space that reduces pain during labor and delivery

Serotonin, Cytokines, and Histamines

• Serotonin is a monoaminergic neurotransmitter similar to histamine, noradrenaline, and dopamine.
• Modulates smooth muscle tone and promotes platelet aggregation

Serotonergic Pathways

• Neurons originate from the dorsal raphe and project their axons to various brain areas

Serotonin Synthesis

• Tryptophan undergoes hydroxylation to 5-hydroxytryptophan via tryptophan hydroxylase, the rate-limiting enzyme (TPH1 and TPH2)
• 5-hydroxytryptophan is then decarboxylated to serotonin
• Once absorbed, 85% binds to albumin, and the rest can diffuse

Serotonin in Pineal Gland

• Serotonin is the precursor of melatonin in the pineal gland
• After synthesis in neurons, serotonin is packaged into vesicles and released into the synaptic cleft
• After its release it is either metabolized (broken down) or reuptaken (recycled by autoreceptors)

Effects of Serotonin

• Effects in periphery:
• Regulates vascular tone
• Controls activity of platelets
• Heart functions
• Organ development
• Intestinal motility
• Cell regeneration
• Effects in brain:
• Controls emotions
• Sleep-wake cycle
• Aggressive behavior
• Food intake
• Anxiety
• Psychosis, schizophrenia

Special Note

• A pill of serotonin is unlikely to be absorbed and enter circulation
• It is an amine and tends to be protonated at pH 7, making absorption difficult
• Infusion is necessary

Diseases Associated with Serotonergic Transmission

• Major depression
• Anxiety disorder
• Attention deficit disorder
• Alzheimer's disease
• Schizophrenia
• Autism

Boosting Serotonergic System

• Blocking serotonin reuptake:
• A drug binds to serotonin transporters and remains in the synapse longer, which increases serotonergic tone
• Tricyclic antidepressants (TCAs):
• Block the reuptake transporters of serotonin and norepinephrine
• Lack of specificity, leading to sleep problems and sexual dysfunctions
• Monoamine oxidase (MAO) inhibitors:
• MAO is responsible for degrading monoamines
• By inhibiting it, neurotransmission is enhanced
• MAO-A inhibits serotonin and noradrenaline
• MAO-B inhibits dopamine
• Selective serotonin reuptake inhibitors (SSRIs):
• More specific, like Prozac
• Have side effects
• Starting Prozac therapy may cause an initial worsening of the symptoms
• This is because it will upregulate autoreceptors which will delay the beneficial effects and, as the treatment progresses, autoreceptors become desensitized and gradually improve the symptoms

Serotonergic Receptors

• Categorized based on brain localization:
• GPCRs
• Ion channels
• Tyrosine kinase
• Intracellular
• 5-HT3 is a ligand-gated ion channel
• 5-HT1A and 5-HT1B are presynaptic autoreceptors

Additional Note

• Inhibition could delay its effects on depression symptoms
• Once autoreceptors become desensitized, the antidepressant efficacy increases

Role of Serotonin in Periphery

• When platelets are activated due to vascular injury, they release serotonin
• This helps stop bleeding by acting on receptors of smooth vessels
• 5-HT3 receptors are found in nociceptive sensory neurons and control the vomit reflex
• Activation can occur due to side effects of chemotherapy, radiotherapy, or surgeries of the stomach/small intestine
• To block serotonin's effect, antagonists are administered
• Ondansetron, Granisetron, Tropisetron
• They are 5-HT3 blockers
• Can cause side effects like constipation and diarrhea
• Serotonin indirectly influences peristalsis via 5-HT4 receptors in enteric neurons
• 5-HT4 receptors can be targets to mitigate excessive serotonin release due to carcinoid tumors of enterochromaffin cells (intestine)

Cytokines

• Large class of compounds with different physiological effects
• Interleukins
• Chemokines
• Monokines
• Interferons
• Colony GFs
• Low molecular weight proteins that have high affinity for receptors and are active in picomole amounts

