Pharmacodynamics / Pharmacokinetics (1) Flashcards
Hyperreactive definition
low dose produces a pharmacologic effect
Hypersensitive definition
Allergic type reactions
Hyporeactive definition
Need a larger dose to get pharmacologic effect
idiosyncracy definition
rare / unpredictable reaction from a drug administration, unrelated to dose or normal mechanism
- e.g. child takes Benadryl = excitation response (from underdeveloped neurological system)
Proteins have 4 major levels of structure: Primary:
determined by the sequence of amino acids
Proteins have 4 major levels of structure: Secondary:
Determined by interaction of negative and positively charged atoms (alpha helix, beta pleated sheet)
Proteins have 4 major levels of structure: Tertiary
Determined by ionic and covalent bods, gives 3D structure
Proteins have 4 major levels of structure: Quaternary:
Determined by binding of two or more independent proteins
Binding site on receptor is affected by (in order strongest to weakest)
(Stronger) Covalent > Ionic > hydrogen > VanderWaals forces (weaker)
binding is rarely caused by just one interaction
Covalent
Shares electrons - often not reversible
Phosphorylation
Turns protein on or off - Very important in many receptor systems
Pharmacodynamics
What the Drug Does to the body - study of the intrinsic sensitivity or responsiveness of receptors to a drug and the mechanisms by which these effects occur
Pharmacokinetics
What the body does to a drug (ADME)
ADME
Absorption, distribution, metabolism, excretion
Pharmacodynamics important factors:
hydrophilic / hydrophobic
Ionization state (pKa)
Conformation and stereochemistry
Ion channel binding, spanning the plasma membrane have what gates?
Ligand gated (hypnosis, benzos, muscle relaxants, ketamine)
Voltage gated (local anesthetics)
Heptahelical receptors:
Spain the plasma membrane coupled to intracellular G proteins (2nd messenger, GPCRs) - most common in humans
Binding to extracellular side of transmembrane receptor acts on intracellular enzyme (receptor linked enzymes) eg =
GH, Insulin, PDE
These drugs diffuse through the plasma membrane
lipophilic drugs
Extracellular enzymes:
target is outside the plasma membrane
Nicotinic Acetylcholine receptor is comprised of these 5 subunits
2 x Alpha (when both alpha subunits are bound the channel opens)
Beta
Gamma
Delta
What is bound to the alpha subunit when it is attached to the GPCR?
GDP (think docked)
When a signaling molecule joins with the GPCR, a conformational change occurs and _______ replaces _______ on the alpha subunit. As a result the subunits (alpha, beta, gamma) dissociate into two parts.
GTP replaces GDP (GTP think Transformational change, transfer, or transport)
2nd messengers include:
Calcium, cAMP, cGMP, inositol
GPCR alpha subunits possess intrinsic:
GTPase activity (hydrolyzes GTP to GDP) causing re-association of the alpha subunit with the Beta Gamma complex
