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What is the definition of pharmacokinetics and what are the components?
- What happens to the drug following administration
- ~ half-life
What is the definition of pharmacodynamic and what are the components?
- How the drug works in the body
- Adverse effects
- Therapeutic effects
The Big Picture
Bioavailability--> Drug Action--> Drug Effect
Name the components for each part as well as what consists of pharmacokinetics versus pharmacodynamics
- Bioavailability (pharmacokinetics)
- Routes of administration
- Absorption and Distribution
- ~ diffusion
- ~ lipid solubility
- ~ ionization
- ~depot binding
- Drug Action (pharmacodynamics)
- ~ Antagonism
- ~ Dose-Response Relationship
- Drug Effects (pharmacodynamics)
- Therapeutic Index
- ~ratio of therapeutic agent that reaches therapeutic level over lethal dosage
- Behavioral Consequences
- Side effects
Drug action vs Drug effect for LSD
- Drug action: inhibits cellular activity in brain stem areas (pons and medulla)
- Drug effect: widespread, including increased heart rate, blood pressure, sweating and chills, sometimes vomiting and nausea
Drug action vs drug effect for carbachol versus morphine
- Drug effect: reduction in the size of the pupil
- Drug action: carbachol: acts at the nerve endings in the iris (topical)
- Drug action: morphine: in the brain areas that modify pupillary responses to light, but has no effect when applied directly to the eye
What are localized drug effects?
- Drugs applied to a targeted area
- Minimum absorption into the bloodstream
What are systematic drug effects?
- Drugs are admninistered through the prescribed route and are absorbed into the blood stream
- Effects and side effects may be seen in many body systems
What is the key with Pharmacokinetics
- Drugs typically go through the body: depending on route of administration
- Drugs can and will act at sites that were not intended: not only in the brain but..
- ~ CNS
- ~ Other organs
What are the processes in the body for Pharmacokinetics
- Administration (in)
- Absorption (through)
- Distribution (through)
- Biotransformation (through)
- Inactivation/Elimination (through)
- Excretion (out)
What are routes of administration?
How and where a drug enters the body determines how much drug reaches the site of action, therefore the magnitude of its drug effects
Routes of administration affects drug absorption by determining...
- Absorbing surface (available blood supply)
- Number of membranes needed to cross
- Amount of drug destroyed (metabolism)
- Amount of depot binding
Name the types of routes of administration
- Intravenous injections (iv)
- Intramuscular injections (im)
- Intraperitoneal injections (ip)
- Subcutaneous administration (sc)
- Oral Administration (po)
- Other (topical, transdermal, Sublingual)
Absorption and Distribution: What influences the rate and amount of drug that enters the bloodstream and therefore the brain?
- Transportation across membranes (key issues is difussion, lipid solubility, & ionization)
- Age, Sex, and Body size (dilution and available depot sites)
- Blood-brain barrier (numerous mechanism for limiting access to brain)
Transportation across membranes: What is the Law of Diffusion and what influences the ability of diffusion to act?
- Dissolved substances move from an area of higher concentration to an area of lower concentration
- This is the power behind the absorption of drugs
- The ability of diffusion to act is influenced by: how easily a molecule dissolves across a membrane (lipid solubility) and whether or not a molecule is electrically charged (ionization)
Transportation across membranes: What is lipid solubility?
- membranes are composed of lipid molecules
- the lipid solubility of a drug is given by its Partition Coefficient
- Drugs that dissolve in fat (lipid soluble) diffuse across membranes easier then drugs that dissolve in water (water soluble)
Membranes are composed of?
Drugs that dissolve in fat diffuse across a membrane______ then drugs that dissolve in water (water soluble)
The lipid solubility of a drug is given by its...
What are ions?
Atoms or groups of atoms (molecules) that gain an electrical charge (+/-) after dissolving in a solution
What is ph?
- the negative logarithm of the concentration of hydrogen ions in a solution
- 7 is neutral: meaning that the number of hydrogen ions equals the concentration of OH- (hydroxide ions)
a lower ph, more hydrogen ions
higher ph, less hydrogen ions
What are the rules of Ionization?
- Molecules become less charged (unionization) when in the same ph environment and become more charged (ionized) when in different ph environments
- The less charged a molecule the easier it will move across membranes
If the drug as well as the environment are the same then the charge will be ____, (less, more), the lipid solubility will be_____ (greater, less), and the potential absorption will be _____ (greater or less)
less, greater, greater
If the drug and the environment are different the charge will be _____ (less, more), the lipid solubility will be______ (greater, less) and the potential absorption will be (greater, less)
more, less, less
Will aspirin (a weak base) be more absorbed in the bloodstream of the stomach or intestines? Why?
stomach- more similar environment because the stomach is acidic
In order for a drug in the blood to enter the brain it must...