Cytokine Action

• Stimulus leads to cytokine-producing cell which releases cytokine
• The cytokine acts on target cell by binding to a receptor and causing a biological effect
• Cytokine-producing cells:
• Macrophages
• T lymphocytes
• Endothelial cells
• Fibroblasts
• Autocrine: affects itself
• Paracrine: affects cells close by
• Endocrine: affects cells remotely
• Pleiotropy: affects multiple cell types
• Cascading: acting sequentially
• Stimulus inducing cytokine production is inflammation

Additional Notes

• To stop inflammation, some cells release anti-inflammatory cytokines
• Fever occurs during inflammation due to macrophages and monocytes releasing interleukin 1 (cytokine)
• This stimulates the inflammatory cascade and the temperature center in the hypothalamus
• Each cytokine could be a drug, but these drugs are protein-based and are broken down by digestive enzymes if taken orally; therefore, they are injected or infused

Clinical Applications of Cytokines

• Colony stimulating factors (CSFs) are used with cancer therapy
• Erythropoietin (EPO) is used for anemia associated with kidney diseases
• Interferon IFN-β is used for multiple sclerosis
• Interferon IFN-γ is used for chronic granulomatous disease
• Interleukin IL-2 is used for kidney cancer and melanoma
• Interleukin IL-11 is used for thrombocytopenia after chemotherapy
• Tumor necrosis factor (TNFα) mab is used for rheumatoid arthritis and Crohn's disease
• Tryptophan is either used for 1% synthesis of serotonin or 30% protein synthesis
• In depression there is more tryptophan used for the kynuretic pathway and less serotonin is produced
• Kynuretic pathway produces nicotinamide adenine dinucleotide (NAD) coenzyme
• First enzyme is indoleamine-2,3-dioxygenase which is stimulated by inflammatory cytokines and if a larger amount of tryptophan is degraded then there is less tryptophan for serotonin

Histamine

• Monoamine synthesized from histidine
• Has 4 types of receptors: H1R, H2R, H3R, and H4R, all G protein-coupled receptors (GPCRs)
• Histamine is secreted in response to gastrin stimulation, which acts on H+/K+ ATPases involved in stomach acid secretion
• Mostly expressed in bone marrow, hematopoietic cells, spleen, and thymus

Histmaine Receptors

• H1R: activated during allergic reactions
• This is a mediator of inflammation and it's upregulated by inflammatory stimuli
• These receptors are GPCRs, and what's different between them is the downstream pathway they activate
• H2R: involved in the secretion of gastric acid by the stomach
• H3R: neurotransmitter
• H4R: involved in immune response
• Histamine is responsible for:
• Itch and pain at sensory nerve endings
• Bronchoconstriction
• Intestinal cramps and diarrhea
• Increased secretion of exocrine glands
• Suppression of appetite, maintaining wakefulness
• Sleep-wake cycle
• Anaphylactic shock

Antihistaminic Drugs

• Used for allergic rhinitis, conjunctivitis, dermatological reactions, bronchitis, motion sickness, and nausea
• Unwanted effects: H1 antagonists are non-selective, leading to side effects like unwanted anticholinergic activity
• Sedation is common with first-generation H1 antagonists because it's lipophilic and easily cross the BBB
• Second and third-generation antihistamines are more hydrophilic and have lower sedative effects.
• Cimetidine, famotidine, and ranitidine reduce acid production
• Omeprazole is a proton pump inhibitor

Catecholamines

• Major part is reuptaken in the pre-synaptic cleft thanks to dopamine transporters

Biosynthesis

• Enzymatic processes starts tyrosine, then dopa, then dopamine, then noradrenaline and them adrenaline

Production

• A part is packed in vesicles
• A part is degraded by enzymes like monoamine oxidase (MAO) in the outer membrane of mitochondria and catechol-O-methyltransferase (COMT) in the cytoplasm within the brain and periphery
• Drugs that degrade these enzymes increase this neurotransmission
• The main metabolite of dopamine is homovanillic acid

Dopamine Receptors

• There are five subtypes, but most belong to D1-like and D2-like receptors that are located in different brain regions
• Vesicular monoamine transporter 2 (VMAT2) transports dopamine into vesicles

Dopaminergic Pathways

• Mesolimbic pathway: soma is located in the ventral tegmental area and projects axons into the nucleus accumbens, where dopamine is released, associated with pleasure and reward
• Mesocortical pathway: associated with the control of emotions and motivation
• Hyperactivation is associated with schizophrenia
• Nigrostriatal pathway: modulates fine movements
• Soma is on the substantia nigra and protects the axon on the striatum
• Degeneration is associated with Parkinson's disease
• Pituitary gland controls the release of hormones, like prolactin

Special Notes

• Increasing the activity of dopaminergic systems has side effects, such as:
• Inhibiting dopamine in the brain, which could lead to less pleasure
• Pharmacological Parkinson's disease
• Psychotic effects
• Cannot act selectively for a specific dopaminergic pathway due to how it will inhibit multiple functions.

