first pass metabolism
Metabolism of drugs before reaching the general blood circulation (drug changes form before reaching the systemic circulation)
- Sites: pass through Liver, gut wall and portal blood
- Occur mostly for the orally administered drugs because they are absorbed from the GI(gastrointestinal) tract and delivered to the liver via the portal vein before reaching the general circulation < lots of steps that can cause the drug to change its form>
*greater first pass effect = less drug will reach the systemic circulation unchanged
The extent of the first pass effect is drug dependent
* Some drugs are extensively metabolised during the first
pass to the extent that they cannot be administered orally
(very low bioavailability)
e.g nitroglycerin
*bioavailability of medication given intravenous (IV) is 100% because it is GIVEN directly into the blood circulation
Ex
aspirin = 70% bioavailable
Morphine = 30% bioavailable (take it as a prodrug → codeine which gets metabolized to morphine)
bioavailability
proportion of administered dose that is
absorbed from the site of administration and
reaches systemic circulation unchanged
Example: A drug is 80% bioavailable means that 80%of the dose reaches the circulation unchanged and 20% is lost/metabolized/ unabsorbed
- What causes the loss of the drug before
reaching the circulation
1. Incomplete absorption
2. First pass effect (first pass metabolism)
route of administration catergories
–>enteral (through/within the GI system)
-oral(by mouth)
-rectal (into rectum (large intestine)) *ไม่ผ่าน
-sublingual (under the tongue)
–> Parenteral (by- pass the GI system)
-intravenous injection(into vein)
-intramuscular injection (into muscle)
-Subcutaneous injection (under the skin→fatty layer)
–>Other routes
-pulmonary (inhaled in lungs) (ex: anesthetics for putting you to sleep, for asma)
-Percutaneous/ transdermal(through patch on the skin) → nicotine patch for systemic effect
-topical (cream,patch applied directly to the mucous membrane for local effect)
oral administration
→ Oral consideration:
Why are some drugs taken with food and others without?
-with food:
Food may protect against gastric irritation in stomach caused by some drugs but it will delay the gastric emptying time e.g iron
For some drugs, bioavailability is increased when taken with food
Some drugs may complex with food, which hinders absorption and ↓ bioavailability (e.g. tetracycline binds to calcium-rich foods)
without food:
Some drugs like laxatives can increase the intestinal motility and thus decrease the absorption of other drugs(more intestinal movement = drug move through instead of absorb)
→ advantage =
-Convenient (easy to administer, pain free)
Economical compare to most other routes since you don’t have to go to the clinic to get injection, can take it easily at home
→disadvantage =
-Drug absorption affected by first pass metabolism
-Drug may be subject to degradation in gastric acid and digestive juices in stomach (require large dose)
-Drug may irritate gastric mucosa
-Slow onset of action, low half life (require higher dose)
-Not suitable for some patients (ex: unconscious)
*Oral administration can also be intended for LOCAL action in the gut that DOESN’T REQUIRE SYSTEMIC absorption into the blood
Ex: vancomycin is poorly absorbed orally but eradicate toxins in gut
enteric coating
created to resist degradation in stomach(gastric acid) but it may reduce absorption in intestine large surface area (e.g. enteric coated aspirin)
extended or controlled release (CR)
→ slow, uniform dissolution and thus absorption of drugs is more than
> 8hrs.
CR = ideal to treat drugs of shorter half life to decrease frequency of dosing to take (two times to once a day since it slow absorption rate which extends drug duration of action→ stays in system longer) and increases patient compliance
Every time the dose drops= we need to take the drug again, if we have controlled release we extend the time that the drug needs to be taken again since drug is consistently and slowly taking more time to absorb → (continuous and slow absorption→ drug stays in body longer)
rectal administration
Drug is administered/absorbed rectally
-used when oral route is UNSUITABLE due to nausea/vomiting, unconsciousness, drug is unstable in gastric pH
-may also be used for local action (topically)
→ lower GI tract(laxative, hemorrhoid treatment)
→ Advantage =
No first pass/degradation in stomach or small intestine
Large dose may be given because rectum can stretch to hold high amount of dose given
faster onset of action( rectum has a rich blood supply and thin walls, allowing for rapid absorption directly into the bloodstream)
→ disadvantages
Irregular absorption, often incomplete
Drug may be irritating to mucosa (mucous membrane)
Less accepted than oral routes (poorer compliance)
sublingual administration
Sublingual: drug is placed under the tongue or held in the mouth for systemic action
– absorbed through thin regions of oral mucosa into general circulation → rapid absorption → rapid onset
Examples:
− Nitroglycerin sublingual tablets (for angina)
− Lorazepam sublingual tablets (acute anxiety
episodes)
Buccal: drug is placed in the space between the gum and cheek (buccal area) where it diffuses through oral mucosa to reach the circulation
Example:
− Buccal midazolam to stop seizures in emergency
→Advantages
* No first pass/degradation, not making it way to the entire GI tract
* Absorbed rapidly
* Rapid onset of action
-only need small doses
→Disadvantages
* Limited to drugs that can penetrate oral mucosa well,
not irritating
* May not be convenient for large doses
*Note that lozenges and throat sprays intended for local surface action in mouth/throat that don’t require systemic absorption into blood are considered topically administered
parental (injections) administration types
Injection route of administration:
-Intravenous(IV) injection is the fastest and most certain route of administration into blood (bypass absorption)–>avoid digestive/GL system → high bioavailability
- Subcutaneous and intramuscular injections of drugs
produces faster effect than oral administration, but they
are dependent on site of injection and blood flow - It may be desirable to delay absorption of injected drugs to produce local effect or increase duration of action
subcutaneous injection
-Injection of drug into subcutaneous tissue from which it is absorbed into circulation(into fatty tissue)
- Absorption into fatty layer is even and slow, affected by blood flow since the drug is delivered into fatty tissue with low vascularity (few blood vessels), forcing it to travel through tissue via diffusion rather than immediate capillary uptake.