- unionized at blood ph
- have a fairly high partition coefficit (lipid soluble)
- Or, existing transport mechanisms (e.g LDOPA)
How does depot binding affect the bioavailability of a drug? Give 3 examples
- 1 Slowed actionMany drug actions will be slowed by depot binding
- 1. drug A bings readily to "silent receptors" (depot sites)
- 2. drug A quickly reaches equilibrium between bound and unbound forms
- 3. blood concentration is dependent on the drugs release from depot sites
- 4. As drug leaves the bloodstream it is slowly released from depot sites
- 2. drug interactions
- Drug interactions can be affected by depot binding:
- Ex) imipramine ( antidepressant), diazepam (Valium), and phenytoin (antiepeleptic) all readily bind to depot sites
- Consequently, the effective dose of one will be greatly influenced by the presence of the others
- Effects of valium on 2 different patients:
- one on imapramine (antidepressant); depot sites are already bound
- one not on imapramine; depot sites need filling first
- 3 Drug termination:Depot binding may terminate a drug's action
- Thiopanel used as IV anasthesia: highly lipid soluble, easily passed from the blood to the brain (rapid drug effects), almost instantaneous sleep
- Meanwhile, blood levels quickly fall due to depot binding
- As blood levels fall, thiopanel moves back from the brain to the blood to maintain equilibrium
- Within 90 minutes, brain gives up its initial peak levels due to various depot sites (muscles, fat)
What is depot binding?
- the binding of drugs to inactive sites (blood proteins, muscles, bone, fat, liver)
- drug effects are related to the concentration of the drug at its site of action (receptor)
- only unbound drugs can pass easily through membranes (i.e reach site of action: receptor)
- bound and unbound drugs are within equilibrium in the blood
What is biotransformation?
- the process of drug metabolism that involves breakdown, detoxification, and removal of chemicals from the body.
- liver is primary site of drug metabolism
- oxidation: drug conversion to more water soluble compound
- Metabolite formation
What are the factors influencing biotransformation?
- Each person metabolizes drugs in a unique way
- Age: reduced metabolism, nutrition, disease
- enzymes: increased, decreased, absent
- Environmental factors: psychological effects
What is metabolism?
- the chemical process inwhich any drug maybe transformed or changed in the body
- This results in metabolites
- Metabolites are formed by enzyme interactions which alters the drug's chemical composition, forming compounds which differ from the original drug
- Metabolites have unique properties which have different effects then the original drug.
- Metabolites may be helpful, harmful, or neutral
What are the different types of metabolites?
- unchanged with regards to activity
- can last longer than the original drug
- may influence the rate at which the drug is metabolized
- Drug interactions
- Drug tolerance
Drugs and metabolites have associated half lifes: what are half-lifes?
- the amount of time it takes for one half of an administered drug to be lost through biological processes (biotransformation: metabolism, and elimination)
- each drug will have an associated half-life
Half-lifes will impact
- Dosing effects
- Drug effects: sustained drug effects,relapse, and side effects emergence
- Drugs cleared through kidneys will have prolonged half-lifes in patients with renal failure (kidney failure)
What is first pass metabolism?
- Drugs administered orally will go directly to the liver before getting into the blood that supplies the rest of the body
- Within the liver, specialized enzymes transform the drug into metabolites
- Water soluble metabolites are quickly and easily excreted
- This can dramatically influence the plasma level of many drugs (therapeutic dosage)
What is first order kinetics?
- the rate of metabolism is proportional the plasma concentration of the drug (exponential)
- e.g 50 % of the drug in blood is removed during each given interval of time
What is zero order kinetics?
rate of metabolism is fairly constant regardless of amount taken (e.g ethanol)
What is steady state metabolism?
Drug absorption equals drug elimation during the dosing interval: therapeutic level
What is enzyme induction?
the increase of enzyme levels with repeated use of a drug- smoking increases p450 enzymes which also metabolize antidepressants
What is enzyme inhibition?
- Reduction of enzyme levels through repeated use of a drug
- MAO-I in both brain and liver
- this blocks the mao enzymes that break down seratonin
How does drug competition change the rate of metabolism?
Drugs that share a common enzyme may reduce the metabolism of each by using up the available enzymes
What factors influence the rate of metabolism
How do drug-food interactions affect metabolism?
- Increased or decreased absorption
- Reduced GI irritation
- ~ aspirin
- Pharmacological interactions
- ~ grapefruit juice
- ~ Vitamin K
What issues affect drug elimination?
- Renal function
- ~ acidity of urine can facilitate reabsorption
- Hepatatic function
- ~ poorer in very young and very old
- ~ Metaabolites can affect renal excretion
- Additional drug effects of same drug
Why is excretion important?
- Required to completely terminate effect of drug
- prevents accumulation of drug in system (including metabolites)
What are the sites of elimination?