***What is - Potentiation?
Medication is enhanced by another that has no activity
***Potentiation examples:
Epinephrine with Local Anesthetic (LA): vasoconstrictor keeps LA there longer but doesn’t itself give you anesthesia
Agonist
Binds to and changes function of the receptor
Antagonist
Binds to receptor without changing function - prevents agonist from binding/stimulating
(Antagonist) Competitive:
increasing concentrations of antagonist progressively inhibit the response of an agonist - high doses prevent response completely
(Antagonist) Non-Competitive
agonist cannot act on the receptor even in high doses
Inverse Agonist
a ligand binds to a receptor activating an inverse response (“turn off” receptor activity)
Partial agonist
a ligand binds to a receptor resulting in a partial activating and partial inactivating response - never have full effect of an agonist
Partial agonist - if they have antagonist activity they are referred to as:
agonist- antagonists
eg. butorphanol
Affinity
degree of attraction
Efficacy
ability to produce the desired effect under ideal conditions
ED50
effective dose in 50% of the population
ED95
effective dose in 95% of the population
LD50
Lethal dose in 50% of the population
LD95
Lethal dose in 95% of the population
Therapeutic index:
Margin of safety between therapeutic and toxic/lethal
The larger the Therapeutic index:
generally the safer the drug (further distance between effective dose and lethal dose)
Generally a drug has a good safety profile if its Therapeutic index is greater than:
10
Sensitivity
can up-regulate or down-regulate in number in response to specific stimuli
Selectivity
the affinity of a drug for a specific receptor
Specificity
Stimulation of the receptor by an agonist ALWAYS yields the same specific response
Stereochemistry
chirality/Enantiomers (the pair): based on a center with three dimensional asymmetry, mirror images that cannot be superposed on each other
- chemically identical pair of molecules existing in two mirror image forms of each other
- dissolved in solution, described by rotation in polarized light (optical isomerism)
- right and left handed but cannot be superimposed
- Dextro (+) right
- Levo (-) left (in general, left rotated molecules have lower potency)
- Racemic - equal parts right and left
Racemic
equal parts right and left
(Stereochemistry) Dextro
Right
(Stereochemistry) Levo
Left
(Stereochemistry) Sinsiter
Left (depending on geometry of the molecule)
(Stereochemistry) Rectus
Right (depending on geometry of the molecule)
(Stereochemistry) Cis, trans
same chemical formula but vary based on where the side groups (functional groups) are located) (cis- same side, trans opposite sides)
(Stereochemistry) Racemic examples:
STP methohexital, ketamine, epi
(Stereochemistry) Levo examples:
1-morphone, 1-bupivacaine
(Stereochemistry) dextro example:
dexmedetomidine
(Stereochemistry) Sinsister isomeer example:
Ropivacaine
Physiochemical properties that affect absorption:
- Structure and size of molecule
- Temperature
- Solubility
- Protein binding
- Ionization affects solubility = most drugs are weak acids or bases
Acids and neutrals bind to
Albumin
Bases bind to
Alpha 1 glycoprotein
pKa =
pH at which 50% of drug is ionized and 50% is unionized
(Absorption) PO:
First-pass effect - hepatic- extensive metabolism - large difference between PO and IV doses
(Absorption) IM, SQ:
dependent on local blood flow
(Absorption) Sublingual/Buccal:
Bypass liver, no first pass.
(***rapid onset)
(Absorption) IV:
***PREDICTABLE plasma concentrations (often defined as having 100% bioavailability)
(Absorption) IV: First-pass pulmonary effect effects what drugs?
***Lidocaine, Propanolol, Fentanyl
What is the First-pass pulmonary effect?
***as much as 75% of a dose of fentanyl is absorbed by pneumocytes (will release later) lungs subsequently serve as reservoir to release drug back into systemic circulation.
Transdermal medication requirements:
- Low molecular weight (<500 Da)
- Affinity for both lipophilic and hydrophilic phases (lipophilic to cross membranes, hydrophilic to get into blood)
- Low melting point (affects the release of drug) so it melts with heat of skin
- non-ionized
- High potency
***What is the rate limiting step for transdermal medications
*** SKIN
IV medication phases
- rapid distribution (central compartment)
- slow distribution (peripheral compartment)
