Exam 1: Kinetics Flashcards
The scientific study of drugs and their effects on a living organism
Pharamcology
Neuropharmacology
concerned with drug-induced changes in cell functioning in NS
Psychopharmacology
emphasizes drug-induced changes in mood, thinking, and behavior
What is the goal of neuropsychopharamacology?
identify chemical substances that act on NS to alter behavior. Neurobiology of behavior
Drug ACTION
Specific molecular changes produced by a drug when it binds to particular target site/receptor
Drug EFFECTS
widespread alterations in physiological/psychological function caused by drug action
Drug-receptor interaction:
1) Favorable effects
2) other effects
1) therapeutic effects
2) side effects
Specific drug effects
those based on the physical and biochemical interactions of a drug with a target site in living tissue
Nonspecific drug effect
those based NOT on chemical DR but on unique characteristics of the individual
Opposite of placebo effect
Nocebo
Pharmacokinetics
Body –> Drug
1) Administration
2) Absorption
3) Distribution
4) Biotransfomration/Inactivation
5) Elimination
Pharmacodynamics
Drug –> Body
Binding and Action
Bioavailability
amount of drug in blood free to bind at specific target sites to elicit action
Depot binding
drug binds to plasma proteins (IM)
Absorption
movement of drug from site of administration to the blood circulation
Absorption = BLOOD CIRCULATION
Agnoist
acts like NT (dynamics)
Antagonist
blocks NT (dynamics)
Alimentary Canal
Mouth down
GI enteral tract (gut)
Stomach and intestines.
Eteral administration
Stomach/intestine
GI tract/alimentary canal
e.i. oral/rectal
Parenteral administartion
all non enteral routes
e.i. topical injection pulmonary
1st pass metbolism
portal vein –> liver, reduces drug bioavailability
Bioavailbility
[drug] in blood that can interact with targets, determined by kinetics
Drugs that effect thinking mood and behavior
Psychoactive drugs
Absorption depends on
administration route, absorbing surface, cell layers, drug destroyed by metabolism, solubility/ionization, etc.
Solubility of drugs and absorption
lipid soluble = passive diffusion across membrane
greater concentration gradient = rapid
Prodrugs (e.i. Heroin)
drug dependent on metabolism to convert inactive drug to active one (BIOACTIVATION)
Properties of drug that allow GI absorption
survive gastric enviornment, resist 1st pass, WS, LS
What contribute to gastric degradation of proteins, peptides and drugs
Chemical: HCl + Pepsin –> gastric juice
Mechanical: muscle contractions (Peristasis)
Hepatic 1st pass metabolism
Intestine –> portal vein –> liver –> hepatic vein –> circulation –> hepatic artery
Ionization depends on
pH and pKa
acidity/alkalinity of environment
pH
pKa
pH of aqueous solution in which drug would be 50% ionized, 50% unionized
Although acid favors stomach, why more in by small intestine?
absorption also determined by length of time in contact with absorptive membrane
Larger surface area/slower movement
What drugs can’t be GI tract?
highly charged drugs in both acid/basic environments
Absorption rating limiting factor
rate at which stomach empties into intestine
GI tract is ___ formed by ___
sealed tube formed by Epithelial cells
intracellular space ~4 A
cells tight against each other
hard for drug to leave
Lumen –> Capillaries
Simple columar
Ionized
no diffusion water shell
water soluble
Passive/Facilitated rate of diffusion depends on
concentration gradient
high = higher rate of diffusion
Passive - lipids, NP
Facilitated - fructose/vitamins
Active transport
need energy
[low]> [high]
e.i. glucose, mineral ions, amino acids
Unionized =
GI absorption and diffusion
Weak Acid + H+
Unionized (LS), absorption
Weak Base + H+
Ionized (WS), no absorption
Weak acids best absorbed at
Low pH
Weak bases best absorbed at
High pH
pH across GI tract
Gets higher (less H+)
Acid Ion Trapping
ionized after passing into area with higher pH and become trapped there (opposite of best absorption pH)
Base Ion Trapping
Base ionized and trapped in low pH area
_____ maintains higher [unionized molecules] in original compartment promoting faster absorption
ion trapping
____ of base allows GI absorption
deprotonization
Small intestine surface area is given by…
cylinder, folds, microvilli, villli
Capillaries with intestinal villi
LS drugs move through lymph vesicle to Lacteal
Small Intestine favored by both Weak acids/base becuase
surface area
less mucous
longer transit time
high pH for weak bases
Distribution
moving through blood vessels
Artery
Thick outer wall
small lumen
thick layer of muscles and elastic fibers
Heart –> Tissue
effects bp
Vein
think layer of muscle/elastic fibers
Large lumen
thin outer wall
Blood –> heart, no as muscular
Capillaries
very small lumen
wall is single layer
drug action
Does movement from CAPILLARIES/blood to tissue depend on solubility? Why?
No, unless bound to protein
Capillaries have a lot of pores
Drug redistribution
Drug moving from tissues with high vasculature (heart, brain, kidneys, liver) back to plasma to maintain equilibrium
Typically Capillary
Intracellular - small gaps
Fenestration- larger openings
Pinocytotic vesicles
Brain Capillary
tight junctions: endothelial cells fused
carrier-mediated transport
astrocytes/glia feet to maintain the barrier, maintain tight junctions.
