Drug Classification and Pharmacology

• Medicine was the prevailing conception of drugs in the 15th century.
• Psychoactive substances, irrespective of medicinal use or legal status, defined drugs in the 17th century.
• Substances capable of producing a psychoactive effect, excluding exempted substances like alcohol, tobacco, caffeine, food and drink, and already regulated medicinal products, are drugs according to the Psychoactive Substances Act 2016 (UK).

How to Classify Drugs

• Drugs can be classified based on the source of their active ingredient.
• Naturally occurring sources include Opium from poppy, morphine from opium, cocaine from coca plant.
• Semi-synthetic production includes Heroin from morphin, LSD from Ergot fungus.
• Synthetics like MDMA, methadone, amphetamine, and fentanyl aren't limited by natural resources.

Chemistry and Pharmacology

• Amphetamine derivatives and part of Benzenoids are part of the chemistry of drugs.
• Pharmacology includes all opioids.
• Natural narcotics: Morphi, Codeine, Thebain
• Semisynthetic narcotics: Heroin Hydromorphone Oxycodone Etorphine
• Synthetic narcotics: Pentazocine Meperidine Fentanyl Methadone LAAM Propoxyphene
• Enkephalins Endorphins Dynorphins occur naturally.
• Similar chemical structures can lead to the same mechanism of action, like binding to opioid receptors
• A classification of CNS/behavioral effects:
• CNS stimulants: Amphetamine, Cocaine, Nicotine
• CNS depressants: Barbiturates, Alcohol
• Analgesics: Morphine, Codeine
• Hallucinogens: Mescaline, LSD, Psilocybin
• Psychotherapeutics: Prozac, Thorazine
• Low doses of alcohol might be classified as a stimulant.

Schedules of Drug Restriction (US)

• Drug restriction schedules are based on addiction risk and medicinal qualities.
• Schedule 1 drugs have the most potential for abuse and dependence and no medicinal qualities; examples include Heroin, LSD, Marijuana, Ecstasy, and Peyote.
• Schedule 2 drugs possess a high potential for abuse and dependence but do have some medicinal qualities; examples include Vicodin, Cocaine, Meth, OxyContin, Adderall.
• Schedule 3 drugs have a moderate potential for abuse/dependence and acceptable medicinal qualities; Doctor's prescription required; examples include Tylenol with Codeine, Ketamine, Steroids, Testosterone.
• Schedule 4 drugs have a low potential for abuse and dependence and acceptable medicinal qualities; a prescription is required with fewer refill regualtions; examples include Xanax, Darvon, Valium, Ativan, Ambien, and Tramadol.
• Schedule 5 drugs have the lowest potential for abuse/dependence and acceptable medicinal qualities; a prescription is required with the fewest refill regulations; examples include Robitussin AC, Lomotil, Motofen, and Lyrica.

Classification Documents (UK)

• The Misuse of Drugs Act 1971 ("Controlled drugs") + Regs are footed in International (UN) conventions.
• The classification is based on how harmful drugs are in terms of physical harm, dependence, and social harm to the community.
• Class A drugs are the most harmful, e.g., LSD, heroin, cocaine.
• Classification changes based on the government and impacts sentencing for drug possession/use
• The Human Medicines Regs. 2012 ("Sale, supply and use of Medicinal products")
• The Psychoactive Substance Act 2016 (".. production, sale and supply of a new class of psychoactive substances")
• Harm ratings are subject to disagreement between experts and governments, resulting in inconsistent alignment between harm levels and control levels.

Reasons for drug use

• Experimentation (Novelty seeking, exploration)

• Pleasure (desired rewards')

• Self-medication

• Peer pressure

• Addiction is not equal to experimental use, recreational/casual use, circumstantial use.

• Alcohol consumption is common, but only a minority meets criteria for abuse and/or dependence.

• DSM-IV criteria are outdated because of varying characteristics of different drugs

• DSM-V now has an added severity scale of addiction.

• DSM-V includes non-drug addictive disorders like gambling.

• DSM-V include “craving".

