Pharmicokinetics Flashcards
Specificity
The drug only produces one effect on the body if it is very specific
Selectivity
Drugs prefers to bind to one specific target (receptor) over others, most drugs are selective
Agonist
Drugs fits the receptor and activates it
Antagonist
The drugs fits the receptor but doesn’t activate it, just prevents its activation by another molecules
What class of drugs have efficacy?
Agonists (efficacy is the ability to produce an effect)
Law of mass action
Affinity
Relationship to Kd
1/KD
From law of mass action plot
KD
Definition
The drug concentration needed for 50% of receptors to be bound by the drug
Potency
Used to compare binding affinities of drugs that bind to the same receptor site and work by the same mechanism
Inverse agonists
Produce the opposite effect as the agonist. They still activate the receptor but instead of triggering a positive response, they cause a negative one.
Dose response curves for different types of agonists
Competitive antagonists
Bind to the same site on the receptor as the agonist
Can be overcome by increasing concentration of agonist
Non-competitive antagonist
Bind to a different site on the receptor than where the agonist binds, but still prevent the agonist from activating the receptor
Irreversible antagonists
Bind permanently to the receptor, often by forming covalent bonds
X - agonist alone
Y - agonist with competitive antagonist
Z - agonist with an irreversible antagonist
Quantal dose-response curves
Used to study how drugs affect a population - aka “all-or-none” curves = measure whether a drug causes a specific effect (yes or no) in a population of patients.
Cumulative frequency distribution
Used to determine ED50 and TD50
When drugs TD50/ED50 <10 we say that the drug has a “narrow” therapeutic index - there is a small variation in drug dosage that causes desired effect vs. harmful effects
For humans we use TD50 (toxic dose in 50% of population)
NSAIDs
Competitively bind cyclooxygenase (COX) preventing arachidonic acid from binding
Aspirin
Non-competitively binds COX receptors (also irreversibly acetylates the enzyme) which prevents arachidonic acids from every binding
Gs proteins
Stimulate adnylyl cyclase - increases cAMP
Gi proteins
Inhibit adenylyl cyclase - reduces cAMP, often resulting in hyperpolarization of cells
Gq proteins
Activate a different pathway using diacyglycerol (DAG) and inositol triphosphate (IP3) as second messengers. Typically when this pathway is activated there is an increase of calcium levels inside cells. When intracellular calcium levels increase, this can promote cell depolarization, release of neurotransmitters, or contraction depending upon the cell type.
When receptors are exposed to continuous stimulation:
Desensitization - often because the receptors uncouple from their G-proteins
Down-regulate - few receptors available on the cell surface
Tachyphylaxis - decrease the situation in which there is a rapid or substantial decrease in the effect of a drug over time
(from AI - rapidly diminishing response to successive doses of a drug, rendering it less effective. The effect is common with drugs acting on the nervous system)
What may occur when receptors are continuously blocked by an antagonist?
The receptors may become supersensitized and up-regulate making the cell more responsive to stimulation when the antagonist dissociates (or competitively displaced)
Autoreceptors
Located on the presynaptic neuron
Limits the release of neurotransmitters
Drugs that act on autoreceptors can affect the amount of neurotransmitter reaching the postsynaptic neuron (leads to either up/down regulation - depending on whether drug is agonist/antagonist)
Absorption
The process of moving a drug from its site of administration into the bloodstream
PO absorption
- Absorbed in the gut
- Travels to the liver via the portal vein
- First-pass effect in the liver
Bioavailability
(F) - fraction (or percentage) of the drug that makes it into systemic circulation after the first-pass through the liver (i.e 40% of a drugs ia metabolized by first-pass metabolism, leaving 60% bioavailable - F=0.6)
What enteral ROA(s) bypass the liver and avoid the first-pass effect?
Sublingual and rectal
Parenteral routes
All routes that do not involve the GI tract - IV, inhalation, transdermal…etc.
