Pharmacokinetics and Pharmacodynamics Flashcards
Define liberation
Liberation is the first step of absorption.
Liberation is the separation of a drug from its vehicle.
Why does atropine cross the BBB while glycopyrolate does not?
Atropine is neutral
Glycopyrolate is + charged and thus can’t cross the BBB
Compare and contrast intrathecal morphine vs. fentanyl
Morphine = hydrophilic –> persists in circulation
Fentanyl = hydrophobic –> binds quickly to surrounding fat and protein affecting nearby nerve roots
Compare and contrast the alpha and beta phases of elimination
Alpha - distribution phase of a drug from central circulation to the periphery right after a bolus
Beta - elimination, metabolism + excretion
Define volume of distribution of a drug
Volume = dose (mg) /concentration (ml)
Volume of distribution exceeds total body volume in fat soluble or highly protein bound drugs
Children have larger volumes d/t larger intravascular and extracellular volumes
Dec protein in elderly, anemia and hypoalbuminemia = lower volume
What is the Law of Mass Action?
And why rocuronium has a quicker onset than equipotent vecuronium?
Larger dose = faster onset
= use a greater quantity of a less potent drug
How many half lives of an oral drug to reach steady-state?
4-5
Explain 1st order elimination
Rate of elimination is proportional to the concentration of the drug. A constant proportion of the drug is eliminated
Exponential decay process:
8-4-2-1
How does an antagonist effect the dose response curve?
Shift curve to the right
• Antagonist – block other drugs but cause no activity
Competitive – physically displace agonist w/o blocking
Non-competitive – irreversibly bind to receptor
How does a noncompetitive antagonist effect the dose response curve?
Shift to right and reduce max efficacy
Non-competitive – irreversibly bind to receptor
How does a partial agonist effect the dose response curve?
Sub maximal response
• Partial agonist – partially activate even at [high]
What is therapeutic index?
TD50 / ED50
GABA receptor belong to what receptor type?
Ligand-gated ion channel
Drug potency is determined by what factors?
Affinity to the receptor
And receptor response to drug binding
Higher potency = lower ED50
What type of agonist/antagonist decreases receptor response to a level below baseline response observed?
Inverse agonist
What type of ligand effect does buprenorphine exhibit?
Partial mu agonist
What type of drug will decrease efficacy of an agonist w/o affecting its potency?
Noncompetitive antagonist
Explain 0 order elimination
Cleared at a constant rate, irrespective of the plasma concentration.
Ex: alcohol
Explain context-sensitive half-life
Fat soluble drugs accumulate over time –> Half-life increases over time.
A continuous infusion has to be dialed back in long cases to prevent overdoses.
However other drugs like remifentanil don’t.
What are the two major plasma proteins that affect drug protein binding?
- Albumin
2. alpha-1 acid glycoprotein (acute phase reactant)
Which plasma protein binds acidic drugs and basic drugs most readily?
Acidic = Albumin
Basic = (alpha-1)(narcotics, amines)
Would a weak acid or a weak base more readily cross the cell membrane?
Weak acid
- it donates H+ becoming non-ionized and can easily cross
What is the pKa of a drug?
The pH at which half the drug is in its ionized form and half in its non-ionized form.
- The lower the pH relative to the pKa, the greater the fraction of drug in the ionized form.
- Local anesthetics are weak bases, infected tissue is acidic –> LA becoming ionized and unable to penetrate the membrane to exert their action
Compare the solubility of high blood: gas coefficient gases to low blood: gas coefficient gases
High blood: gas = more soluble = passes easily from air to blood
What factors make a molecule transfer across cell membrane more quickly?
low degree of ionization
low molecular weight
high lipid solubility
high concentration gradient
What causes the initial decline in drug concentration of a lipophilic drug and what is it dependent on?
Redistribution
Dependent on cardiac output - high CO tissues = faster equilibrium
CO is based on LEAN body mass
What drugs are metabolized by CYP3A4?
Tylenol, dexamethasone, lidocaine, midazolam, methadone, fentanyl, alfentanil, sufentanil, little bit of propofol
Name inhibitors of CYP3A4
grapefruit juice anti-fungals protease inhibitors “mycins” SSRIs
Name inducers of CYP3A4
Rifampin rifabutin tamoxifen glucocorticoids carbamazepine barbiturates St. John’s Wort
What drugs are metabolized by CYP2B6?
Propofol, codeine, oxycodone, hydrocodone
What class of drugs inhibits CYP2B6?
SSRIs
What drugs are metabolized by plasma esterases?
Remifentanil, succinylcholine, esmolol
Succinylcholine – pseudocholinsterase or butylcholinesterase can be cleared slowly with genetic defect
What drugs are extensively really cleared?
Steroidal muscle relaxants
85% pancuroniu
20-30% vecuronium
10-20% rocuronium
What is the formula for calculating CrCl?
Cockroft-Gault
(140-age) x weight (kg) / 72 x serum Cr (mg%)
Women are this x 85%
Old people with normal Cr STILL have lower clearance
What drugs utilize the Ligand-gated type receptor?
Propofol midazolam thiopental ketamine muscle relaxants
Define tolerance
reduction in the pharmacologic response to a drug following exposure to the drug or a similar drug
Inc amounts to produce same effect
What are the types of drug tolerance?
- Innate - genetic predisposition that renders one less sensitive to a drug = Opioid receptor gene polymorphisms
- Acquired - increased metabolism as a result of liver enzyme induction (barbiturate and ketamine), receptor down-regulation (opioids) or desensitization (a reduction in the efficacy of a receptor-bound drug to produce its effect).
What are the mechanisms for tolerance?
- receptor down-regulation
- desensitization
- enzyme induction
What is tissue tolerance?
increasing quantities of opioids are required to produce analgesia, euphoria, and respiratory depression, but tolerance to miosis and constipation does not develop
What is tachyphylaxis?
Acute tolerance
What is one mechanism for the development of tachyphylaxis?
depletion of neurotransmitter stores
Name 5 drugs associated with tolerance and tachyphylaxis besides opioids.
ephedrine (depletion of norepinephrine stores)
nitrates (depletion of sulfhydryl groups)
succinylcholine (prolonged ion channel opening)
desmopressin (depletion of both Factor VIII and vWF)
Epidural lidocaine