Addiction

• Addiction is a syndrome manifested by a behavioral pattern that prioritizes psychoactive drug use over other valued behaviors, leading to compulsive drug use.
• Addiction also exhibits characteristics of a chronic relapsing disorder.

Pharmacokinetics

• Pharmacology: The branch of medicine that deals with the uses, effects, and modes of action of drugs.

• Pharmacokinetics: The subfield of pharmacology dealing with absorption, distribution, biotransformation [metabolism] and excretion of drugs, signifying movement of a drug to (and from) its site of action.

• "Kinesis" = movement

• As soon as a drug enters the system processes begin to degrade/metabolize drug

• The liver is the main site of drug metabolism - enzymes break down drug

Factors affecting drug absorption of drugs

• Drug solubility
• Ionisation - Degree of electrical charge of the molecules
• Blood circulation at the site of administration
• Drugs need to enter the circulatory system to reach receptors in the brain
• Surface area of the absorbing surface

Routes of administration

• Oral (peroral/PO) (e.g., alcohol) causes Absorption through gastrointestinal tract [intestines]
• Not very efficient because drug must pass through stomach acids to reach its absorption point (intestines), resulting in longer-lasting but slower absorption.
• Quickly leads to first pass metabolism - in the liver.
• Safer than other methods because when it reaches the circulatory system it has already began to be broken down by liver – lesser risk of OD than other methods like IV
• *first pass metabolism most often results in drug degradation but it can also be used in drug design

Routes that mostly avoid 1st pass metabolism (less safe but more efficient)

• Nasal (insufflation)

• Fairly efficient; the nose is highly vascularized; example: cocaine.

• Sublingual

• Under the tongue; a small surface area that is fairly vascularized.

• Rectal Metabolized by lower intestines

• Pulmonary absorption (inhalation - very rapid):

• Very efficient & relatively non-invasive with a highly vascularized area and large surface. Goes directly into the brain and heart, example: nicotine, crack cocaine.

• Transdermal (invasive - breaks through skin): Absorption through the skin is very long, examples: nicotine, fentanyl patches.

• Subcutaneous: SC (under the skin); fairly slow absorption

• Intramuscular: IM is commonly used for medicinal use, size of the muscle determines efficiency [highly vascularized, big surface area vs small]

• Intravenous: IV is most efficient, straight into the circulatory system, dangerous.

Other less common administration methods

• Epidural above the dura matter, for spinal anesthesia/analgesia
• Intrathecal is into CSF (cerebrospinal fluid) in subarachnoid space [in between meninges], for spinal anesthesia
• Intra-arterial is a medical procedure [e.g., sodium amytal into the carotid artery - numbs 1 side of your brain ]

Methods used in animals

• Intra-peritoneal: IP in the peritoneal cavity allows for fast absorption.
• Intracranial Fastest
• Intra-cerebro-ventricular: ICV.

Factors influencing route of admin

• Amount of drug destroyed during 1st pass metabolism (by stomach and liver enzymes).

• Blood circulation at the site of administration.

• Surface area available for absorption.

• Binding to inactive sites (depot binding).

• Number of cell layers to blood.

• IV and IM have faster effects

• SC and PO much slower effects & less effective

• Half-life is the measure of how long the drug lasts, or the time for plasma drug concentration to fall to half of peak level.

How to choose the route of admin

• It depends whether the objective is a high peak concentration, or a steady state (example: methadone).
• Drug users often prefer a route that provides the highest peak concentration for a shorter period of time -> To achieve a feeling of rush or euphoria.
• For most medical applications, the goal is to treat a condition with the minimum effective concentration over an extended period
• E.g., fentanyl Transdermal (in patches) is used to provide prolonged, steady analgesic effect to relieve serious pain
• Sublingual (in lollipops) can be used in combination with patches for rapid adjustment of pain levels, absorbed through buccal membranes
• For maximum effects may be smoked or injected IV

How does drug distribution occur

• To get to a brain site, drugs typically need to cross multiple membranes (stomach wall, skin layers, ...) => drug movement across membranes is a key factor influencing the dose available at site of action
• Simple diffusion occurs as the drug absorbed by the membrane moves from high to low concentration, driven by concentration gradient.
• Limiting factors to drug diffusion include size and shape of drug molecule, lipid solubility & ionization.

