Neuropharmacology and Pharmacokinetics Flashcards
Parts of a neuron
Dendrites- branch like projections receive information from other cells and conduct it toward the cell body
Axon- transmits information received from the cell body to other cells through the terminal axon fibers which house the terminal/synaptic button
Terminal/synaptic button- holds the chemical neurotransmitters until they receive a signal to release into the synaptic gap
Cell body- Command center- contains nucleus, ribosomes, mitochondria and the Golgi apparatus of the cell. It integrates info received from the dendrites and sends it electrically to the axon
Postsynaptic cleft- gap between vermin button and next cell- area of postsynaptic transmission
Flow of information summary
Dendrite receive information –> Cell body integrates information –> Information sent down the axon –> sent to terminal axon buttons –> released into presynaptic cleft to transmit the info to the next neuron
Connection Between Pre and Post Synaptic Neuron
Presynaptic neuron- sends information into the cleft, neurochemical processes (via NTs)
Postsynaptic neuron- receives info at the cleft, neurochemical processes
Mitochondria
Located in the cell body of the neuron
Energy source! Provides the energy for the initiation of neurotransmission by sending electrical impulses through the neuron to the terminal axon fibers’ synaptic buttons
Neurotransmission Process
Presynaptic neuron
- Sends the message along the axon terminal via ELECTRICAL impulse to form a synapse with the dendrites of the postsynaptic neuron
- Electrical impulses in the presynaptic neuron are converted to chemical signals at the synapse between the presynaptic and postsynaptic neurons
Postsynaptic neuron
- Receives information primarily at the dendrites; However, information may also be received at other sites along the axon and even at the cell body
Modes of Exchange: Chemical and Electrical
Within the neuron: Information is passed along the axon via ELECTRICAL PROCESSES fueled by the mitochondria
Between neurons (across gaps/synapses): Information is exchanged via NEUROCHEMICAL PROCESSES
Neurotransmitter Classifications: Amines
- Quaternary amines = Acetylcholine (ACH)
- Monoamines = Catecholamines:
Norepinephrine (NE), Epinephrine (adrenalin), Dopamine (DA), Indoleamines (Serotonin, 5-HT)
*These work more slowly
NT classifications: Amino Acids
- Gamma-aminobutyric acid (GABA)
- Glutamate
- Glycine
NT classifications: Neuropeptides
Opioid peptides:
- Enkephalines (Met-enkephalin, Leu-enkephalin)
- Endorphines (beta-endorphin)
- Dynorphins (Dynorphin A)
NT classifications: Peptides & Gases
Peptides
- Oxytocin
- Substance P
- Cholecystokinin (CCK)
- Vasopressin (regulates retention of water)
- Hypothalamic-releasing hormones
Gases
- Nitric oxide
- Carbon monoxide
Soma (cell body)
Present in all cells of the body except red blood cells
Has a nucleus that contains basic genetic material (DNA) for the cell
Has mitochondria which provides the biological energy for the neuron
- Energy is in the for of adenosine triphosphate (ATP)
- Available for various chemical reactions
RNA- In réponse to stimuli, the DNA is transcribed into a 2nd similar molecular form- strands of ribonucleic acid (RNA) goes thru a series of steps
- It is then exported to the cytoplasm (liquid part of the cell) of the soma. The edited RNA is called messenger RNA and it is translated from the nucleic acid code of the RNA into the amino acid sequence for the protein that is to be expressed
DNA gives message to RNA to give message to cell of what specific NTs, enzymes, or receptors to make
Acetylcholine
Deficiencies in ACh secreting neurons is associated with the dysfunction seen in Alzheimer’s
- in order to get into the cell enzyme esterase breaks down ACH into acetate and choline
- following breakdown, acetate and choline are taken into nerve terminal where ACh is synthesized in a one-step reaction from 2 precursors (choline and acetyl CoA) and then stored in synaptic vesicles for later release
Its action is terminated by acetylcholinesterase
Catecholamine Neurotransmitters: Dopamine and Norepinephrine
Catecholamine refers to compounds that contain a catechol nucleus to which is attached an amine group
In the CNS- dopamine and NE
In the PNS- epinephrine
Chemical synthesis similar but NE has an additional step
Inactivation occurs primarily by reuptake
Serotonin
Investigated as a NT in the 50’s when LSD was found to structurally resemble serotonin
Plays a role in depression and other affective states, sleep, sex, and regulation of body temperature
Inactivated primarily through reuptake processes
Glutamate
Major excitatory NT
Found on the surface of almost all neurons
Precursor for the major inhibitory NT (GABA)
Plays a critical role in cortical and hippocampal cognitive function, as well as motor, cerebellar, and sensory functions
May place a role in the neuronal injury that accompanies alcoholism, Alzheimer’s, and head injury
After used, taken up into neighboring support cells and converted back to glutamate and stored
GABA
Inhibitory transmitter- reduces excitability
Action associated with anxiolytic, amnestic, and anesthetic effects
Chemical Puff
Neurotransmission that occurs away from synapse and through the process of diffusion
(NTs released by neuron but not room in the next one, so in cleft- can be picked up by other NTs with right receptors- if neurons are not specific to NT, then it will not send the message)
Pharmacokinetics
How drugs are handled in the body
Involves four basic processes: absorption, distribution, biotransformation, and excretion
Taken together, they determine the bioavailability of a drug (how much of the drug administered actually reaches its target) *Each of these factors are affected by individual differences
Absorption
The movement of the drug from its administration site (route) to the blood stream (mouth, skin, vein, etc.)