- Renal: kidneys (primary site)
- Hepatitic: liver
- GI tract (intestines)
- exocrine glands (sweat, saliva, milk)
What are the major issues of aging populations and pharmacokinetics?
- Physiological changes with aging
- ~ increased fat (decreased lean body mass)
- Decreased GI motility and blood flow
- Decreased liver function
- Decreased renal function
- Medication issuescumulative drug effects
- medication noncompliance
- ~ memory issues
- ~ medication refusal (side effects, lack of knowledge, ideaology)
Aging and Pharmacokinetics: What is an indication of drug toxicity?
- behavioral changes
- do not assume mental status changes are a normal part of aging
what is a receptor?
a molecule, usually a protein, that is present on the surface or within a cell and which is the initial site of action of a biologically active agent.
What are dose response curves?
- graphical representation of the amount of biological or behavioral effect (response) for a specific drug concentration (dose)
- with increasing drug concentrations (x-axis) there is an increase in biological or behavioral effect (y-axis) until the maximum effect is achieved.
- for each drug, increasing the dose produces greater analgesia (elevations in pain threshold) until the maximum response is achieved.
Dose response curves: mechanisms of action
- despite great differences in potency among the 3 opiate drugs, their maximum effectiveness and shapes are the same.
- this similarities indicate that the 3 drugs are acting at the same receptors, but with different assessibility, affinitiy, and efficacy
What can the dose response curve tell us?
- The relative effectiveness of a drug across biobehavioral responses
- drugs are absorbed and distributed all over the body and may act at multiple receptors having multiple actions.
Receptor Antagonism: Drug Interactions?
Many drugs will act at a given receptor and each drug may have a host of of effects, all of which potentially influencing the ability of other drugs or neurotransmitters to do their job.
What is an antagonist?
( general terms for actions/interactions)
A drug that binds to a receptor, but has no intracellular effect. consequently, they may block the effects of neurotransmitters or agonists drugs for this receptor.
what is an agonist?
A drug that binds to the same receptor as a neurotransmitter and does initiate intracellular changes.
what is irreversible antagonists?
an antagonist that does not follow the rules of reversible binding and forms an almost inseperable bond with the agonist receptor site
- A drug that binds reversibly to a region of a a receptor in common with an agonist but occupies the site without activating the effector mechanism
- the effects of a competive antagonist maybe overcome by increasing the concentration of a an agonist, thereby increasing the proportion of receptors which the agonist occupies.
- an antagonist thar reduced the effectiveness of a neurotransmitter or agonist through a mechanism other than binding to the agonist receptor site.
- For example, pcp: reduces the eficacy of Glutamate receptor, but rather by binding to a separate receptor site on the same receptor molecule.
- a drug which produces an effect opposite to that of an agonist, yet acts at the same receptor
- If receptor X opens the door to the house when activated by its agonist, then the inverse agonist would cause the receptor to now shut the door
- the inverse agonist still activates the receptor, but with the opposite consequences in regard to drug action
Adverse drug reactions: harmful effects of a drug due to high levels of the drug in the body
- Iatrogenic effects: illness caused by medical txt.
- adverse side effects
Adverse drug reaction?
- high drug dose
- dosing too frequently
- patient sensitivity
- reduced excretion
- narrow margin of safety (therapeutic index).
What influences desirable versus undesirable side effects?
- will differ from patient to patient
- must guide prescribing decisions
- Drugs are chosen to take advantage of side effects that may benefit the patient:
- I.e. when choosing an antidepressant, if patient is having trouble sleeping, may avoid drugs that cause insomnia like Prozac and choose a drug that causes drowsiness such as nortryptilline, a tricyclic antidepressant, giving it at bedtime
Adverse side effects: mild
- maybe tolerable, may not be noticed
- may lessen with duration of treatment
Side effects: severe?
Side effects: allergic reactions
- rash and itching (urticaria)
- anaphylaxis: life threatening
- Laryngeal edemea, dyspnea, wheezing
- shock, blood pressure drop, cardiovascular collapse
- treatment: epinephrine, benadryl, steroids
- What is one person's therapy, may be another person's side effect
- a measure of thearapeutic usefullness and safety
- effective dose 50 : the dose at which 50% of people experience the therapeutic effects of a drug
- Toxic dose 50: the dose at which 50 % of people experience a toxic side effect of a drug (respiratory depression)
- Therapeutic Index (formal definition)
- the ratio of the td50/to the effective dose ed 50
When given the choice between drugs, a __________ (lower, higher) therapeutic index should be used?
Chemical neurotransmition: What is START?
