ADME Flashcards
Explain Plasma Concentration vs. Time
- Non-IV route
- Onset, duration, peak plasma concentration
- Therapeutic range or window
- Narrow vs broad
-Drug level monitoring
trough - lowest concentration/more dose
peak - highest concentration/no dose
What is Pharmacokinetics
Effects of BODY on the DRUG
What is Pharmacodynamics
Effects of DRUG on the BODY
(include pharmacological effects)
- —-Therapeutic
- —-Toxic
What are the four processes of pharmacokinetics
- Absorption
- Distribution
- Metabolism
- Excretion
Can drugs overcome barriers?
Drugs overcome many barriers to reach site of action (Physical and chemical)
Explain how all 4 proceses of PK are involved in drug movement.
- Drugs must enter bloodstream
- It must leave the vascular system to reach sites of action
- Must cross membranes to undergo metabolism and excretion
What is the cell membrane structure
- Hydrophobic tail (lipid)
- Hydrophilic head (water loving)
Pass vs between cell membrane
Drugs must usually pass through the cell vs. between them
How do drugs cross the cell membrane
- Pores and Channels
- Transport systems
- Direct penetration of the membrane
Pores and Channels
- Small and specific
- Na+, K+ ions
- A lot more electrolyte related
what are transport systems and name an example
- Move drugs from one side of cell membrane to another side
* Example: P Glycoprotein
What are glycoproteins and where are they located
They transport drugs OUT of cell.
- Intestines
- Kidney
- Liver
- Placenta
- Brain
How can drugs directly penetrate through the cell membrane?
They must be lipophilic
What happens if drugs are not lipophilic
if they are not lipid soluble they cannot penetrate the membrane (polar and ions)
In what case would you need to give a LIPID ONLY Med to a patient?
If they are in severe pain and need immediate drug effects
What are polar molecules
- no net charge
- uneven distribution of charges
- water (H+, O-)
What are ions
- net electrical charge
- Either positive or negative
- Unable to cross membrane
what is ionization
the process for acid and base to be converted to a charged particle
What type of environment would cause a weak acid to become a charged ion?
Basic Environment
What type of environment would cause a weak base to become a charged ion?
Weak Environment
Weak acids
proton donator
Weak bases
proton acceptor
Drugs can either be??
Either weak acid or weak base
pH-dependent ionization
some drugs can exist in either charged or uncharged forms
If ions are unable to cross membranes what is the solution?
pH-dependent ionization
Charge vs. uncharged forms depende on?
pH and ionization constant of drugs
Acidic drugs tend to ionize where?
A-
In basic pH environment
Basic drugs tend to ionize where
BH+
In acidic pH environment
What is Ion trapping
-It is a manipulation of pH of different fluids to create this ion trapping effect.
in other words, unionized form changes to changes to Ionized form and is trapped and cannot cross.
Why can’t the ionized part of the drugs cross the membrane?
They are charge and attract water molecules thus forming larger molecules making them less lipid soluble
What drugs can easily cross membrane?
Unionized drugs
Is aspirin acidic or basic?
-Acidic (salicylic acid)
Where would Aspirin absorb from?
GI Tract
pH is at 1
What happens to the pH of your GI tract as aspirin moves along from stomach to intestines?
- The pH of the GI tract as it moves along from the stomach to the intestines will become more basic.
- It is able to cross cell membrane into blood stream
- As it gets to basic environment, it will become ionized and can no longer cross cell membrane. It gets stuck in the plasma
- As it reaches its basic environment less of the drug is absorbed so to overcome we give larger doses of aspirin
Name the four “enteral” routes of administration
- Oral
- Rectal
- Sublingual/buccal
What are the advantages of oral route of administration?
- Most convenient
- Economical (Inexpensive)
What are the disadvantages of oral route of administration?
- First pass effect
- Patient compliance
- Irregular absorption (influence of food or medications)
- Many formulations
What are the advantages of rectal route of administration?
- Hepatic first-pass effect (less than oral)
- Useful for pediatrics, vomiting, or unconscious patients
What are the disadvantages of rectal route of administration?