Soluble drugs are absorbed faster than insoluble
Large particle drugs are absorbed more slowly than small
When the particle size of a drug is reduced it increases the bioavailability
The route of administration affects bioavailability
Absorption Terms:
- Buccal & sublingual
- Ionization
Buccal (by mouth) & Sublingual (under the tongue)- non-invasive, rapid absorption, prevents first pass effects by preventing exposure to acidic environment of the stomach and by first metabolism in the liver
Ionization- degree of dissociation of drug from the pH of the medium in which it is placed
- Most drugs are weak acids
- Non-ionized compounds are lipid soluble and can penetrate the cellular membranes
- Ionized drugs are more water soluble
Absorption terms cont’d
- Surface area
- Blood flow
- Gastric emptying
Surface area - most drugs taken orally are absorbed from the small intestine – larger surface area
Blood flow – The perfusion rate affects the absorption of drugs. To increase absorption, increase the perfusion rate - massaging the site after an injection increases perfusion
Gastric emptying – drugs are absorbed faster on an empty stomach. Fat reduces absorption rate
Absorption terms cont’d
Hepatic first pass effect
The loss of the drug as it passes through the liver the first time (sublingual route avoids this past effect)
(if metabolized by the liver you lose part of the drug before it reaches the site of action)
Liver function must be considered when drugs are used as a method of treatment
Distribution
The movement of the drug from the blood to the rest of the body
Blood flow Binding of drugs to plasma proteins Site of action of drugs Potency and efficacy Affinity and intrinsic activity Pharmacologic and physiologic antagonism
Biotransformation (Metabolism of Drugs)
The alteration of drugs through enzyme catalysts occurring in the body (how the drug is broken down by enzymes in preparation to leave the body)
Pharmacogentics – hereditary variation of drug metabolism
Immaturity - of drug metabolyzing enzymes
Drug - Drug interactions
Disease – liver disease
Excretion
Routes through which drugs can leave the body:
- Kidneys – most drugs leave the body in urine (Unchanged or as a metabolite of the original drug, Many must go to liver first to be broken down into metabolites)
- Lungs – highly volatile or gaseous agents (general anesthetics or small amt of alcohol)
- Bile
- Skin
- Saliva
- Breast milk
Factors Affecting Excretion
Water versus lipid soluble
- Psychoactive drugs are usually too lipid soluble to be excreted passively in the urine
- Must be transformed into metabolites that are more water soluble and less lipid soluble, less biologically active or actually inactive when compared to parent molecule
- Enzymes used to metabolize drugs in the liver
Cytochrome P450 enzyme family
- Located in the hepatocytes
- Major system involved in drug metabolism
Genetic, environmental, cultural, and physiological factors can impact the increase or decrease in rate of drug elimination
Half-life
Knowledge about the relationship between the time course of drug action and its pharmacological effects is essential for:
- Predicting optimal dosages and dose intervals needed to reach a therapeutic effect
- Maintaining a therapeutic drug level for the desired period of time
- Determining the time needed to eliminate the drug
The time required for the drug concentration in the blood to fall by one-half (Continues to decrease by half (half of half, etc.)
It is also the determinant of the length of time necessary to reach a steady state concentration
Half-Life Example
- 100 mg of a drug with a 4 hour half-life administered at noon.
- 50mg of the drug remains in the body at 4 PM
- If an additional 100 mg of drug is taken at 4 PM, 75 mg of drug would remain in the body at 8 PM (25 mg of the 1st dose and 50 mg of the 2nd dose
- If this administration schedule is continued the amount of drug in the body would continue to increase until a plateau (steady state) concentration is reached
Steady State
- The level of drug achieved in the blood with repeated, regular interval dosing
- At 98.4% (concentration achieved after six half-lives) the drug concentration is essentially at a steady state
- The steady state concentration is achieved when the amount administered per unit time equals the amount eliminated per unit time
Therapeutic Drug Monitoring (TDM)
Threshold plasma concentration of a drug is needed at the receptor site to initiate and maintain a pharmacological response
TDM is an indirect, although usually quite accurate, measurement of drug concentration at the receptor site
Blood samples drawn at several time periods during both acute and chronic therapy
Narrow therapeutic level would mean not much room between therapeutic level and toxic level so you would want to check this because it wouldn’t take long to put them in a toxic state