- Action Potential Initiated Release
Synthesis (from START)
mechanisms by which neurotransmitters are created
Microtubules: internal filament network that provides cellular structure and mobility molecules
Action Potential Initiated Release
The calcium initiated biochemical events leading to the release of transmitters into the synaptic cleft
Receptors (From Start)
The intermediaries between chemistry (drugs, transmitters) and cellular effects (chanel opening, enzyme activation
The various mechanisms by which actions of transmitters at their receptors are terminated
What are the two methods of synthesis?
- Synthesis by enzymes: small molecule family, synthesized within the synaptic terminal
- Protein synthesis: large molecule family, synthesized within the cell body and vesicle
Synthesis small molecule family?
- ex: Acetylcholine
- choline (dietary)
- Acetylcoenzyme A
- Specialized enzymes:
- Choline acetyltransferase (CHAT)
Synthesis: Large molecule family
- Protein synthesis (genetic expression) of precursor protein
- package precursor and specialized enzyme in vesicle
- enzymes creates peptides during transport to synapse
Action Potential Initiated Release (START): Sequence of effents
- Arrival of the action potential (trigger)
- calcium influx (enzymes)- (gun powder)
- Mobilization of vesicles ( bullet casings)
- Exocytosis (bullets fired)
- Recycling of vesicles ( clean up)
What are receptors?
Small, Chemically (protein) defined areas (of a cell) which initiate a biological response upon uniting with chemically complementary areas of natural or foreign molecules (drugs)
What do receptors do?
- immediate: convert chemical signal (neurotransmitter) into an electrical signal
- Excitatory Post synaptic Potential ( EPSP)
- Inhibitory Post synaptic Potential (IPSP)
- Long-term/wide spread: permanetly alter cellular behavior via feedback onto protein synthesis
Where are receptors located?
- Presynaptic: referred to as "autoreceptors" located anywhere on the presynaptic neuron
- typically serve as a negative feedback mechanism that slows or shuts down the further release of neurotransmitters
- Postsynaptic: receptors located on the postsynaptic neuron - a feedback mechanism inwhich the activity of the presynaptic neuron influences the subsequent behavior of the post synaptic cell
Name the common features of receptors
- Extracellular domain: thought to be the domain inwhich primary receptor binding occurs
- Transmembrane domain: thought to be the location of binding for modulatory chemicals (i.e. allosteric modulation
- Intracellular domain: amino acid loops that, in may receptors, interact with other proteins to initiate biological responses
Receptors: the super families:
What is the iontropic super family
- typically 4 transmembrane regions
- the four transmembrane units make up a single subunit.
- typically 4-5 subunits come together to form a pore (ion channel) in the membrane
What is the metabotropic Super family?
- typically 7 transmembrane units
- the intracellular loops can bind and activate g-proteins (separate protein that activates effector systems)
What is a transporter super family?
- typically 12 transmembrane regions
- uses energy ATP-dependent mechanisms to shuttle transmitters across cell membranes
- i.e neuronal membrane transporter (serotonin reuptake
Ionotropic super family
- directly opens ion channels
- fast synaptic transmission (milliseconds)
- receptor binding leads to
- a molecule alteration in the subunits configurations
- this results in the opening of an ion pore
- ions are now free to move across the membrane (electricity)
- subtypes within this superfamily are selective for specific neurotransmitter (glutamate, gabba, Glycine)
- each channel pore will be selective for a particular ion (e.g K)
- the cellular consequence of receptor activation is therefore dependent on the receptor subtype and its particular channel properties
- Literally means other site
- on the same protein, the function of one receptor is influenced by the activity at another receptor
- the process modulators (drugs) bind to regulatory sites distinct from the active site on the protein
- this results in conformational changes that may profoundly influence protein function
- benzodiazapines - increase the frequency of channel openings
- barbituates (sedatives and anticonvulsants) -increase the duration of channel openings
Metatropic Super Family
- functional purpose:
- not directly connected to ion channels
- slow synaptic transmission
- receptor binding leads to ...activation of g proteins
- activation of a specific effector system
- ion channel opening/closing --> changes in gene expression
- selectivityall transmitters have multiple subtypes of g-proteins coupled receptors
- each subtype may result in the activation of a distinct effector system
- the biological consequence of receptor binding is therefore dependent on the receptor subtype and its particular effector system.
mechanism for altered function:
what is down regulation? (desensitization)
- a decrease in the number of available receptors within a synapse
- methods: change in gene expression (transcription factors)
- receptor phosphorylation by enzymes
what is upregulation (sensitization)
- an increase in the number of available receptors within a synapse
- change in gene expression (transcription factors)
- receptor dephosphoralation by enzymes
Name the ways to erminating Neurotransmission
- reuptake: special transporter proteins
- e.g selective serotonin reuptake inhibitors (SSRI)
- Enzyme breakdownspecialized enzymes within the synapse
- Diffusion into extracellular spaceneuropeptides quickly diffuse away from the receptors into the surrounding medium
- these may inturn influence neighboring synapses and neurons