-Erratic absorption (highly vascularize can’t predict absorption time)
What are the advantages of sublingual/buccal administration?
- Rapid onset of drug effect.
- Absorption into venous circulation
- It bypasses hepatic (the liver), and avoids first pass effect.
Where are oral drugs mostly absorbed, regardless of ionization, and why?
- Absorbed via GI tract
- Larger surface area and better blood flow.
Name the 6 “parenteral” routes of administration
- IV
- Intramuscular (IM)
- Subcutaneous
- Inhalation
- Transdermal
- Topical
What are the advantages of IV administration?
- Rapid Onset
- Reliable
- Bioavailability 100%
What are the disadvantages of IV administration?
- Irreversible
- need for patient IV access
- narrow therapeutic window
What are the advantages of IM
What are the disadvantages
- Depot delivery possible
- Painful
What are the advantages of subcutaneous
What are the disadvantages
Smaller volume
Slower onset vs IM
What are the advantages of Inhalation
What are the disadvantages
- Rapid Onset
- Less systemic exposure
What are the advantages of transdermal administration?
- Simple, convenient, painless
- prolonged action
- improved compliance (birth control patch)
- Systemic Delivery
What are the disadvantages of transdermal administration?
-May be irritating to skin
Topical
Skin, otic, nasal, vaginal
Less systemic exposure
Explain parenteral routes
- They avoid 1st pass
- They don’t go through absorption they go straight into the distribution phase
What is absorption
Drug moves from site of administration to systemic circulation
What are a few factors that affect absorption
- First pass effect
- % of uncharged form
- Blood flow (can cause slow absorption)
- Pgp-multidrug REVERSE/EFFLUX transporter
- Surface area (villi of sm intestines)
- Contact area (severe diarrhea)
- Food
Why does the solubility of a drug matter in relation to drug absorption?
More lipid soluble, aka lipophilic (lipid LOVING) can pass through cell membranes easily
What effect does ionization have on drug absorption?
Drug absorption is greater if the drug is in non-ionized, lipid soluble form. The ionized form is water soluble and possesses an electrical charge which is repelled by the cell membrane.
What is the first pass effect?
Drugs absorbed from the GI tract enter the portal vein and pass through the liver before entering circulation.
What are the disadvantages of the “first pass effect”?
- Decrease drug to body
- Decrease bioavailability
- May require alternate route of administration
Define bioavailability
- The fraction of dose that reaches the systemic circulation / quantity of drug administered
What factors affect bioavailability
- First pass effect
- Formulation
- Chemical Characteristics
- P-glycoprotein reverse transporter
What is distribution?
Drugs move from systemic circulation to tissues
What are a few factors that affect distribution?
- Drug Characteristics (crossing membranes)
- Blood flow
- Capillary Permeability
- Blood Brain Barriers (BBB)
- Plasma Protein Binding (PPB)
- Patient and disease factors (obesity, fluid accumulation)
What are blood brain barriers
- they favor lipophilic, small molecules
- tight junctions
- So only drugs that are lipid soluble or have a transport system can cross BBB
- low Plasma Protein Binding
What are Plasma Protein Binding?
Drug binding proteins
What is the most common type of drug binding protein
Albumin
What makes albumin so special?
- Prevalent protein
- Most drugs bind to it
Describe the characteristics of PPB
Reversible (drugs may be bound or unbound)
Free drug (active)
Bound drug (inactive)
Name a few factors that affect PPB
- nutritional status (poor diet results in a decrease in albumin)
- plasma protein levels (the availability of albumin)
- Displacement (possible drug to drug interaction)
What is elimination?
Removal of drug from body
What components does elimination include?
Metabolism and Excretion
Name a few factors that affect Elmination
- Renal function
- hepatic function
- Genetic Variations
- Concomitant meds
- Age
Describe metabolism
- Also known as biotransformation
- Enzymatic alternation of drug structure
Where does metabolism occur?
- MOSTLY in the liver
- Also in GI tract, lungs, skin, kidneys
How does metabolism occur
Through enzymes!
