Pharmacology Principles Flashcards
What are the determinants of drug deposition in the body?
Absorption (enteral/paraenteral)
Distribution: How it enters the blood and perfuses tissue
Metabolism: tissue enzymes catalyse the usually lipid soluble drug to a polar and less active form that is rapidly excreted.
Excretion: remove drug or metabolites from body (usually renal(
What PHYSIOCHEMICAL factors influence absorption of drug?
- Degree ionization (influences lipid solubility dec. abs.)
- Chemically unstable (therefore easily destroyed by HCL for example, dec. abs.)
- Lipid to water partition coefficient
What factors influence the movement of drug between fluid compartments?
- ionised and unionised drugs that are not bound to protein can diffuse freely
- Only unionised drugs move READILY by diffusion
What does lipid to water partition coefficient mean?
Rate of diffusion across membrane for given concentration of drug on either side of membrane.
The higher the coeffcient the greater the rate of diffusion.
TRUE/FALSE
Only unionised forms readily diffuse across the lipid bilayer
True
What two factors does degree of ionization depend upon?
pKa of drug
Local pH
What is pKa
pH at which 50% of drug is ionised and 50% unionised
What is the Henderson Hasselbach equation?
pH=pKa + log(A-/AH)
A- = conjugate base
AH= weak acid
rearranged to pKa = pH+ log(AH/A-)
What does the Henderson Hasselbach equation do?
Calculates proportions of ionised and unionised drugs.
Can work out the pH or rearrange and work out percentage of total drugs ionized i.e. conjugate base/ total amount drug
A-/A-+AH
How does the local pH affect drug absorption?
Acidic drugs less ionized in acidic environment and basic drugs less ionized in BASIC environments.
Less ionized = more readily lipid soluble
What is considered a strong acid? (pKa)
pKa<3
What is considered a strong base? (pKa)
pKa>10
What factors affect GI absoprtion?
Motility
pH
Blood flow to stomach/intstine
Manufacture of tablet/capsule - release rate
Transporters - if present in epithelial cells can facilitate absorption
What is oral availability?
amount drug in systemic circulation/ amount drug administered
What is systemic availability?
amount of drug in systemic circulation/ amount absorbed (enteral/paraenteral
TRUE/FALSE
drugs administered intravenously (IV) have 99% systemic availability
false
HAVE 100%
What is first pass or presystemic metabolism?
When drugs absorbed orally are inactivate by enzymes in gut wall or liver before reaching circulation
What are the major fluid compartments in the body?
PIFIT Plasma Interstital fluid Fat Intracellular fluid Transcellular fluid
What is Vd?
The APPARENT volume of distribution
amount of drug in tissue/plasma concentration
What does Vd<10L indicate?
Drug largely retained in vascular compartments - drugs bound to protein unable to diffuse across cap wall
What does 10-30L indicate?
Drug is largely restricted to extracellular water - drugs with low lipid solubility
What does Vd>30L
may indictae distribution through total body water
or accumulation in in certain tissue
or drug bound extensively to tissue protein
What is meant by MEC?
Minimum effective concentration: minimum dose to elicit effect
What is meant by MTC?
Maximum tolerated concentration: minimum amount that results in unwanted side effects
What is meant by therapeutic window?
Window between MEC and MTC.
Small = risky
Large = good
What is first order elimination?
Rate of elimination of drug directly related to drug concentration
What is t 1/2
T1/2 is the half life. TIme it takes for conc at any given time to fall by 50%
What is Cl?
Clearance is the volume of plasma cleared of drug in a given unit of time!
How can you work out rate if elimination?
Clearance x Plasma concentration (Cp)
What is steady state?
Rate of administration= rate of elimination (Cpss)
How can you work out Cpss?
maintenance dose rate/ clearance
With regards to drug dosing to steady state - what is the difference between oral and IV dosage?
Same principle, but in oral administration the plasma volume fluctuates around an AVERAGE with each dose.
Iv is hyperbolic.
What is a loading dose?
Higher dose of drug given at the start of treatment before stepping down to lower maintenance dose (to get to steady state.)
Why is a loading dose used?
Decrease time taken for drugs with long half-lives to reach steady state.
What is the relationship between loading dose and volume of distribution? ORAL
Oral admin: Ld=Vdx target concentration of drug in plasma
What is the relationship between loading dose and volume of distribution? IV!!!!
Ld= (Vdx target concentration of drug in plasma)/ systemic availability
What are zero order kinetics?
Initally eliminated at a constant rate (unaffected by concentration)
How do most drugs leave the body?
Via urine, usually as highly charged or polar compounds and LESS pharmacologically active.
Why does drug metabolism convert parent drugs to polar metabolites?
Prevents them from being reabsorbed by kidneys (non-polar lipid soluble), facilitates excretion.
