Principles of Pharmacology- Ch 4-5 Flashcards
What are the 2 branches of pharmacology?
Pharmacokinetics
Pharmacodynamics
What is Pharmacokinetics?
Branch that describes what the body does to the drug and how the drug concentration in the plasma changes over time
What is Pharmacodynamics?
Branch that describes what the drug does to the body, the relationship between drug concentration and effect
What are the 4 stages of Pharmacokinetics divided into?
ADME
What does ADME stand for?
Absorption from site of admin
Distribution within the body
Metabolism
Excretion
Why is it important to understand the differences between routes and formulations for drug administration?
Because different adminatration methods affect how quickly and how much drug enters the systemic circulation
important in determining the peak plasma concentration, action duration
chosen route for a drug depends on desired outcome
Are all administration routes suitable for all drugs?
No
What does adminstration of drug formulations depend on?
-Route of administration
-Time-course of action
-Active drug concentration
What are the 3 main types of administartion?
Enteral
Parenteral
Topical
What is Enteral administration?
Entry of drug through the Gastrointestinal (GI) tract
-Absorption occurs somewhere between mouth and anus
What is Parenteral Administration?
Not by GI tract
What is Topical administration?
Drug is administered by the skin/mucous membrane
-Ointment, creams
What is Oral enteral administration?
Results in drug absorption through the stomach or small intestine
What is oral enteral absorption?
<100%
What does oral enteral absorption depend on?
-Solubility
-GI tract acidity
-Stability of drug (does acid/digestive enzymes destroy it?)
-Gastric emptying/motility
-GI blood flow
What are the benefits of Oral (PO) administration?
Easiest, safest and cheapest
No need for drug to be sterile or pure
What are the drawbacks of Oral (PO) administration?
-Acid-sensitive and protein drugs are unstable
-Patient must be conscious and cooperative
-Variable absorption and bioavailability
-Possible upper GI tract irritation
Where do most drugs given orally pass through before entering systemic circulation?
The liver
-Major site of drug metabolism
What is the name of the effect of orally given drugs dropping in concentration during liver metabolism?
First Pass Metabolism
or Pre-systemic elimination
Are all drugs extensively metabolized by the liver?
No drug metabolism is drug-to-drug dependent
-Some are very metabolized, some are not metabolized
e.g, Drug A: 100% dose taken —liver–> 100% of dose enters blood
e.g, Drug B: 100% dose taken —Gut wall–> 70% of dose —Liver–> 15% of dose enters blood
What is Rectal (Pr) enteral administration?
Absorption is through the rectal mucosa
What are the benefits of Rectal (Pr) enteral administration?
Rapid absorption
Cheap, easy
Useful when patients can’t/won’t swallow
Less first pass effect
Why is there less first pass effect when drugs are given via Rectal (Pr) enteral administration?
Fewer rectal veins enter the liver
What are the drawbacks of Rectal (Pr) enteral administration?
Absorption often incomplete
Many drugs irritate mucosal lining
What is Sublingual (SL) Enteral administration?
Drugs placed under the tongue
What are the drawback of Sublingual (SL) Enteral administration?
Many drugs taste bad
What are the benefits of Sublingual (SL) Enteral administration?
Rapid absorption
No first pass effect
Suitable for acid-senstive drugs (mouth pH= 7)
Fast, easy, cheap
Why is there no first pass effect when Sublingual (SL) Enteral administration?
It allows for direct entry into systemic circulation
What pharmacokinetic profiles are Sublingual administration similar to?
SC, IM and IV administration
Why is SL administration similar to SC, IM and IV administration pharmacokinetically?
Drug crosses mucosa into systemic circulation
-no first pass
Bioavailability very high and consistent
Bypass stomach and intestine environment
What are the formulations of enteral administration?
Tablets
Caplets
Capsules
Liquids
Buccal film
What are capsules?
Powder in a gelatin coating
-Allows faster absorption
What are liquids formulations?
Aqueous (dissolved in water)
Suspensions or emulsions
-Even faster absorption
What are buccal films?
Drug absorbed between gum and cheek
What is parenteral administration subcutaneous injection?
Drug is injected under the skin
What are the benefits of subcutaneous injection (SC)?
Rapid effect via general circulation
Useful for local drug delivery (e.g, local anesthetics)
Easy self-administration
Can subcutaneous drug absorption into circulation be controlled?
It may be controlled
e.g, Vasoconstricting agents
What are the drawbacks of subcutaneous injection (SC)?
Requires sterile drug
Some patents do not like injections
Absorption greatly affected by blood flow and injection volume
What is parenteral administration of Intramuscular injection (IM)?
Drug injected into skeletal muscle
What are the benefits of intramuscular injection (IM)?