- terminal phase (elimination phase)
Central compartment
Kidneys, Liver, Lungs, Heart, Brain (receives 75% of CO, only represents 10% of the body’s mass)
Peripheral compartment
large calculated volume, extensive uptake of drug - fat, cartilage, muscle
Volume of distribution equation
Vd = dose/CP
Vd = volume of distribution
CP = plasma concentration
Vessel-rich group
Body mass
CO
Perfusion (mL/100g/min)
Body mass - 10%
CO - 75%
Perfusion (mL/100g/min) - 75
Muscle group
Body mass
CO
Perfusion (mL/100g/min)
Body mass - 50%
CO - 19%
Perfusion (mL/100g/min) - 3
Fat group
Body mass
CO
Perfusion (mL/100g/min)
Body mass - 20%
CO - 6%
Perfusion (mL/100g/min) - 3
Vessel-poor group
Body mass
CO
Perfusion (mL/100g/min)
Body mass - 20%
CO - 1%
Perfusion (mL/100g/min) - 0
Steady state is achieved after how many half-lives have occurred
4 to 5 half-lives
Steady state is achieved when:
drug input = drug output (this means the drug is in all compartments, and the plasma has a steady amount
Factors affecting steady state:
- Bioavailability
- clearance
- dose
- dosing interval or frequency of administration
Bioavailability definition
Amount or concentration (Cp) of a drug that actually reaches the site of action (receptor) or a fluid or tissue reservoir with access to the receptor, regardless of route of administration
For IV meds bioavailability =
1 (since it is injected directly into the bloodstream
Drugs can be changed in these 4 ways
- active to inactive
- active to active or reactive (toxic metabolite)
- inactive prodrug to active drug
- unexcretable to excretable
Phase 1 reactions (CYP450)
Hydrolysis (usually drugs w/ester bond)
Oxidation (electron loss)
Reduction (electron gain)
Phase 2 reactions (conjugation reactions)
coupling of drug with endogenous substrate such as glucuronate, acetate, or amino acid so drug can be ionized and thus excreted)
Example of Phase 2 enzymes:
Glutathione-S-transferase and
N-acetyl-transferase
All conjugation reactions except for conjugation of glucuronic acid are catalyzed by:
Non-CYP450 enzymes
eg. esterases in liver, plasma, GI tract
Glucuronidation metabolizes what drugs:
Propofol, opioids, midazolam
What is Glucuronidation
A metabolic pathway that uses glucose to conjugate and metabolize compounds into glucuronides
Glucuronidation is catalyzed by:
UDP-glucuronosyltransferases (UGTs)
UDP-glucuronosyltransferases (UGTs) are found where?
found in many cells, tissues, and organs, but are especially concentrated in the liver, kidneys, and intestines
Conjugation of glucuronic acid (glucuronidation) DOES involve:
CYP450 enzymes
CYP2C8:
allows potential drug binding to glucuronides, which then allows the drug to become ionized and excreted
CYP450 are found:
in most body tissues, concentrated in liver, intestines, and kidneys
Majority if anesthesia related CYP activity is generated by:
CYP3A4, CYP2E1 and CYP2D6
CYP3A4
metabolizes majority of all drugs
CYP2D6 and CYP2E1
second most important to anesthesia
CYP2D6
responsible for Phase 1 reaction in 25% of drugs - analgesics, antidysrhythmics, amide LAs, ketamine, propofol, antiemetics, beta-blockers
CYP2E1
Metabolizes inhaled anesthetics
Hepatic extraction ratio of 0
no drug elimination during single pass through the liver
Hepatic extraction ration of 1
all drug is eliminated during a single pass thought the liver
Drugs with a HIGH hepatic extraction ratio =
more sensitive to a reduction in hepatic blood flow
Drugs with a LOW hepatic extraction ratio =
more sensitive to a decline in hepatocellular function (i.e. enzymatic activity)
Drugs with HIGH Hepatic extraction ratio examples:
Propanolol, morphine, ketamine, propofol
Drugs with LOW hepatic extraction ratio examples:
Benzos, methadone, naproxen, alfentanyl, warfarin, rocuronium
Half life is estimated by knowing you need ___ to ___ half times to mostly eliminate the medication
4 to 5 halftimes to mostly eliminate the medication
First order Metabolism:
Constant fraction, certain % is metabolized (most drugs) (curved line)
Zero Order Metabolism:
Contant amount (strait line)
example: alcohol
First order metabolism can be turned into zero order how?
by overwhelming the receptors
(increase) Lipid Solubility
(increase) Ionization
(increase) Protein Binding
**(increase) Lipid Solubility -
(increase) Potency
**(increase) Ionization -
(decrease) Onset
***(increase) Protein Binding - (increase) Duration