BBB is ___ permeable
selectively permeable
lets in lipid soluble
WS by carrier protein
Enzymes made by endothelial/astrocytes can degrade chemicals passing by membrane
Bidirectional
Area postrema
chemical trigger zone BBB free induces vomiting allows WS works with oral ingestion located in medulla
WIDE SPACING BETWEEN ENDOTHELIAL CELLS
Capillaries have single layer of ___ cells
ENDOthelial
Capillary structure: continuous
intracellular spaces, basement membrane
Capillary structure; fenestraed
fenstrations, pores in body of cells
Capillary: Sinusoid
Huge gaps in some capillaries
Plasma Protein Binding (PPB)
reduces bioavailability/drug effect
induces side effects
extends time of drug in body.
PPB: drug interactions
free up more due to competition
PPB: liver dysfunction
increase bioavailability
pass 1st pass
reduces liver’s synthesis of proteins
Storage depot binding
binding of drug to inactive site
Bone, fat, enamel
decrease bio-available/drug effect
bad effects:
lead/bone
thiopental/fat
tetracycline/enamel
Functions of BBB
stable environment, prevents access of various chemicals, prevents access of many types of drugs
BBB structure mainly determined by
tight junctions between endothelial cells
BBB structure all parts
tight junctions
basement membrane- support
astrocytes release factors that anchor junctions
Astrocyte jobs
- synthesize proteins that support tight junctions between endothelial cells
- uptake/degrade molecules that evade BBB
Enzomatic barrier
glia cells degrade foreign stuff
Transcytotic transport where drug and rector in vesicle to go across BBB is used by
Insulin/transferrin
Biotransformation
Alteration in chemical structure of drug molecule by action of enzyme
Most common site: Liver
(also stomach, intestine, blood, kidney, brain)
sinusoid
irregularly shaped liver blood vessel
allows things to access hepatocytes, large gaps
Hepatocytes
Contain enzymes needed for drug biotransformation
Connected by tight gap junctions
Enzymes
proteins with binding sites
reuseable
decrease energy needed for reaction
can break down/add stuff to molecules
Phase 1
Nonsynthetic
Catabolic - tear things up
(oxidation, hydroxylation, dealkylation, deamination)
SUBTRACTIONS
Phase 2
synthetic
Anabolic- build things up
(-COOH, -OCCH3, -CH3, -C6H10O7, methyl, amine, carboxyl, glucuronic acid, sulfhydryl)
CONJUGATIONS
Cytochrome P450
phase 1
mixed function: oxidases
non-specific
inducible
inducible
make more enzyme or increase affinity of enzyme
Transferases
phase 12
transfer groups to drug molecule
specific
inducible
Do drugs have to go through both phase 1 and 2 or in that order?
no
Metabolism of Aspirin
Phase 1: hydrolysis CP450
Salicyclic Acid (active form)
P2: glucuronic acid transferase
Ether glucuronide
Ester glucuronide
_______ is the most common type of P2 conjugation, catalyzed by transferase enzyme: ____
glucuronidation
UDPGT
1/2 life
time for plasma [drug] decline by 50%
First Order (exponential)
constant % drug removed each interval
Looks like curve
most common type
Rate of metabolism higher at higher plasma concentration of drug
at very high [drug], metabolism becomes zero order
Zero Order
Constant AMOUNT of drug in blood removed each interval
Rare
e.i. aspirin, ethanol, phenytonin
Rate not effected by plasma [drug]
Genetic copies cyto450
0 (PM)/ 1 (IM): adverse response, overreaction
2(EM): good
3+ (UM): too many enzyme, don’t respond to medication
Factors affecting biotransformation
genetic variation age sex species illness drug history
What does excretion
kidney
Ureter
connects kidney to bladder
Nephron
1.5 million/kidney
functional unit of kidney with renal corpuscle/tubule
H2O leaves descending loop
Na+Cl- leaves ascending limb
Renal tubuae
in kidney
moves out, gets ride of stuff
GLomerulus
fist of capillaries in kidney
How do water/solutes enter kidney tubules?
Bowman’s capsule, surrounds glomerulus
_____ too large to enter kidney
blood cells/plasma proteins
Most drugs that are LS when in kidney are
reabsorbed by blood
Epithelial Cells:
GI tract vs. Renal Tube
GI: simple columner
Renal: simple cuboidal
Drug excretion: _______ are excreted in urine, _____ reabsorbed by blood.
Unionized (LS) reabsorbed
Ionized (WS) excreted urine
Acids excreted faster
high pH, ionized
Bases excreted faster
low pH, ionized
pH of kidney tubules
4-8 and varies
Factors affecting elimination by kidneys
acid/base
pKa
pH tubules
Anti-Diuretic Hormone (ADH)
Peptide synthesized by hypothalamus stored in posterior pituitary facilitates water re-absorption increases aquaporins at collecting tubules
Increases permeability of luminal membrane to H2O by inserting water channels
increases bp
regulates distal duct in nephron
Aldosterone (steroid hormone)
Synthesized/release by adrenal gland
acts on collecting tube
facilitates Na+ re-absorption
Diuretics that increase urine output: ethanol/caffine
Ethanol: inhibit ADH, more fluid out
Caffeine: increase glomerular blood flow rate
Steady State Plasma level determined by
Half-life
the desired blood [drug] achieved when absorption/distribution = metabolism/excretion phase.
microsomal enzymes
liver enzyme that metabolize psychoactive drugs
located on smooth ER
lack specificity, metabolize variety of things
ex: CYP450
Enzyme induction
repeated drug uses causes increase in liver enzyme
speeds up biotransformation of this drug and toerhs
Enzyme inhibition
repeated drug use causes decrease in liver enzymes, reduces metabolism of drugs metabolized by that enzyme