Can be into a large muscle mass
Self-administration
Can intramuscular drug absorption into circulation be controlled?
It may be controlled
e.g, Oil-based formulations allow slower absorption
-‘depot’ bolus (inject a drug and it can last for weeks)
What are the drawbacks of intramuscular injection (IM)?
Can be painful
What is parenteral administration intravenous (IV)?
Drug injected directly into vein either as rapid bolus (IV push) or as continuous infusion (IV drip)
What are the benefits of IV administration?
All of drug enters bloodstream (100% bioavailability)
Rapid distribution and onset of action
Large drug volumes
WHat are the drawback of IV administration?
Requires skilled administration and close monitoring
Drug must be sterile
Greater cost
What is another route of drug administration?
Inhalation
What is inhalation administration?
Drug inhaled into airways
What are the benefits of inhalation?
Useful for local action (e.g, Bronchodilators) but can alsp be absorbed into pulmonary circulation
No first-pass effect
Useful for gasses
What are the drawbacks of inhalation?
Limited absorption of large proteins
Possible irritation of lung lining
What formulations are used for inhalation?
Gasses or gas mixtures
Inhalers for pulmonary use
Pressurized aerosol
When are inhalers used?
Particulate powders
Nebulized (mist)
What do pressurized aerosols and other containers allow for?
Unused products to remain uncontaminated for later use
In summary what are all the enteral administration methods?
Oral (PO)
Rectal (pr)
Sublingual (SL)
In summary, what are all the parenteral administration methods?
Subcutaneous Injection (SC)
Intramuscular Injection (IM)
Intraveous (IV)
Intra-articular injection (Joints)
Intra-cardiac injection (heart)
Epidural injection
Spinal injection (into spinal fluid)
Whata re the topical administration routes?
Skin
Eyes (drops - gtt; ointment)
Ears
Nose
Vagina
What is Transdermal topical administration?
Absorption through skin for local effects and systemic effects
What are the benefits of Transdermal topical routes?
Cheap, easy
Simple local administration
no first pass effect
What are the drawbacks of transdermal topical routes?
Not suitable for many drugs e.g, fat insoluble
Absorption affected by skin hydration
What are some formulations used for transdermal topical administration?
Creams, gels, ointment
Suspension in an oily vehicle (enhances absorption)
Controlled-release patches (e.g, nicotine)
Topical aerosol spray
What is drug absorption?
Entry of drug into the circulatory system
Example of drug absorption?
Orally administered drugs
-Pass through epithelial cells of the GI tract then into blood flowing through capillaries of GI wall
What chemical factors affect drug absorption?
Drug size
Lipid solubility
Drug charge
Bioavailability
The proportion of drug that passes into the systemic circulation after administration.
-Takes into account both absorption and local metabolic degradation
Is bioavailability high or low with PO administration?
Low
-Often much less than 100% if po
Is bioavailability high or low with SC, IM and IV administration?
High
What affects bioavailability?
First-pass effect
Drug absorption
(Solubility, stability and formulation of the drug)
What is Drug distribution?
After absorption, the drug is mixed throughout the blood very quickly
-Average time for blood circulation is ~1 minute
What does the initial rapid distribution of a drug depend almost entirely on?
Rate of blood flow to a given tissue
e.g, tissues with a high blood flow will be exposed to more drug, more quickly, than those with low blood flow
Examples of tissues with rapid distribution?
Heart, liver, kidneys, brain
Examples of tissues with slow distribution?
Muscle, skin, fat
What does the second slower phase of distribution depend on?
Where a drug ‘likes’ to be
-Can take minutes to hours
What factors affect second, slower phase of distribution?
Lean mass (watery environment e.g, muscle)
Fat solubility of the drug - drug accumulation
Plasma binding protein
In general, what three factors determine drug distribution?
Blood flow distribution
Exiting the vascular system
Entering cells
Do most drug molecules float around within blood?
No drugs are often bound to a plasma protein (Plasma protein binding)
The % of a drug bound to protein can be quite high (90% of more, slows distribution)
What is the most common plasma protein and major carrier of drugs?
Albumin
What happens to someone with liver disease in regards to plasma protein binding?
The liver makes albumin, therefore diseased liver = decreased albumin —> Increased free drugs (rapid distribution, unpredictable)
How does our body get rid of drugs?
Metabolism
Excretion
Metabolism
Modification (change) of drug molecule by cell enzymes
Excretion
Removal from body
Where does most drug metabolism occur?
Mostly in liver
-Also occurs in the gut, kidney, lungs, plasma and placenta
What family of enzymes are drugs largely metabolized by?
Cytochrome P450
How are the Cytochrompe P450 enzymes identified?