What are some UNUSUAL pathways for metabolized drugs?
Go from inactive to ACTIVE to satisfy purpose (codeine to morphine)
No change in activity
Metabolite may have a DIFFERENT spectrum of action
What is the USUAL pathway for drug metabolism? PHASE 1
CATABOLIC PROCESS
Drugs become polar due to addition of chemically reactive group. This is done via oxidation, reduction or hydrolysis.
What is the USUAL pathway for drug metabolism? PHASE 2
ANABOLIC PROCESS
Addition of endogenous compound to increase polarity and prime for excretion.
What is the cytochrome P450 family of monooxygenases (CYP)?
Enzymes that mediate a lot of phase 1 oxidation reactions of drugs
What are the products of the c. monooxygenase pd450 (CYP) cycle?
Two products:
H20
hydroxyl product (hydroxylated parent drug)
What are some common Phase 2 reactions?
Addition of more stuff to chemically reactive group on drug (following phase 1)
i.e. adding stuff to hydroxyl group
What is glucuronidation?
Phase 2 reaction involving transfer of GLUCURONIC ACID to electron rich atoms of the substrate
TRUE/FALSE
Many endogenous substances are subject to glucuronidation (e.g. bilirubin, adrenal corticosteroids)
True
Which part of the systemic circulation does the glomerular capsule associate with?
The interlobular artery/arteriole
Which part of the systemic circulation does the TUBULE associate with?
The peritubular capillary network
Under what conditions does glomerular filtration occur?
- drugs with a MW less than 20 000 (most)
- drugs NOT bound to large plasma proteins
- drug charge is unimportant
TRUE/FALSE
if a drug binds appreciably plasma protein, its concentration in the glomerular filtrate will be MORE than total plasma concentration
FALSE it will be less as proteins cannot pass into glomerulus
TRUE/FALSE
Up to 80% of renal plasma flow filtered through the glomerulus, but remaining 20% delivered to the peritubular capillaries
FALSE
most plasma will flow through the peritubular capillaries
Epithelial cells of the —– contain —–, independent, transporter systems that —— secrete drugs into the lumen of the nephron
proximal tubule, two, actively
Which transporter system in the proximal tubule secretes ACIDIC drugs?
OAT
Organic anion transporter
Which transporter system in the proximal tubule secretes BASIC drugs?
OCT
Organic cation transporter
TRUE/FALSE
Proximal tubular secretion of drugs is a SATURABLE process
True
each carrier has Tm transport maximum for particular drug
TRUE/FALSE
Proximal tubular secretion CANNOT secrete drugs that are highly protein bound
False, it can :D
What is the effect of proximal tubular secretion (of drugs) on the concentration of FREE DRUGS?
Free drug concentration reduced because:
- secretion establishes a NEW equilbrium between bound and unbound drug
- causes drugs to dissociate from proteins
Factors that increase reabsorption in the kidney
High lipid solubility
Increased production of urine (diuresis)
Unpolar drugs - highly polar drugs excreted without reabsorption
What is the effect of urinary pH on reabsorption in the kidneys?
Alkaline pH increases excretion of ACIDS
Acidic pH increases excretion of BASES
(opposite makes more polar!)
?What is depolarization
Membrane potential becomes LESS negative
What is hyperpolarization?
Membrane potential becomes MORE negative
TRUE/FALSE
Na+ flows inwardly
True,
electrochemical gradient more Na+ on outside
Why does K+ generate an outward current?
Lower conc outside cell - electrochemica gradient
K+ channel opening?
effluc K+ and hyperpolarization
Na+ channel opening ?
influx
Na+ depolarization
TRUE/FALSE
Action potentials are all-or-none
True, generated when threshold is reached
Activation of K+ channels is due to which type of feedback?
Negative. Self limiting, outward movement causes repolarization which turns off stimulus for ppening
Activation of Na+ channels is due to which type of feedback?
Positive, some open then more open. Self-reinforcing.
Phases of Na+ channel inactivation?
Maintained depolarization enter inactive state. This is a refractory period!
Needs repolarization to CLOSE.
Depolarization causes it to OPEN.
TRUE/FALSE
Absolute refractory period is when Na+ channel is CLOSED following repolarization
FALSE, this describes relative refractory period
TRUE/FALSE
Relative refractory period describes the inactivation of Na+ channels during maintained depolarization
FALSE, this describes absolute refractory period. No stimuli can open this at this time.
Features of un-myelinated axons?
Passive spread of current
“leaky” axon
Current does not spread far from site of origin as some of the current goes outside the cell.
How to increase passive current spread?
Increase membrane resistance (rm) this is done by adding insulating material such as myelin and oligodenrocytes
What is the node of Ranvier?
Gaps between areas of axon wrapped in myelin sheath. AP jumps from one NoR to another.
