Pharmacokinetics: Drug Administration Methods

Module 1: Pharmacokinetics

• Pharmacokinetics defines the bodily absorption, distribution, metabolism, and excretion of drugs, summarized as ADME.

Drug Administration Methods: Advantages and Disadvantages

• Oral administration is inexpensive, easy to self-administer, and generally safe, but can lead to vomiting and stomach distress.
• Oral administration lacks accurate absorption calculation due to differences in metabolizing enzymes.
• The acid in the stomach can destroy some drugs, such as insulin.
• Rectal administration bypasses the stomach, useful if a patient is vomiting or unable to swallow, but absorption is unpredictable.
• Many drugs can irritate membranes in the rectum.
• Inhalation allows for rapid absorption due to the large surface area in the lungs, leading directly to the bloodstream.
• With inhalation, the route goes from the lungs to capillaries, pulmonary veins, heart, aorta, and then the brain.
• Few drugs are suitable for inhalation.
• Intravenous injection results in immediate absorption and extremely precise dosage, allowing for drug dilution and stopping administration if needed.
• Intravenous injection has increased risk of side effects, must be injected slowly, and is unsuitable for oily/insoluble substances.
• Intramuscular injection enables rapid absorption from aqueous solutions and slow, steady absorption from oily solutions, quicker than stomach absorption but slower than IV.
• Intramuscular injection is impossible when a patient is on anticoagulants and interferes with some diagnostic tests.
• Subcutaneous injection is suitable for oily solutions and moderate volumes, including some irritating substances.
• Rapid absorption from aqueous solutions and slow, steady absorption from oily solutions (depot shot)
• Subcutaneous injection is unsuitable for large volumes and may cause pain or necrosis from irritating substances.
• Injections in general exhibit rapid concentration, meaning little reaction time for unexpected reactions.

Body Membranes in Drug Distribution

• Cell membranes are barriers permeable to small, lipid-soluble molecules, but impermeable to large, lipid-insoluble molecules.
• Cell membranes facilitate passage of drugs from the stomach and intestine into the bloodstream and fluid surrounding tissue cells into the cell interior.
• Cell membranes also facilitate passage from the cell interior back into the body and from the kidneys back into the bloodstream.
• Capillaries have pores that allow small molecules and most drugs to pass through, even fat-insoluble drugs.
• The blood-brain barrier maintains a protected brain environment via tightly packed capillary cells without pores, covered by a fatty glial sheath.
• Drug passage into the brain must be fat-soluble and small to pass rapidly.
• Most psychoactive drugs can pass the barrier, while some, like penicillin, cannot.
• Placental barrier separates maternal and fetal circulatory systems, with membranes resembling cell membranes elsewhere in the body.
• Drugs cross the placenta via passive diffusion, with fat-soluble substances diffusing rapidly.
• Large molecules like glucose, insulin, amino acids, and vitamins enter the brain via special transport systems known as transcytosis.

Drug Metabolism: Hepatic Enzyme System, Kidneys, and Liver

• The hepatic enzyme system metabolizes drugs and other substances with enzymes in liver cells, or hepatocytes, on smooth endoplasmic reticulum membranes.
• Enzymes are collectively referred to as the cytochrome P450 enzyme family, which turns fat-soluble compounds into more water-soluble compounds, making them polar.

Phases of primary reactions catalyzed by p450 enzymes

• Oxidation (losing negative electrons) results in positive charge.
• Reduction (adding electrons with a hydrogen atom) results.
• Hydrolosis (adding water to split a molecule into two polar molecules) results.

Phase 2: Conjugation

• Conjugation takes place with the combining a drug with another molecule, such as glucuronidation, where glucuronic acid binds to the drug.
• Kidneys excrete liver metabolites and regulate bodily fluid levels, but lipid-soluble drugs are reabsorbed along with 99% of reabsorbed water; kidneys alone cannot eliminate most psychoactive drugs.
• The nephrons contain a glomerulus to filter blood and remove waste.
• The liver picks up reabsorbed drug molecules (with hepatocytes) and uses enzymes to transform them into metabolites less likely to be reabsorbed and excreted in urine.