Cytochrome P450 family. Family. Subfamily. Isoform
e.g, CYP2D6
[CYP= Cytochrome P450 family] [2= Family] [D= Subfamily] [6= isoform]
What are the therapeutic consequences of drug metabolism?
Accelerated renal drug excretion
Drug inactivation
Increased therapeutic action
Activation of prodrugs
Increased or decreased toxicity
What is the most common therapeutic effect/consequence of drug metabolism?
Accelerated renal drug excretion
-Aids water solubility
Do all drugs metabolise the same in every indivdual?
No there is variation between individuals
Doing what to CYPs can be dangerous?
Inhibition
What inhibits CYPs?
Grapefruit juice
Other drugs (competition)
What is CYP enzyme induction?
Cells stimulated to make more enzymes
Where does most drug excretion occur?
Through the kidney
What other places does drug excretion occur?
GI tract (including via bile)
Sweat
Breast milk
What does drug excretion depend on?
Plasma protein binding
Drug fat solubility/charge
What is the filtration unit of the kidney?
Nephrons
-each kidney contains about 1 million
How do drugs enter tubular fluid?
Filtration through glomerular capillaries (blood to urine)
Active transport through specialized carriers
Are some drugs able to be excreted in an unaltered form?
Yes
e.g, some antibiotics
Most drugs must undergo what process first before excreteion?
Metabolism
What does metabolism do to a drug before it is excreted?
renders it inactive
Makes the drug more water soluble/less fat soluble
Effective treatment requires…?
Optimal dosage regime
-Dose size and frequency
What largely determines the duration of the effects of a drug?
Metabolism and excretion
What is a drug steady state?
When there is a consistent level of drug in the body
- Drug accumulates in the body until the amount being administered equals the amount being eliminated.
What is the half-life of a drug (T 1/2)?
The time required for the amount of drug in the body to decrease by 50%
Measure of the rate at which drugs are removed from the body
The time to reach a steady state depends on what?
The drug’s half-life (T 1/2)
Steady-state reach in 4-5 T1/2
Drug entry = drug exit
If a drug has a long T1/2?
It takes a long time to reach a steady state (with repeated dosing)
If a drug has a short T1/2?
It takes a short time to reach a steady state (with repeated dosing)
Explain morphine’s steady state
Morphine T 1/2 = 4hours
~18 hours needed to reach a steady state
Explain Digoxin’s steady state
Digoxin T 1/2= 36hours
~7 days to reach a steady state
What are most drugs metabolized/excreted according to?
Principles of percentage loss of drug over time
-NOT a fixed amount
Do any drugs leave the body at a constant rate?
A few leave the body at a constant rate
e.g, 10 mg in 3 hours regardless of how much is present
Examples of drugs that leave the body at a constant rate?
Ethanol (alcohol)
Phenytoin (epilepsy drug)
What is usually required for drugs to elicit an effect on the body?
They must interact directly with cells (bind to receptors)
What are drug receptors?
Protein targets, or sometimes DNA (some anti-tumour drugs) and cell membranes (some antimicrobial agents)
What should drugs exhibit for their receptor?
Selectivity
-Interact only with their target molecule, cell or tissue
What might drugs lose at high concentrations?
Selectivity
What are the 2 common possibilities of drug action?
Drug A + Receptor —> Drug A-receptor —> Response
(Agonist)
Drug B + Receptor —> Drug B-receptor —> NO response
(Antagonist)
What does binding of a drug depend on?
Affinity of drug for its target
Affinity
‘Stickiness’
The degree to which a substance tends to combine with another.
What is an Agonist?
Elicits a response
What is an Antagonist?
Prevents a response to endogenous agonist
What are Dose-response relationships?
Relationship between the size of an administered dose and the intensity of the response produced
What do Dose-Response Relationships determine?
-Minimum amount od drug to be used
-Maximum response of a drug can elicit
-How much to increase the dosage to produce the desired increase in response
Onset
The time it takes for the drug to elicit a therapeutic response
Peak
Time it takes for a drug to reach its maximum therapeutic response
Trough
Lowest blood level
-If too low the drug is ineffective
Minimum Effective Concentration (MEC)
Plasma drug level that must be reached for a therapeutic effect
Duration
Time for which a drug concentration is sufficient to elicit a therapeutic response
Therapeutic Index
Measure of a drug’s safety
Ratio of the amount at which a drug’s toxic : Amount at which drug is effective
A drug with a larger therapeutic index is ______?
Safer
A drug with a smaller therapeutic index is ____ _____?
Less safe
-Called NTI’s (Narrow Therapeutic Index drugs)
Describe the responses of Non-receptor drugs
Simple physical or chemical interactions with other small molecules
Examples of receptorless drugs
Antacids
Saline laxatives
Chelating agents