factors affecting drug absoption

• Drugs are either weak acids or weak bases, therefore solubility is determined by ionization

• The degree to which a drug is charged and determines ionization

• Solvents (environment they are in) are wither acidic or basic

• More ionized drug > less lipid soluble > less absorption/diffusion > less effect

  • drugs that are weak acids ionize more in basic [alkaline] environments
  • drugs that are weak bases ionize more in acidic environments

• pKa= pH of solution in which 50% of the drug is ionized and 50% not ionized

• Base higher pH results in higher absorption/lower ionization.

• Acid higher pH results in a lower absorption/higher ionization.

• Different body fluids have different pH, thus drugs will be absorbed to different extents in different body compartments.

Examples of drug effects

• Inactivation usually by metabolism particularly in the liver by microsomal enzymes.
• Biotransformation mostly produces more ionized molecules that do not have brain access.
  • These more ionized metabolites become trapped in kidney tubules and are then excreted in urine & might also be eliminated through sweat, saliva.
  • But not all metabolites become inactive! E.g., heroin in the brain is metabolized into morphine.

Individual variation alter drug metabolism:

• Reduced levels of gastric alcohol dehydrogenase in women compared to men, as a result, a given dose of alcohol, more enters the bloodstream.
• Chronic drinkers have higher levels of alcohol dehydrogenase & contributes to developed tolerance.
• Older people have have a reduced liver function as well as reduced ability to metabolize alcohol which can lead to sensitization.
• Genetic component may increase or decrease the likely hold a polyorphism in certain populations.

Pharmacodynamics

• Pharmacodynamics examines the biochemical effects of drugs and their mechanisms of action
• Receptors are molecules that drugs interact with to initiate biological effects.
• Drugs modify the rate of ongoing cellular events, not create new/unique biological effects.

Drug receptor interactions

• Interactions may involve various chemical bonds, usually noncovalent/weak to allow for readily reversible association and dissociation.
• Drugs are promiscuous, acting on various neurotransmitter systems and/or receptor subtypes; example: MDMA binds with a high rate of affinity to serotonin receptors.
• The magnitude of the drug effect is proportional to the number of receptors occupied.
• A drug produces its maximal effect when every receptor is occupied according to the law of mass action/law of effect.

key elements in dose-response/effect curves

• Effective dose (ED100) is reached if adding more of a drug dose not increase the observed drug effect or the max drug effect. → because there are no more receptors available that don't already have drug at their binding sites
• ED50 is the effective dose or dose that produces response in 50% of subjects.
• TD50 is is the toxic dose or dose that produces a given toxic effect in 50% of subjects.
• LD50 is the lethal dose or the dose that kills 50% of subjects.
• The Therapeutic Index (TI) = TD50 / ED50.
• Safety margin = LD50 - ED50.

Comparing different drugs

• Compare potency (amount of drug needed for an effect)
• Compare maximum effect (max effect a drug can produce) - depends on what you are comparing (e.g., bhvrl effects vs direct drug effect) Differences in potency and efficiency reveal that:
  • Drugs have different pharmacokinetics = their time/availability in the brain.
  • Affinity differs across drugs -> Affinity = opposite of Kd rate of dissociation Drugs with high affinity are more likely to stay bound to receptor and thus keep on having an effect
• Drugs may have more or less intrinsic activity at the same receptor