Half-Life and Steady-State Concentration

• Half-life measures the time for drug concentration in the blood to reduce by half.
• Steady-state is reached when the amount of drug absorbed balances with the amount being eliminated.
• Half-life affects how quickly steady-state is approached.
• About six times the drug’s elimination half-life is the time to reach steady-state concentration, independent of dosage.

Drug Tolerance and Drug Dependence

• Drug tolerance is a progressively decreasing responsiveness to a drug, so increasing doses are needed for the same effect.
• Metabolic tolerance refers to the increased amount of enzyme becomes available to metabolize a drug
• Cellular adaptive tolerance refers to neurons adapt to the accumulation of a drug either by reducing the number of receptors available to the drug or by reducing the receptors' sensitivity to the drug (down regulation)
• Behavioral conditioning processes also play a role in tolerance.
• Drug dependence is a state where drug use is necessary for physical or psychological well-being and differs from drug tolerance, though they often occur together.

Key Terms

• Bioavailability: The amount of administered drug that reaches its target and how long it persists.
• Blood-brain barrier: A structural barrier maintaining a protected brain environment.
• Cross-tolerance: Tolerance to one drug reduces response to another.
• Cytochrome P450 enzyme family: Liver proteins metabolizing endogenous and exogenous substances, turning lipophilic fat-soluble drugs into more water-soluble compounds.
• Drug absorption: Processes for drugs to enter the bloodstream, usually from the stomach and intestine. Drug administration: Procedures for drug entry into the body, like oral intake, inhalation, or injection.
• Drug dependence: Drug use is necessary for physical or psychological well-being.
• Drug distribution: Drug movement between the blood and body tissues.
• Drug tolerance: Progressively decreasing drug responsiveness, requiring increased doses for the same effect.
• Half-life: The time for half the drug amount to be eliminated.
• Intramuscular injection: Injection directly into muscle.
• Intravenous injection: Injection directly into a vein.
• Lipid solubility: Ability of a chemical to dissolve in fats and oils.
• Pharmacodynamics: Study of drug interactions and receptors responsible for the action of the drug in the body.
• Pharmacokinetics: Study of factors influencing drug ADME.
• Pharmacology: Branch of science studying drugs and their actions on living systems.
• Physical dependence: Drug required for a person's normal physical functioning.
• Psychoactive drugs: Drugs that alter mood or behavior due to brain alterations.
• Psychological dependence: Compulsion to use drugs for pleasurable effects.
• Psychopharmacology: Study of drug effects on the brain and behavior.
• Redistribution: Drug movement from more to less perfused organs.
• Side effects: Effects accompanying the primary or therapeutic drug effect.
• Steady-state concentration: Plateau in drug concentration at regular intervals, reached after a time depending on half-life.
• Subcutaneous injection: Injection just under the skin.
• Therapeutic drug monitoring (TDM): Correlating plasma drug level with therapeutic response. Therapeutic window: Range of blood levels for optimal clinical response. Transdermal patches: Bandage-like system for continuous, controlled drug release.
• Withdrawal syndrome: Symptoms following abrupt drug discontinuation or dosage decrease once the user has become dependent.
• Absorption is usually oral, unless the drug must be given as an injection
• Distribution of most psychoactive drugs is in the blood, to reach the brain
• Metabolism breaks the drug down, usually into inactive by-products
• Elimination is the excretion of these by-products in urine

Module 2: Neurotransmission and Chemical Signaling

• The central nervous system divisions include the forebrain, midbrain, and hindbrain.