→ Advantages
* Slow, even absorption provides
sustained effect
* No first pass/degradation in GI
→ Disadvantages
* Limited to small volumes of
non-irritating drugs
intramuscular injection
Injection of drug into skeletal muscle tissue (into muscle tissue) from which it is absorbed into circulation
* Rapid absorption of aqueous solutions
- Slow/even absorption can be achieved by suspending drug in oil (depot injection)
e.g, contraceptives, antipsychotics (Haloperidol)
Advantages
* Rapid absorption → rapid
onset of action(muscle tissue has a high concentration of blood vessels (rich vascularity))
* No first pass/degradation in GI
Disadvantages
* Limited to small volumes of
non-irritating drugs
* Strongly acidic or alkaline can
cause abscesses
intravenous injection
Drug is injected directly into circulation (100% bioavailability
* Accurate, precise and immediate drug concentrations
1)Bolus injection – requires several circuits through vascular system for even distribution(directly into vein, using intravenous line)
2)Slow infusion – allows drug conc. in blood to be titrated. (IV Drip, allow drugs to be titrated into blood) Maintain constant drug levels over extended periods, larger dose can be given
→ Advantages
* Precise, almost immediate onset of action
* Large doses may be given for slow infusion
* No first pass/degradation in GI, 100% bioavailability
→ Disadvantages
* Greater risk of
toxicity/overdose – less so
with slow infusion
* Potential adverse effects like
embolism, infection, bleeding,
vascular injury
pulmonary administration
-Inhaled gases, vapors, and aerosols are absorbed
through alveolar surface or bronchiole mucosa into
systemic circulation
* Absorption is rapid due to thin membranes, large
surface area, and high blood flow to the lungs
- May also be used for local action only (e.g. asthma
agents)
Examples:
− General anaesthetics
− Nicotine, opium, or cannabinoids
from smoking
− Amyl nitrite for angina
Advantages
* Rapid onset of action
* Rapid access to the brain
* Easy to administer, painless
Disadvantage
Hard to regulate exact dosage with puffers,
smoking
* Suitable only for volatile
agents and aerosols
* Irritation/tissue damage in
lungs possible
Percutaneous or transdermal administration
Examples:
✓ Fentanyl patch for breakthrough pain
✓ Nitroglycerin patch for angina pectoris
✓ Nicotine patch for smoking cessation
✓ Birth control patch
✓ Scopolamine plasters for motion sickness
→ Advantages
* No first pass/degradation
* Controlled long term release → stable blood
levels
* Easy administration
* Good patient compliance
* The 3 L’s: lipophilic, low dose, low molecular weight
→ Disadvantages
* Highly dependent on drug
Properties → favourable physicochemical properties: small and lipid soluble
- Surface area important → Drug must be concentrated/potent enough
- Skin irritation may occur
Topical administration(using patches,gel,cream)
Examples:
− Skin ointments, creams, lotions
− Eye/nose/ear drops
− Mouth/throat/rectum/vaginal sprays, solutions, tablets, suppositories
− Body cavity injections (e.g., corticosteroids into joints, antibiotics into
pleural space or local pockets of infection)
− Intrathecal injections (into cerebrospinal fluid bathing)
→ Advantages
* No first-pass/degradation of drug
* Decreased unwanted or adverse effects
– Little - no drug action at unintended sites
* Can achieve high conc. in
hard-to-reach places
* Rapid onset of action
→Disadvantages
* Limited to small volumes/doses
* Not suitable for systemic diseases/targets
* Some are highly impractical to administer
(e.g., intrathecal
injections)
factors affecting route of administration
A) Drug-related factors
1. Drug physicochemical properties
e.g insulin is degraded by proteolytic enzymes in the GI and thus not administered orally ( Rate and extent of absorption)
2. Bioavailability, extent of metabolism in the liver/GI (does it avoid first-pass ) → will it reach site of action in its unchanged form
3. Whether the drug requires bio-activation (i.e, a prodrug) → onset and duration of action
4. Dose to be given (toxicity and adverse effect)
B) Drug indication-related factors (therapeutic objectives)
1. Emergency situation vs daily administration (Desired speed of onset and duration of drug action)
2. Target site location (ability to reach the target site)
e.g pocket of infection
3. Intended “reach” of treatment (systemic vs. local/topical )
C) Patient-related factors
1. Patient condition
e.g unconsciousness, seizures, difficulty in swallowing
2. Patient convenience
D) Setting (practicality and convenience)
1) cannot always give IV injection