Different types of ligands

• Agonist: Drugs that bind to receptors and cause biological response -> have intrinsic activity.
• Antagonist: Drugs that bind to receptors – have affinity but have no intrinsic activity → produce effect by blocking the action of an agonist or an endogenous ligand (e.g., a neurotransmitter) at that same receptor; Antagonists tend to form weak non-covalent interactions that are readily reversible But some are irreversible
• Competitive antagonists Binds to same receptor site as agonist an competes for available binding sites; Shifts the dose-response curve for agonist to the right, makes it less potent; Effect can be overcome by increasing the dose of agonist Narcan is an example of a opioid competitive antagonist with high receptor affinity & used to treat heroin overdose
• Non competitor antagonist Do not compete with agonist for the same receptor binding site and shift the dose-effect for agonists to the right but also change its shape , lowers potency and efficacy.
• Have mixed agonist/antagonist effects
• Have intermediate levels of intrinsic activity at a receptor lower dose-effect than agonist and/or antagonize in the presence of full agonist (e.g., buprenorphine is an opioid partial agonist and used addiction therapies)
• Inverse against - Drugs that produce a descending dose-effect curve & produce opposite effect to that agonist
• Tolerance: effect of a drug decreases or shifts right on the curve

Effects on a full against from:

• B is A in the presence of a competitive antagonist, lowers agonist activity level -B is another full agonist (different drug) with lower potency
• B is A in the presence of partial agonist

Affect of drug is affected by experience

• With chronic administration, the effects on the brain and behavior can change ⇒ If a drug effect gets smaller - this is called tolerance ⇒ If a drug effect gets bigger - this is called sensitization
• Tolerance occurs when more drug is required to produce the same effect [shift to the right in dose-response curve]
• Sensitization occurs when fewer drugs required to produce the same effect [shift to left in dose-response curve].
• Degrees of tolerance can differ for varying drug effects may make drugs more dangerous

Types & mechanisms of tolerance

• Acute tolerance occurs when effects of drug decrease quickly within a single session.
• Protracted tolerance occurs when the Effect decreases with repeated administration (e.g., frequent drinkers).
• Cross tolorence- Drug effects decrease with repeated admin of another drug
• Tolerance may reflect homeostatic adaptations of the body ► Tolerance: Changes also occur to receptors and their corresponding signaling pathways. E.g., receptors may become fewer in number, or change their intracellular location Learning factors can also be important. ► Pharmacodynamic tolerance: Changes also occur to receptors and their corresponding signaling pathways. E.g., receptors may become fewer in number, or change theirintracellular location. ► Pharmacokinetic tolorence: changes can be pharmacokinetic/metabolic, such as enzyme induction
• Drug tolerance can be specific to particular contexts and conditioning can evoke drug like or drug opposite effects.

Dependence and Withdrawal

• Dependence exists when tolerance has developed so that ceasing drug use will result in withdrawal symptoms and are typically opposite to acute effects of the drug.

Sensitization

• Sensitization can arise from a variety of factors, including metabolic [e.g., reduced alcohol metabolism leads to more drug reaching the brain ]

Behavioral Pharmacology

• Behavioral pharmacology seeks to determine the relationship between the pharmacological actions of drugs and their effects on behavior and psychological function
• Strict ethical limitations with the inability determine causality is one reason that humans aren't used in studies

Evaluation categories

Primary evaluation which is the first step in drug development which determines the drug's effecs

Example of primary:

Test example: Rota-rod test of balance and motor function

• Drugs do not create new behaviors, rather they alter the probability of behaviors already in the organism's repertoire

• Second evaluations run tests of specific functions to certain drugs

Analgesia (pain relief) Tail-flick test & Hot plate test

Anxiety: Test anixiety levels Elevated plus maze

• measure how long it takes to animals to move away from hot surfaces
• measure the levels of rodents bright light

Cognitive Function: Radial arm maze Morris Water maze

• Used for contextual memory
• Abuse and addictive liability
• Drug discrimination Deals with what does a drug feel like?/examining the stimulus properties of drugs

How can drugs be used as reinforcers?

• Positive reinforcement
• Negative reinforcement
• Conditioned Secondary reinforcers
• Conditioned placed preference

Disadvantages: Not measuring the drug reward itself

IV injections: most precise control time and time again Animals are and can only use nearly all drugs and if those individuals can't they will

• Ratio schedules
• Variable ratio
• interval schedules
• fixed interval schedule
• variable intervals

Stimuli can reinstate responding: Drug cue Drug context Stress

Techniques in Neuropharmacology

• To study where in the brain a drug is acting, we consider targets/receptors.
• In-vitro approach involves testing effects of biological entities outside of normal biological context. Drugs act on certain molecules on the synapse (transporters (presynaptic neuron)- receptors (postsynaptic neuron))
• Histological methods include perfusing with 4% PFA, sectioning with a cryostat/microtome, and autoradiography in brain slices.
• In-Vivo study by using biological entities tested on whole living study subjects which are usually animals
• Brain imaging- using pet scans for detection Positron Emission Tomography (PET) which is be used to visualize things like receptors in live study subjects
• Human is situ hybridization (used to analyze RNA that is radio active, which attaches to RNA)
• hybridization is used to quantify its expression for the Soma.