Acting on Dopaminergic Transmission

• Stimulating synthesis or degradation
• Acting on storage of dopamine into vesicles
• Increasing the release of dopamine
• Inhibiting reuptake

Drugs that affect the Dopaminergic System

• Dopamine agonists are prescribed for Parkinson's disease
• Antidepressant drugs
• Antipsychotics are antagonists
• Stimulants

Parkinson's Disease

• Degeneration of the nigrostriatal pathway of the basal ganglia
• D2 is the receptor modulating it
• Normal brain produces and releases dopamine in the striatum, which is also controlled by acetylcholine
• Parkinson's is the degeneration of equilibrium between dopamine and acetylcholine, shifting towards acetylcholine

Regaining Equilibrium

• By increasing dopamine through inhibiting the enzymes that degrade dopamine or potentiating D2 activity using dopaminergic agonists
• By decreasing acetylcholine using anticholinergic drugs

Additional Notes

• Levodopa (L-dopa) increases dopamine by boosting dopaminergic neurons
• It can cross the blood-brain barrier (BBB) and be transformed into dopamine
• Once in the gut and absorbed into circulation transform L-dopa that causes side effects
• Side effects are dyskinesias
• Dopamine agonists activate dopamine receptors
• MAO inhibitors such as Selegiline and Rasagiline are drugs to reserve dopamine

Schizophrenia

• Hallucinations, disorganized speech or behavior
• Negative symptoms involves a blunted affect, emotional withdrawal and passivity
• Cognitive symptoms involves attention problems, memory

Schizophrenia Symptoms

• Affective symptoms that include depressed mood, anxiety, guilt and worry
• Aggressive symptoms that include verbal or physical abuse and self harm
• Causes increased activation of the dopaminergic system and hypoactivation of the mesocortical pathway
• Abnormalities can be affected by neurochemicals, environment and genetics

First vs Second antipsychotics

• First-generation antipsychotic drugs blocks the D2 receptors, generates a pharmacological Parkinson effects
• Second-generation antipsychotic drugs weight gain, may not have the risks of the pharmacologicalparkinson effects

General Notes

• General side effects are:
• Hyperprolactinemia
• Decreased libido
• Weight gain
• Type II diabetes
• Blurred vision
• Dry mouth
• Agranulocytosis

Some antipsychotics used for ADHD

• methylphenidate
• amphetamine, D2 antogonist
• By giving DOPA it'll increase to the brain and acts in the periphery
• Drugs we have now do not affect the cognitive symptoms

Addiction

• Chronic, relapsing disorder characterized by craving, compulsive drug use, and loss of control.
• Factors affecting the possibility to develop addiction are the:
• Drug
• Individual
• Environment
• In addiction, there is dopamine involvement in the mesolimbic pathway, involving a reward pathway of pleasure

Process

• Substances bind to the receptors to increase the dopaminergic cells and increase dopamine levels in the nucleus accumbens

Regions

• Addictive Symptoms- compulsive behavior, continued abuse despite negative consequences and structure/ function of the brain.

How to Study?

• Is when it causes a person to have a Free choice, condition and want Self-Administration
• Dopamine influences on movement and with a activated rewarding feeling.

Other Notes

• Antagonisits are for help stop receptors activated by the addictive substance and taking and antagonist won’t work by itself.

Alcholism

• Alcoholism and it is metabolism is ineffective in the liver
• To convert and prevent acetaldehydrat into acetate alcohol it is worse.
• This also caused Withdrawal Symptoms

Symptoms

• Physiological changes that occur when chronically abusing.
• Using opiate to withdraw to Alleviate the risk

The Question

• starting drug use is too Feel good and better for temporary
• and to Prevent Major Psychiatric Disorders

VTA Impact

• DRUG intake in teenagers often triggers activity from the VTA
• While in adulthood there a activity in the prefrontal cortex by people contributing to addiction by being sick or have already an issue.