Brain Divisions and Functions

• The forebrain includes the diencephalon (hypothalamus and thalamus) and the telencephalon (basal ganglia, limbic system, and cerebrum).
• The hypothalamus regulates hormonal output of the pituitary gland.
• Thalamus relays information between multiple subcortical areas and the cerebral cortex.
• Basal ganglia help coordinate voluntary motor functions.
• The limbic system, including the amygdala (emotion), and hippocampus (memory), and cingulate cortex integrates information and involves the ventral tegmental area (reward circuit).
• The cerebrum is the largest brain part and separated into left and right hemispheres connected by fiber tracts.
• Mesencephalon connects the pons and cerebellum with the forebrain.
• The medulla controls vital processes.
• The cerebellum integrates movement and posture.
• Pons control sleep, wakefulness, and breathing.

Neuron Structure and Synaptic Transmission

• Neurons have a soma (cell body) containing a nucleus (DNA) and mitochondria (energy).
• A Golgi body packages neurotransmitters (NTs)
• ER (endoplasmic reficulum) is for ribosomes and transports products)
• Ribosomes make proteins.
• Axons transmit signals from the cell body to other neurons.
• Dendrites receive signals from other neurons.
• Synaptic vesicles store NTs in axon terminals.
• Terminal buttons are ends of axon branches where NTs are released.
• Synaptic transmission begins with an action potential transmitted down an axon.
• When it reaches the presynaptic membrane, ion channels open for Ca2+ to enter the axon terminal.
• Calcium causes synaptic vesicles to fuse with the terminal membrane, releasing NTs into the synaptic cleft.
• NTs then attach to and activate receptors on the postsynaptic membrane.

Terminating NT Activity

• Enzymes in the synaptic cleft break down NTs.
• Transporter proteins take up some NTs for potential future release.
• NTs may bind to autoreceptors to regulate presynaptic neuronal activity.

Ways Neurotransmission Termination

• An enzyme in the synaptic cleft breaks down NT molecules, creating metabolites that are taken back up into the presynaptic neuron to be made into new NTs, (acetylcholine).
• Transporter proteins in the presynaptic membrane take NTs back into the presynaptic neuron to be repackaged for later release, (serotonin, norepinephrine, dopamine.)
• Molecules are taken into adjacent glial cells and broken down into metabolites that are then recycled back into presynaptic neuron (glutamate).

Major Neurotransmitters and Receptor Types

• Amines:
  • Quaternary amine: Acetylcholine (ACh)
  • Monoamines:
    • Catecholamines: Norepinephrine (NE), Epinephrine (adrenaline), Dopamine (DA)
    • Indolamines: Serotonin (5-hydroxytryptamine; 5HT)
• Amino Acids and Neuropeptides:
  • Gamma-aminobutyric acid (GABA), glutamate, glycine
  • Opioid peptides: Enkephalins (met-enkephalin, leu-enkephalin), Endorphins (b-endorphin), Dynorphins (dynorphin A)
  • Peptides: Oxytocin, substance P, cholecystokinin (CCK)
  • Purines; Adenosine
  • Lipids- Endocannabinoids (anandamide, arachidonoylethanolamine (AEA))
  • Gases: Nitric oxide and carbon monoxide

Neurotransmitter Cell Bodies

• Acetylcholine (ACh) has peripheral and brain tissue actions and two cholinergic receptors: nicotinic (stimulated by nicotine, contracts muscles) and muscarinic (stimulated by muscarin).

• AChE Inhibitors (acetylcholinesterase; used as cognitive enhancers treating alzhiemers)

• ACh is produced in:

  • The forebrain: originating in the septal nucleus and nucleus basalis and projecting to the cerebral cortex.
  • The midbrain: projecting to the reticular formation, pons, cerebellum, and cranial nerve nuclei.

• Norepinephrine projects from the brainstem to the cortex, limbic system, hypothalamus, and cerebellum, producing an alerting, focusing response, feelings of reward, and analgesia.

• Dopamine has three classic circuits:

  • From the hypothalamus to the pituitary gland.
  • From the substantia nigra to the basal ganglia.
  • From the ventral tegmental area (VTA) to the cortex and limbic system, particularly the reward system.