Methods to detect drug effects

• genetic manipulation used on subjects can come in form of mutant mice/rats knockknios and knockouts local manipinualtion done in test subjects brains E.g., injection of dopamine receptor antagonists [e.g., flupenthixol] in the nucleus accumbens to see if dopamine signaling in this area plays a role in drug self-administration. Stereotaxic surgery ensures that drug is implanted at a specific location (diff from other methods of injection which distribute compound all over the brain) Used to implant electrodes, inject drugs, produce lesions Can also implant cannula to inject compounds Study through detecting proteins and how they react when effecting neurons in specific parts of the brain . Can be found in brain slices immuno chemistry used for colorimetric reasons in studies.
• Brain imaging
• eeg studies
• intracranial electrophysiology

Can be used to determine which areas in the brain are being affected when drugs interact

• Local lesion studies
• Intra cranial drug injections
• opogenetics
• Channelrhodopsin stimulation

Studing specific neurotransmitter levels:

Microdialysis and Voltammetry studies

• used in vivo
• measures how and why the dopamine levels in the stratum are increased by addiction

Whole cell electrophysiology measures functional changes in Glutamate and GABA when it comes to how synaptic functions are affected because of drug usages.

Signalling signals between Neurons

• Neurotransmitters
• neurons transport signals through synapse
• electrical signals transport electrical signals through gap junctions and mostly used for transportation when other mechanisms are unable to perform properly

Neurotransmitters are released

Are able transport action due to action potentials firing and calcium coming in and transport protein through transport process of exocytosis

• InActivation(transporters)
• Neurotransmitter Diffusion/Inactivation
• rapid diffusion to postsynaptic receptors (not reliable or trigger release)

Modulation of releases and receptors

action potentials influence releases auto receptors-Negative systems that down regulate transportation of NT

Receptors- Ligator channels (Fast actions) Metabotropic: Single neurons with high-level proteins which effect activity Kinies- used in amplifying signals to break down molecules and transport

Messengers regulation- proteins-influence what is effecting the neuron activity and gene regulations etc

Glutamatergic Systems:

Glutamate-most important thing and is required in neurons (fast chemica reactions)

Synth/Transmit

VGLUT-creates glutamate from receptors

Receptors for GLUT Fast chemical interactions

Stimulant Mode of action

Stimulants are diverse and can vary

Types: Categoryamines Indoleamines

Serotonin = mood regulation + is reuptake Inhibitor

How do we synthesize NT?

Through Tryoxine which comes form amino acids TYH is slow Used in the brain 🧠 as precursor to make different things How do monoamines act?

• All packaged to vesicles (VAAT2 type2-NT
• Deconstruction is caused through Mao All transported to -Dopamine

In the Striatum: D1 receptors-Stimulatory D2 receptors-inhibitory

Most neurons are located in the striatum and project between the frontal cortex dopamine is essential motor movement and motivation- Dopmainic Populatoins-system+nigrostriatal Ventral tegmental creates areas involved with motivation and reward

Stimulant studies with Dophamine dopanmine increased in dorsal compared to that of accummbuns

In rat experiments it shows in the stratum helps with the dopamine process DA release occurs which can result in reverse actions to receptors

Study results due to interactions with the Brain

• correlatinal 60% need to occupied in subjects high is needed 6hoDA used to destroy dopamine terminals Accumbuns/stimiluants help with locomotive. Dopamine-more active

Nucleaus=Important (rewads+locomitve Activty D=Dorsal striatum (Steroitypes and motor)

Bath salts-stimulant