Foundations

of Pharmacology Notes

https://www.youtube.com/watch?v=aIRCp38AypI
https://www.youtube.com/watch?v=8-Qtd6RhfVA&index=1&list=PLzl4lgX_3RvdGiqSs3hmmUdWEAqL3dEY7

Pharmacokinetics- what the body does to the drug
Pharmacodynamics- what the drug does to the body


Pharmacokinetics
1. Absorption
2. Distribution
3. Metabolism
4. Elimination



Absorption
o Enteral = GI (oral)
o Parenteral = bypassing the GI system (IV, IM)
o Transdermal = patch on skin (slowly absorbed through the skin- time released)
o Respiratory droplet- inhaler, nebulizer
o For examples below, the dose of the drug given is identical for each route
o Oral Administration- Move through the entire system (takes quite some time so you see a slow rise in blood
concentration and a slow fall)
o Cmax is quite low and the Tmax is quite
large
o IV Administration
o Cmax is larger and Tmax is smaller
§ Inhalation Administration
o Much larger Cmax and an even small Tmax
than IV administration

o Area under the curve is the same for all 3 routes
of administration because the amount of exposure
to the drug (dose) is the same for all three
examples
o Why are some drugs excreted at different rates? 1st order kinetics- Rate of excretion is proportional to the
current concentration of the drug
o Half-life of the drug is the same regardless of route of administration because half-life is a property of the drug;
not a property of the route of administration
o It will take the same amount of time for the drug to reach ½ Cmax orally as it would to reach ½ Cmax intravenously
because the Cmax is different for each route of administration and the rate of excretion is proportional to the
current concentration of the drug
o Clinical Significance
o If you need pain relief quickly then an IV analgesic will get into the system much quick than an oral one
o A drug which has side effects at high concentrations may be toxic if given intravenously, but the same dose
might be safe if given orally










Distribution

o Vd= Volume of distribution- ratio of amount of drug administered to the amount of drug in the plasma
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o 𝑉" =
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o Factors affects volume of distribution
§ Blood flow to tissues (more blood flow= the more able you are to distribute)
§ Lipid solubility- lipid soluble drugs get stored in adipose tissues
§ Molecular size of drug-
§ *Plasma proteins- drug that is protein bound is inactive (only free drugs are active)
• If you have liver disease then you are unable to synthesize albumin so you have a lot of
albumin floating in blood stream which will bind onto some drugs causing them to be
inactive (so you will need a lot of drug to be given to get desired effect)
• If you have liver disease and you cant produce very much albumin then it wont bind
much drug so you don’t need to give much drug because all the drug that you give will
be in the free form (active drug)
o Bioavailability- % of drug that makes it into the system that can actually be used and is available for our biologic
processes
o Two factors accounting for bioavailability
§ Absorption- if you give 100 units and you only absorb 50 units then you have 50%
§ Extraction- of the amount absorbed, how much can actually be used by the body
• If the extraction is 50% of the above 50% then ultimately bioavailability is 25%
o Parenteral dosing via IV route- bypasses absorption and extraction phases (100% bioavailability)
o Loading Dose- give high dose of drug so we can reach peak concentration of drug as quickly as possible
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o
=.'%>%.6%/.6.*0
o If you have kidney disease, the loading dose will stay the same
o Maintenance Dose- want to maintain drug at specific value so you give drug at the same rate of elimination
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o
=.'%>%.6%/.6.*0
o If you have kidney disease (end stage renal disease) your clearance capacity is going to ↓ drastically so
more of that drug will stay in your system
§ So if you have kidney disease you need to change your maintenance dose because you don’t
need to give as much of the drug to maintain it around your peak/target concentration
o When a drug is placed into a compartment, it is often assoc. with binding molecules (often proteins such as
albumin)
o This process sequesters the drug within the compartment- increasing the compartment’s storage
capacity
o Unbound drug is free to move to another compartment so equilibrium is maintained between adjacent
compartments
o When a drug moves into a new compartment, some of that drug is sequestered by binding molecules
within that compartment
o This process continues until there is a balance between each compartment and a balance between the
amount of free drug and bound drug within each compartment
§ Equilibrium constant is dependent on:
• Permeability of barriers between compartments
• pH within the compartments
• Binding capacity within the compartment
• Fat-solubility of the drug (especially important for those moving into the fat
compartment)









Metabolism- transformation phase

o Taking Drug X à active metabolitesàinactive metabolites
o Phase 1 reactions- oxidation, reduction, and hydroxylation (CYP 450 System in the liver)
§ Goal: make polar, water-soluble molecules (active metabolites)
o Phase 2 reactions- glucuronidation, acetylation, sulfation (converting active metabolites to inactive
metabolites) which will then be excreted
o “First pass effect”- liver encounters drug before it enters the system (oral enteral administration)
o Drug gets absorbed in the intestines àportal circulation (connects intestines to liver)àhepatic portal
vein (where metabolism takes place)àcentral veinàhepatic veinàdrains into inferior vena cava
àheart (Systemic circulation)
o Bioavailability will be decreased