• Serotonin transmitter pathway is similar to dopamine, with the raphe nuclei sending info to the cerebral cortex, basal ganglia and cerebellum

• Glutamate binds to NMDA, kainate, AMPA receptors and is a major excitatory neurotransmitter

• GABA is found in high concentrations in the brain and spinal cord and is a major inhibitory neurotransmitter

• Diseases associated with neurotransmitters include alzheimers (acetylcholine) and parkinsons (dopamine).

Key Terms

• Acetylcholine: activates nicotinic and muscarinic cholinergic receptors and is synthesized directly in the terminal pump.
• AChE inhibitors block AChE action, can be "irreversible or reversible compounds", and are used to delay memory decline in Alzheimer’s disease.
• Amygdala: Brain structure important for emotion and fear.
• Autoreceptors: Receptors on presynaptic neurons that regulate NT release.
• Basal ganglia: Coordinates motor functions.
• Brain stem: Medulla, Pons and midbrain
• Catecholamine: Neurotransmitter with a catechol nucleus and amine group (dopamine, norepinephrine).
• Central nervous system (CNS): Brain and spinal cord.
• Cerebellum: coordinates movement and posture, located behind the brain stem,
• Cerebral Cortex: outer layer of the cerebrum; in each hemisphere and is divided into four lobes (occipital, temporal, parietal, and frontal)
• Cerebrum: the largest part of the brain, covering the brain stem
• Cingulate Cortex: involved in sensory integration
• Dopamine: invloved in motor control and cognitive function
• Endorphins: reduces pain
• Exocytosis: releases substances from cell
• Forebrain: anterior part of brain, controlling sensory perception Gamma aminobutyric acid (GABA): nonessential amino acid used as a major inhibitory transmitter
• Glutamate: major excitatory neurotransmitter Hindbrain: involved in involuntary functions
• Nucleus: critical role in learning and memory
• Hypothalamus:a collection of neuronal structures near the junction of the midbrain and the thalamus just above the pituitary gland regulates hormonal output of pituitary gland
• Limbic System: includes the amygdala, hippocampus and cingulate cortex and integrates sensory, motor, visceral, motivational, and emotional information
• MAO inhibitors (MAOls): act by blocking monoamine oxidase, thereby increasing the amounts of dopamine and norepinephrine available for synaptic release
• Midbrain: involved in motor regulation
• Muscarinic Receoptors: Acetylcholine receptors used for memory.
• Neurotransmitter: brain chemicals which transmit signals across a synapse.
• Nicotinic receptors: Acetylcholine receptors divided into two groups: muscle receptors and neuronal receptors.
• NMDA receptors: A type of glutamate receptors that can be blocked by PCP and ketamine.
• Norepinephrine: produces alerting focusing response, produces a positive feeling of rewards
• Norepinephrine Peptide
• peripheral nervous system (PNS): includes the nerves that originate in the spinal cord
• Reward circuit: Nerve pathways connecting the brain structures that mediate feelings of pleasure and satisfaction
• Serotonin: plays a role in depression, anxiety, and cardio function
• Spinal Cord: group of nerves through the center of the spine and send the message from everywhere in the body to the brain Substance P: involved in transmitting sensory information Synapse: neurotransmitters cross to reach specific receptors, such as dopaminergic D1 to D5 receptors
• Synaptic cleft: The space between neurons across which neurotransmitters travel.
• Thalamus relays information and fibres pass through.
• Transporter proteins: a protein that moves ions and molecules across a biological membrane
• Ventral tegmental area: major component of the reward circuit in the brain

Module 3: Pharmacodynamics

• Pharmacodynamics describes what drugs do to the body, contrasting with pharmacokinetics, which studies what the body does to drugs.

Ionotropic Receptors

• Made up of 5 subunits forming an ion channel.
• Each subunit contains 4 helical coils.
• When a NT or drug binds to the receptor, the pore enlarges, allowing ions like chloride to flow into the neuron and resulting in any action potential.
• Drugs and NTs may bind to different sites on ionotropic receptors.