Other Note

• Peers who contribute to use a substance, as well as the ability to get drugs

Psychostimulants are

• Increase the activity of neurotransmitters.
• some risk factors is the Toxicity of the genetics

Common Traits

• increasedalertness, Well Being and energy increase alertness, insomnia

Nicotine Side Effects

• This acts By stimulationor depending effects of the dose
• Can cause tachycardia
• cause nausea tolerance
• Some will Succeed to try and stop

withdrawal symptom

• irritability, anxiety, Gain weight. hostillity
• Treatment- Therapy and to avoid the nicotine
• Can be from Rimonabant or Bupropione

Other Subatances

• Such As varenicline and other amphetamines that have cause tachycardia and can be dangerous.
• This substances are also used by athletes/Doping that start minutes after
• Some can have lechargy and irritbility

Cocaine

• That gives obv, increase of dopamine in nucleus accumbens.
• Cocaine effects leads euphoria

Cocainr toxicity

• Ischemia
• Myocardities
• Vasodilaion
• Causes Nose Bleeding

The Cocainr effects

• Is to block the reuptake and have toxic for cocaethlene
• Such as depression as sleep more and has a decrease appetite.
• Where in the brain causes a trigger for amygdala that can be caused by the psychoachelic called “ecstasy” or MDMA
• That where there are decrease in the noradrenergic and dopermergic and Visual hallucinacions

Hallucinogens

• cause hallucinations
• Psilocybin
• Ketamine that act as glutamine

Key notes

• Hallucinations can lead to Visual, Auditory, Perception and olfactory
• Hallucongenic 2nd generatiinh have high affinity for Reduce effects to the brain with 5 HT2A
• Methcathione is oral and innalation for 45-60mins And effects sexsual arousal
• PCP can cause deliitum and is very addictive

The cannaboinoids

• Comes from body and can’t cause any type of affection.
• CBD: Is Base for Maria

Receptors

• CB1 IS HOGH,Y EXPREESED IB ABRAIN
• CB2: is for imumne

Cannibinoid Functions

• Release hormones that bind CB1 and 32

Other Receptor Function

• Inhibit appettite For the drugs
• And others can CAUSE NAUSEA and ANOREXIA
• Cannabinoids also CAN ACT AS TRANSIISSION

Receptors and more

• Marinol has high effects on AIDs
• More Potent is also called Cesamenr

What this Drigs Used for?

• Treats antiinflammatorys and tumors.
• Doesn’t activate CB receptors.
• If THC is added then there’s less paycho affect

Opioids

• Have a release to enkaphalims, denoprhins and endorphins
• Help With serotonin being released

Three receptors

• MOR: Analgesia
• KOR: Spinal analgesic
• DORL helps breathing
• Some will lead to addictive

Agonist

• Are Endogenous that synthietic the body.
• Can be morphine
• Not can BE emotinal pain or nuetopathif

General Notes

• Opioid receptors found GABA- reuptake O-Receptors and activate the repstatory and dose can effect

Codeine and morphibe

• Leads HA
• Releases a and is a Agonsit

Drug

• Used In low doses is also a cough medicine.
• Can be taken and is a semi product in the body that used for pain.

Codeinr

• Can BE used through out
• Morphing is for treat

Potencies

• Help If You are the morphine is to get the fentanyl and sulfentanl

Hypo- cretin and systems

• Regulares BEHAVIOR
• Inject to increase

The drugs

• Are Orexanf and emborevant that have the anti insonmia
• They are more potent that telagepant

Other Information

• As a monoclonal antibies and has a high cost
• that have and a Gaba erigical function for the brain

They Used to Treat Anxiety and is different if has a hypnosis

and is an sleep state

• Has different drugs that give a effect. And can have bad effects

Clodisine helps a reuptake for the heart and serotonin

• benzodiazepines are what have a dose dependent to help the body.
• They help the inhibit for the GABA. Where used for Cognition