Drug Disposition Flashcards
Module 2
ADME:
Absorption
Distribution
Metabolism
Excretion
Entral:
Absorption through the GI tract
- Oral
- Rectal
Parenteral:
All other routes; injections, sublingual, inhalation, topical
The rate of diffusion is dependant on:
Surface area of membrane
Concentration gradient
Partition coefficient
Diffusion coefficient
Thickness of membrane
Rate of diffusion = (D.R.A.DC) / Dx
(D.R.A.DC) / Dx
Surface area of membrane (A)
Concentration gradient (DC)
Partition coefficient (R)
Diffusion coefficient (D)
Thickness of membrane (Dx)
Bulk flow:
In the bloodstream, lymphatics, or CSF
Diffusion:
Molecule-by-molecule, over a short distance
Chemical nature impacts diffusion. T/F
False. Makes no difference
There are four main ways by which small molecules cross cell membranes:
- Diffusing directly through the lipid
- Combining with a solute carrier (SLC) or other membrane transporter
- Diffusing through aqueous pores formed by special proteins (aquaporins) that traverse the lipid
- Pinocytosis.
Non-polar molecules dissolve freely through lipids, through to the cell membrane. T/F
True
Many acids are weak acids/bases, and exist ____
In both ionised and unionised states
Ionised compounds:
Cannot cross cell membrane
Unionised compounds:
Can cross cell membrane
Body compartments ____ reach equillibrium
Rarely
To pass endothelial barriers:
Molecules must transverse >2 cells to pass from one-side-to-another
Gaps within endothelial cells are packaged with ____
Filter proteins
Vascular endothelium separates:
Intra-vascular form extra-vascular
An unbound drug is pharmacologically active. T/F
True
The amount of drug that is bound to a protein depends on:
- Conc. of free drug
- Affinity for binding site
- Conc. of protein
If a drug is absorbed within 30 minutes, it will have a ____ plasma concentration as oppose to being absorbed over several hours
Higher
Strong bases are poorly absorbed. T/F
True
Aspirin, a weak acid, is un-ionised at a low pH –> predominant absorption at the stomach; but why does it get absorbed within the small intestine?
The stomach lacks microvilli and its comparatively small to the small intestine.
A larger surface area and microvilli makes the small intestine a more convenient site of absorption
At peak plasma level:
The rate of absorption is equal to rate of metabolism and excretion
Oral administration of drugs is convenient because…
However….
75% is absorbed within the first 1 - 3hrs
Some drugs are not well absorbed, and may irritate gastric lining
Rectal administration avoids…
First-pass metabolism
A disadvantage of i.v. administration is…
Some drugs are toxic in high quantities. Once you inject a drug, you cant get it out of the bloodstream
Drugs administered via i.v. are digested within the GIT. T/F
False. I.v. is parentral
The optimal administration for emergencies is via:
i.v.
Sub-cutaneous injections extends…
Time of pharmacological effect
S.c. administration must be administered with…
Oily solutions
Drugs administered via s.c. are vasoconstrictors only. T/F
True
Intramuscular injection increases…
Perfusion to the muscles
Hormone injections are administered through:
i.m.
The epidural for childbirth is administered via:
Intrathecal (i.t.)
Inhaling of drugs is effective due to the…
Thin diffusion barrier
Sublingual absorption is useful because….
The tongue is highly vascularised
Topical injections penetrate the skin rapidly. T/F
True
Topical injections require ____ doses
Lower
Following oral administration, the expected major pathway of absorption would be….
The small intestine
Passive re-absorption primarily occurs at the:
Distal tubule
Strong acids and strong bases are absorbed well. T/F
False.