Metabotropic Receptors

• G-protein-coupled receptors do not form ion channels.
• They release an attached G protein.
• Release of the attached G protein can:
  • Directly activate ion channels in nearby ionotropic receptors.
  • Indirectly activate ion channels by activating an enzyme, which then produces second messenger molecules that activate ionotropic receptors and trigger alternative responses in the neuron.

Membrane Proteins

• Transporter proteins transport NT molecules and some drugs against concentration ingredients for recycling back into the presynaptic neuron. These NTs were lingering in the synaptic cleft
• Many drugs act by blocking transporter proteins associated with specific NT, such as SSRIs blocking the presynaptic transporter of serotonin.

Dose-Response Curve.

• Acute effect is immediate, as seen with Methylphenidate with ADHD.
• Chronic effects are more long-term such as long term changes in the receptors.

Agonist, Antagonist, Partial Agonist, Inverse Agonist, and Allosteric Modulator

• Agonists mimic a NT, bind to a receptor, and active it like methylphenidate, which has direct action on the dopamine system.
• Antagonists block a NT action by binding to a receptor without activating it.
  • Competitive antagonists bind to the same sites as NT
  • Noncompetitive antagonists bind to a different site
• Neurons adapt when agonists or antagonists are continually in contact with receptors
• Can result in:
  • Downregulation decreases postsynaptic receptors in response to excessive NT molecules or agonist is present and leads to decreasing the receptiveness of the receptors, needing more drug like heroin tolerance
  • Upregulation occurs when there are fewer NT numbers or antagonist and leads to an increase in the number and sensitivity of the receptors - like antipsychotic medications
• Full agonists elicit the maximum response once bound to any receptor
• Antagonist does not activate receptors once it is bound
• Allovetric modulator is that group that binds to facilitate transmitter binding
• Inverse Agonist - Binds to a receptor but produces the opposite pharmacological effect of an agonist

Actions from Bindings

• Binding to a normal endogenous neurotransmitter site that initiates a similar celular esponse (agonistic action).
• Facilitates transmitter binding (steric actions).
• Blocking access for transmitter to binding site (antagonistic actions).

Dose-Response Curve and Variability

• Binding Affinity is the strength which a drug binds to a receptor. Efficacy determines what the effect will be.

Therapeutic Index and Drug Interactions

• Therapeutic index measures drug safety regarding that ratio of lethat dose to effective dose; toxicity is determined based on the ratio between these two doses.
• A higher TI is safer, while a lower safety means that drugs may be more potent or have less side effects.

Placebo Response

• Placebo effects have been defined as positive clinical outcomes attributable to the psychosocial context and individual treatment expectations that rather to the effects of the medication or other treatment.
  • Psychological factors are not alone during placebo, so through neurotransmitters there can be physically measurable data to prove how effective placebo can be. It can also influenced by - - practitioner and the patient, the expectations of the patient, also genetics are a huge roll.

Key Terms

• Affinity: The strength with which a drug binds to a receptor.
• Agonist: a drug that mimics a NT by binding to and activating its receptor.
• Antagonist: a drug that blocks the acton of a NT by binding to and NOT activating its receptor.
• Dose-response relationship: the relationship between the dose of a drug and clinical, resulting from drug and receptor interaction.
• Downregulation: a decrease in post synaptic receptiveness due to too many NT molecules.
• Drug-receptor Binding: Attachment of a drug on he surface of a neuron.
• Efficacy
• G protein: activator
• lonotropic Receptors: receptors found on post synaptic membranes, effects excitatory or inhibition in effect.
• Isomers: a molecular forumla with a different atomic construction.
• Metabotropic Receptors: receptors found on post synaptic and pre-synaptic membranes, affects the neurons.
• Placebo Effects: expectation of the patient that the drug will work and it works.
• Polypharmacy: the practice of combining medications to improve therapeutic outcomes
• Potency: amount needed to produce a response
• Racemic Mixture: equivalent quantities of two optical illusions
• Second Messenger: molecule produced in g-protein.
• specificity: binds to just one Receptor
• Therapeutic Receptors
• Transporter Proteins: carry neurotransmitters
• Upregulation: too little NTs so the synapses are more sensitive.