Also bypasses first-pass metabolism
Hydrophilic drugs
Need to be small enough to pass through aquaporins
P-glycoprotein
Work to efflux drugs from cells.
OATP1B1 and OATP1B3
Help transport drugs into cells
Breast Cancer Resistance Protein
Pumps drugs out of cells
Organic cation transporters and multidrug and toxin extrusion proteins
Move drugs in and out of renal cells
Factors affecting absorption
- Drug size
- Formulation (i.e. tablet, capsule)
- pka
- pH of surrounding environment
- Dose administered and resulting concentration gradient
- Surface area and blood flow at absorption site
Apparent volume of distribution (Vd)
Helps estimate how much of the drug is found in different areas (compartments) of the body.
Vd assumptions: drugs is distributed equally throughout all body compartments and instantaneous distribution
Vd = Dose/C0
C0 represents the drug’s inital concentration in plasma.
Properties that help drugs cross BBB and/or placental barrier
- Low-ionization
- High lipophilicity
- Low amount of non-specific protein binding to ablumin
- Small size
If small enough (~equal to the mw of water) then things molecules will readily diffuse through the barrier with water, regardless of ionization state
Enterohepatic recirculation
Acts like a resevoir for the drug
After being metabolized by the liver, some drugs are excreted into the bile and then passed back into the instestines. Under favorable conditions, the drug may be reabsorbed from the intestines back into the bloodstream, extending its time in the body
Estrogens (i.e. oral contraceptives) undergo enterohepatic recirculation - helps maintain their levels in body.
Infants
Impact of age on drug absorption/distribution
Have higher levels of extracellular fluid compared to adults, which can change the distribution and plasma concentration of some durgs
Older adults
Impact of age on drug absorption/distribution
Typically have more body fat than younger people, which can affect how fat-soluble drugs are stored and released
Also tend to have less p-glycoprotein activity at the BBB, so more drugs may enter the CNS
Main goal of biotransformation
To make drugs more water-soluble - allowing them to be more easily removed from the body
Phase 1 rx’ns
Include oxidation, reduction, and hydrolysis
Often referred to as unmasking or non-synthetic reactions because they expose or add a functional group to the drug, but they do not involve combining 2 large molecules to make a new one
Phase 2 rx’ns
Involve conjugation - and are sometimes called synthetic rx’ns
Combine the drug with another molecule like glucoronic acid, sulfate, or glutathione to form a new, more water-soluble compound
Oxidation of phase 1 rx’ns
Most common type of phase 1 rx’n
Often carried out by specific enzymes call ctyochrome P450 (CYP) enzymes in the liver
P450 inhibitors
Cimetidine (OTC histamine-2 receptor antagonist), “azole” antigungals, some HIV medications
P450 inducer
Increases the activity of the CYP enzyme, causing more enzyme to be made or stabilizing the mRNA that encodes for the enzyme.
Leads to faster breakdown of other drugs that are metabolized by the same enzyme, may reduce other drug’s effectiveness.
Antiepileptic meds (carbamazepine, phenobarbital, phenytoin) and rifampin are potent P450 inducers
Hydrolysis rx’sn
Peptidases/esterases/amidases
Phase 1 rx’sn
Glucoronidation
Glucuronyl transferase adds glucoronic acid to the drug, making it easier to excrete
Infants under 1 y/o have immature glucuronidation capabilities, and toxicities can result
Phase 2 rx’ns
Some drugs that are glucuronidated are excreted into bile and can undergo enterohepatic recirculation
Glutathione conjugation
A small peptide added to detoxify harmful drug metabolites
Phase 2 reactions
Phase 2 rx’ns
Sulfation, acetylation, and methylation
Along with glutathione conjugation and glucuornidation
Two pathways of drug elimination
Metabolism - drug is chemically altered (mainly liver) and excretion (mainly kidneys)
Drug clearance
Refers to the volume of fluid (usually plasma) from which a drug is completely removed over a given period of time - mL/min
What factors influence hepatic clearance?