Strong acids and strong bases are poorly absorbed
Once within the plasma, a drug travels…
- Plasma
- Bulk-flow
- Lymph
___BBB___ - CSF
Atropine and opiates reduce GI absorption because they…
Inhibit gastric emptying
Plasma concentration is directly proportional to the drive across components. T/F
True
Equilibrium =
K1 * cPlasma = K2 *cTtissue
Values of K1 and K2 are determined by…
- Blood flow
- Tissue volume
- Lipophilicity
- Ionisation
- Plasma + Tissue barriers
____ drugs are available to diffuse through peripheral tissue
Unbound
Drug binding is a saturable process, such that…
The fraction of unbound-drug in the plasma can change with concentration
Because drugs compete for plasma binding….
One drug can displace a second –> Incr. free concentration
Protein binding acts as a drug reservoir, and gives…
Incr. Half-life
Incr. Protein binding
Elderly people may require a lower dosage of medication because…
They produce less plasma proteins –> less absorption
Protein binding is inversely proportional to the distribution into the tissues. T/F
True. Diazepam has a 99% affinity for protein binding, and very poor tissue distribution
Ethanol is…
Always unionised
Polar
Lipophillic
Gives a large area for distribution
Ion trapping is described by…
Acidic drugs accumulating in a basic environment
Basic drugs accumulate in an acidic environment
Drugs partitioning into adipose tissue gives…
- Non-polar environment
- Accumulation of lipophillic drugs
- Reservoir for slow release
Drugs crossing the BBB must be…
- Small
- Lipophillic
- Substrate for specific transporters
Most drugs leaving the body must be…
- Uncharged
- Polar
Phase l enzymatic reactions:
Catabolic
Incr. chemical reactivity
–> May also incr. toxicity
Phase ll enzymatic reactions:
Anabolic Add water-soluble moiety to a drug: - Glucuronyl - Sulfate - Acetyl - Methyl
P450 uses…
Fe3+ at active site
- mostly in ER
P450 enzymes are essential for…
Metabolism of drugs
P450 enzymes can be induced or inhibited by drugs. T/F
True
P450 enzymes are…
Bound to membranes within a cell (cyto) and
Contain a heme pigment (chrome and P) that absorbs light at a wavelength of 450 nm when exposed to carbon monoxide
Inhibition is CYP enzymes occurs when…
2 drugs are metabolised by the same p450 enzyme
Phase ll reactions occur within the…
- Liver
- Lungs
- Kidneys
Bioavaliability =
Fraction of drug that reaches systemic circulation
Organic cation transporters are involved in….
Passive reabsorbtion
Organic anion transporters are involved in
Active reabsorbtion
Drugs are filtered into the urine at the…
Bowmans capsule
Active secretion of drugs is at the…
Proximal tubule
Water is reabsorbed in the…
Loop of Henle
Passive reabsorbtion of drugs is at the…
Collecting duct
Distal tubule
Only unbound drugs are filtered at the glomerulus. T/F
True
Renal failure may prolong drug half-life. T/F
True
There is substantial absorption at a pH of 5 as oppose to…
pH of 8
If the drugs are excreted into the bile?
Drugs appearing in bile will enter the intestines and may be reabsorbed resulting in enterohepatic circulation
enterohepatic circulation
Reabsorbed across the intestinal mucosa and returned to the liver via portal circulation
HW eq:
1 = A2 + 2Aa + a2
Autosomal Dominant
One allele dominates such that the phenotype is the same in AA OR Aa individuals
Autosomal Recessive
The phenotype is only present if both alleles are present (must be homozygote; AA or aa).
X-Linked Recessive
Phenotype only occurs on the X-chromosome.
Autosomal Co-dominant
Phenotype is the average of each allele.
NAT2 is within the…
Liver and responsible for most drug acetylation
Within pharmacogenetics, inter-variability may result in…
- Lack of efficacy
- Unexpected harmful effects
It is common for drugs to have a prolonged effect within babies and the elderly. Why is this?
Drug elimination is less efficient at these ages.
Can morphine be used during pregnancy?
No. Morphine is not used as an analgesic in labour, because drug transferred
via the placenta has a long half-life in the newborn baby
and can cause prolonged respiratory depression.
Half-life determines the time course of drug accumulation
during repeated dosing. T/F
True