What does metabolism do to drugs
Makes the drugs more polar/H2O soluble
What are CYP450 Enzymes
- Large family of enzymes
- Catalyze oxidation rns
- Families 1,2,3
Drug interactions
CYP450 Enzymes
Characteristics of CYP450 Enzymes
- responsible for 70-80 % of drug metabolism
- There are 57 CYPS in humans
- Synthesis of steroid hormones, bile acid.
- Influence expression or function
Name the different components of metabolism
Substrate
Metabolite
Pro-drug
What are metabolites? Name them
Product of transformation
- Inactive metabolite - active to non-active - Active metabolite - non-active to active - Toxic metabolite
Describe what is a pro-drug
Inactive drug that undergoes METABOLISM to ACTIVE form
What happens if the drug is not active?
No activity on body until it i has been metabolize to in an active form
Name a few factors that affect metabolism?
- Age
- Sex
- Genetic Variations
- Diet (GRAPEJUICE, CHAR GRILLED)
- Smoking occupation
- OTHER DRUGS (drug to drug interaction)
Is pro-drug a product of metabolism?
NOOOO
What is Induction?
- Drugs can induce enzymes!
- Increase transcription
- Increase # CYP450 enzymes to work harder
- Increases rate of drug metabolism
- Results in decrease of plasma drug levels
What is a an inhibitor
- Decreases rate of drug metabolism
- Leads to increase adverse effects & toxicity
- AKA drug accumulation
What is a competitive inhibitor
- Drug competes with another drug for enzyme spot
- can decrease rate of which one or both agents are metabolized
- Drug accumulation
What is a irreversible inhibitor
No matter what you do, Drug I will never get off the CYP450 enzyme.
Describe Excretion
Removal of drug or drug metabolites from body
Where does excretion take place?
KIDNEYS
-GI tract (bile), lungs, skin, Lungs
Name a few factors that affection excretion
- impaired renal function
- Age
Name the renal excretion steps
- Glomerular Filtration
- Passive Tubular Reabsorption
- Active Secretion
What happens during the Glomerular filtration phase?
- Moves drugs from blood to urine
- Blood cells, large proteins and albumin bound DO NOT GET FILTER BACK
What happens during the Passive Tubular Filtration phase?
- As drugs are being filtered into urine, drug concentrations in the blood are lower than drug concentration in the tubule (urine)
- Passive diffusion of lipophilic drugs diffuse back into bloodstream
- Ion and polar compounds (non-lipid soluble) are excreted in urine
What happens during the Active Secretion phase?
The active transport of tubules pump organic acids and bases from blood to urine
What are elimination patterns and what does it include
-1st order of elimination - most drugs
a constant fraction % will be eliminated
-Half-life (t½ )
What are half-life?
- It is the time it takes to eliminate 50% of a drug from the body
- unique half life for each drug
- determines duration of action and dose interval
helps us figure out “how long will the drug last” and when do we need to redose patients
About how many half-lives does it take to clear a single dose from the body for a drug
check powerpoint
For a drug with half - life 24 hr, about how long will it take to leave the body after a single dose?
checkpower
If we have a long half-life….
we don’t have to give doses frequently because they leave body slowly
If we have a short half-life……
we need to give does frequently because they leave body quickly
What is steady state?
steady = equilibrium
Rate going in = rate going out
What causes drugs levels to reach plateau?
When the amount of drug eliminated between doses equals the dose administered, average drug levels will remain constant and plateau will have been reached
Maintenance dose (no loading dose)
Oral dosing
- Takes longer to reach MEC since plasma concentration builds up slowly (good route)
- Not appropriate for cases of an emergency
Loading dose
Oral dosing
- Shorter time to get to therapeutic response (to reach MEC quicker)
- Appropriate in serious conditions or emergency situations where the need us a drug is to effective immediately
To achieve a steady state you need how many half lives?
4 to 5 half lives
Large volume of distrubtion
With some drugs, especially those with a large volume of distribution, it may be necessary to give a loading dose (a big dose) initially to get above the minimum effective concentration and get the beneficial effect quickly.