Factors that influence:
1. Enzyme induction or inhibition
2. Liver blood flow
3. Protein binding
Renal clearance
Equation
CIrenal = UV/P
U = concentration of drug in urine
V = urine volume formed per minute
P = concentration of drug in plasma
Main processes of renal clearance
Glomerular filtration - passive procces where small, unbound drugs are filtered from the blood into the renal tubule (creatinine clearance used to estimate kidney function)
Active secretion - some drugs are actively transported from the blood into the urine using ATP. Involves protein carriers, which can be saturated and lead to drug interactions
Reabsorption - drugs that are lipid-soluble can passively diffuse back into the bloodstream from the renal tubules. However, polar or ionized drugs are more likely to stay in the urine and be excreted.
Making urine more acidic (with Vit C) or more alkaline (NaHCO3) can help excrete certain drugs faster by preventing their reabsorption
Gray baby syndrome
Due to immature hepatic enzymes needed for glucoronidation of chloramphenicol
Antagonism
Drug interactions
Pharmcologically: at the receptor level, where two drugs compete for the same receptor
Physiologically: When drugs act through different body systems but have opposing effects
Chemically: two drugs form a chemical complex
Synergism
Drug interactions
Combining antigoagulants and antiplatelets can increase overall blood-thinning effects
Pharmacokinetic drug interactions
Absorption: one drug can interfere with the absorption of another, either by altering the stomach’s pH or forming complexes that reduce absorption
Distribution: Drugs can compete for binding sites on proteins like albumin, affecting how much of each drug is “free” to act in the body
Metabolism: some drugs speed up or slow down liver enzymes - this can lead to one drug being metabolized too quickly or slowly
Elimination: drugs can affect each other’s clearance, especially through the kidneys, either by competing from transport proteins or altering pH of urine
Time-response curves
Useful for calculating bioavailability
Area under the curve represents total drug exposure over time
Zero-order elimination kinetics
Alcohol is the key example
Enzyme(s) responsible for eliminating drugs are sturable (i.e. alcohol DH)
First-order elimination kinetics
Applies to most drugs
Rate of elimination is proportional to the drug concentration
A constant fraction of the drug is eliminated per unit of time - rate of elimination depends on how much drug is in the body
Calculation of Vd
Formula for calculating steady-state concentration
Cpss = MD/Cl
MD = the maintenance dose
Cl = clearance
How long does it take to reach steady state plasma concentration?
4-5 half lives if a drug is administered once every half-life
This is regardless of ROA
Once steady state is achieved it takes 4-5 half-lives to completely clear the drug from the body
How to calculate the elimination constant
One vs. two compartment models
Calculate bioavailability of oral drug
F = AUCoral/AUCIV
What increases serum concentration fluctuation?
Extended dosing intervals
Cl = clearance
Most drugs gain entry into cells by?
1.Passive diffusion with zero order kinetics
2.Passive diffusion with first order kinetics
3.Active transport with zero order kinetics
4.Active transport with first order kinetics
5.Passive diffusion through membrane pores
Elimination half-life
t1/2 = 0.692 (Vd)/Cl
Vd = L
Cl = mL/min.
An elderly patient is prescribed a beta receptor antagonist to treat his atrial fibrillation. These drugs act at post-synaptic receptors of the heart. Which of the following changes do you expect within the first 2 weeks of therapy?
Beta-receptor numbers increase
Which of the following provides information about the variation in sensitivity to a drug within a population being studied?
Quantal dose-response curves
Which of the following is correct about the concept of volume of distribution?
This is a value that remains relatively constant in a specific person who is taking a specific drug.
Which of the following processes accounts for MOST movement of drugs across biological barriers?
Passive diffusion
Efficacy vs. potentcy
Efficacy - considers response
Potency - considers binding affinity
What aspect of the cell contains steroid receptors?
Cytoplasm, receptor is then translocated into the nucleus