Elimination

o Two routes: kidney (urine) or GI system (bile/feces excreted)
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o 𝐶𝑙𝑒𝑎𝑟𝑎𝑛𝑐𝑒 =
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o If you increase the plasma concentration, you are going to decrease the clearance of the drug
o Half-life (T1/2) = time it takes to eliminate 50% of the current concentration of drug from the body
H.JKL × ;<
o Half-life =
963%,%)73
o An increased half-life time indicates it takes a long time to clear the drug
o It will take approximately 5 half-lives to get rid of the drug entirely
o First-order elimination kinetics
o Dependent on drug concentration**
§ The more drug you have in your system the quicker it will be eliminated
§ The smaller amount of drug you have in your system, the slower it will be eliminated
• Once you are down to the left overs- it takes more time to get rid of the drug
o Drugs- all other drugs besides ones that are zero-order elimination kinetics




[Drug]

Time
o Zero-order elimination kinetics
o Constant rate- getting rid of the drug at a constant, certain rate no matter concentration of drug in the
system
o 100 units; and getting rid of a drug at 10 units/min so you could get rid of 100% of drug in 10 min
o Drugs that undergo this: *Phenytoin, *salicylates, *ETOH (alcohol), theophylline



[Drug]

Time
o Accumulation
o If you are getting rid of the drug at a constant rate, but you are on a maintenance dose that exceeds this
constant rate
§ Ex: if you are eliminating the drug at 10 units/min but you are dosing it at 100 units/min you
will have an exponential accumulation curve


o If we give a person a drug at time zero, we will see the concentration of the drug go up to a maximal efficacy point
and then it will fall slowly as the drug is removed from the body
o Cmax- highest concentration of drug in the body- good for predicting the therapeutic benefit and also the
likelihood of side effects
o Tmax- time which Cmax occurs
o Half-life- time it takes to remove 50% of the current drug concentration from the body
o Area under the curve=represents total exposure to a drug that the body receives
§ Function of how high the drug concentration gets as well as how quickly it is excrete

[Drug]

Cmax


½ Cmax

Time
Tmax T1/2


More drug More drug
in than out out than in

• Distribution- https://www.youtube.com/watch?v=kLvYCOSnPDc&feature=related
o Begins when drug molecules enter the blood through the liver where they have been metabolized
§ Transported to target sites and to tissues where they will exert no action (storage sites, sites of
inactivation, sites of excretion
§ Travel in blood and go through endothelial cellsàinterstitial fluidàtissues
§ Entry rate of blood into tissue depends on:
• Rate of blood flow to the tissue
• Tissue mass
• Rate at which entry and exit of the drug molecules between blood and tissue
equilibrates
o Distribution may be uneven when there are differences in:
§ blood perfusion
§ tissue binding of the drug molecule
§ regional pH
§ permeability of specific cell membranes

• Absorption- https://www.youtube.com/watch?v=xiuWdJYyIKs&p=31C5C377745469C5
o Refers to the transport of drugs across the membranes of mucosal cells in the GI tract
o A drug enters the GI tract through the mouth and moves into stomach through the esophagus
o Once in the stomach the drug dissolves
§ Acidic drugs are absorbed in the stomach because of its acidic contents cause the acidic drugs to
remain unionized (uncharged) which can be easily absorbed
§ Alkaline drugs which cannot be absorbed in the acidic stomach, pass through the pyloric
sphincter to the first part of the small intestine and are absorbed there
o Once dissolved in the blood, drug molecules travel to the liver via the portal system
§ Some drugs are immediately metabolized in the liver (first pass)
§ Others may be secreted back into small intestine and bile (enterohepatic cycling)
§ Other parts of oral dosage may be absorbed in the large intestine or fecally excreted
o All of the drug molecule may not be absorbed
§ Drug molecules may bind with intestinal contents which prevents the passage through the
membranes of mucosal cells
§ Or they may be broken down by bacteria in the ileum and colon




• Drug Binding- https://www.youtube.com/watch?v=07Tr__R_koE&feature=related
o Most drugs act on cellular level by chemically binding to receptors on cell membranes or inside cells
o Cell membrane contains receptors for many types of cells such as hormones and neurotransmitters
o As a drug binds to its receptors, reactions are initiated that stimulate or inhibit regular cellular function
§ One type of reaction actives, deactivates, or otherwise alters intracellular enzymes
• Almost all cellular functions are catalyzed by enzymes
• Drug interactions can greatly increase or decrease the rate of cellular metabolism
§ Another type of reaction involves changes in cell membrane permeability
• A drug molecule binds to an ion channel receptor to open or close ion channels to allow
or prohibit the movement of ions into the cell
o In nerve cells, for example, movement of Na ions into the cell usually excites the
cell while movement of K out of nerve cell inhibits nerve cell excitability and
function

• Excretion- https://www.youtube.com/watch?v=4X8pAizadWI&feature=related
o Excretion occurs through the bowels, skin, lungs, and most often the kidneys (eliminated in the urine)
§ Renal excretion of drugs and metabolites involve 3 processes:
• Glomerular filtration (primary)- drug molecules filtered through glomerulus and then
filtrate (substance that has been filtered) move into proximal tubule
• Passive tubular reabsorption may occur in proximal tubule as filtrate moves through
• Active secretion of drugs or its metabolites in proximal tubule
o Compounds that are secreted also usually undergo glomerular filtration
§ Renal excretion is then a combo of passive filtration and active excretion