Module 4: Tolerance and Addiction

Schedules of Controlled Substances

• Schedule I: No medical use, lacks safety, has high abuse potential (heroin, LSD, marijuana, ecstasy).
• Schedule II: Has medical use, but can lead to psychological or physical dependency (Methadone, Oxycodone, Hydrocodone)
• Schedule III: Less potential for abuse than I or II and may lead to low physical dependency.
• Schedule IV: Low potential for abuse compared to schedule III, the anxiety band
• Schedule V: Low potential for abuse compared with schedule IV, consists small amounts used for cough

Substance Use Disorder (SUD)

• Behavioral disorder: loss of control, constant use, and constant thinking.
• Mesolimbic Dopamine Tract- brain pathway for Dopamien to reach areas (VTA to cortex)
• VTA/Nucleus is important because it feels pleasing
• Amygdala- emotion
• Pre-frontal- counteracts behaviour
• Drug induced neuroplasty

1. Increased Dopamine Release:

• Many drugs, particularily those of abuse( cocaine, ampheramines, act by enhancing dopamine by releasing more by blocking the take uptakes.
• Ventral T egmental Area( VTA): often increases the firing rate of these VTA, enhancing dopamine.
• The dopamine receptor

2. Desensitization of Dopamine Receptors:

-Over time, brain is not to have dopamine signals, so requires a greater amount of a more potent drug that is the development of tolerance

• Glutamatergic Neurons- feedback from prefrontal to the down flow of the circuit reward.

• glutamate helps the brain to become more reactive

• Brain Disease model of addiction- brain disorder more so over will power.

• Dopamine has the strongest for stimulants, nothing for alcohol etc

• Blocking the Dopatime is non-effective

• Can lead to addiction to new meds.

• Full Agonist: prescribed to bind to and make activate receptors.

• Partial Less substance of Abused: partial substitute that binds to the same receptor.

• Angonist Treatment: reduces the effectiveness because taken compliance.

Key Terms

• Addiction
• Brain- disease model of addiction
• Cravings
• Mesolimbic Dopamine pathway
• Substance abuse
• Substance use disorder addiction

Module 5: Psychomotor Stimulants

• There are different types of cocaine, each with different duration of effects.

• After oral Ingestion caffeine absorbed in 45 minutes

• Cocaine is metabolized by Butyrocholinesterase that can be found in the urine for two days and hair months.

• When used the effect is enhanced and it is toxic on the heart and lives increases

• Local anesthetics There are 3 pharmacological actions:

• Vasoconstrictor

• Pyscostimulant

• There is release of dopamine into the presynaptic

• Amphetamines

• Binds to the presynaptic causes transporters to reverse causing more of the action

• High binds to MAO prevents degradation dopamine

• Highs include energy decreased appetite and euphoria

• Amphetamines

• Increased BP/HR

• Low doses -Respirationstimulation

Cocaine is metabolized after 50 minutes where amphtetmies last +11 hours Meth has many negative effects: hallucinations, anxiety, can lead to neuronal death immunity reduction.

• Tolerance develops to the euphoria for meth
• Lower d2 Effects of caffeine benefits and side effects. Work by blocking receptors for Adrenalin Constricts blood vessels helps with headaches.

Nicotine is highly absorbed through lungs the effect is only 2 hours half-life. Binds to the presynaptic receptors. Also, impacts receptors Releases all kinds of receptors dopamine

• Lowers the amount of dopamine, but increases the sensitivity Nicotine helps people. Most patients increase the use. Vaping a new method causes much more Nicotine is a stimulant that stimulates adrenalin receptors.

Key Terms

• Amphetamines and it's variants
• Armodafinil: longer-acting form of madofitnal, use for narcolepsy Cocaethylene: is a by project of using it for stimulant
• Cocaine blocks Dopamine
• Cocaine Base
• DMAA: Non amphetamine stimulants
• Modafinil: Used to treat sleep disorders.
• Synthetic cathinones
• END*