Week 5/6 Flashcards
Drug disposition*
*Disposition = the way something is placed or arranged in relation to other things
- Absorption
- How a drug gets into the body (the plasma) - Distribution
- How a drug moves around the body - Metabolism
- How a drug is changed in the body - Excretion
- How a drug is removed from the body
Dependent on:
1. Differences between drugs – chemical nature, size, formulation, route
2. Differences between people – age, sex, health and genetics..
Absorption
passage of drug from site of administration to plasma
Routes of Administration
1) enteral- absorption through the gastrointestinal tract (GIT)
2) parenteral- all routes other than via the GIT
ENTERAL = oral, rectal, sublingual
PARENTERAL = injections, inhalation, topical
Enteral Administration
Oral (p.o.)
ADVANTAGES
* Convenient (>compliance)
* ~75% absorbed in 1-3 hr
* slow-release formulations
DISADVANTAGES
* some drugs not well absorbed or not stable to stomach / digestive conditions (proteins – Antibodies / peptides / penicillin)
* irritation to gastric/intestinal mucosa
* food can delay/affect absorption (variable)
* much slower absorption than parenteral
* inactivation by ‘first-pass’ metabolism by the liver
Sublingual
- Dissolve tablet under the tongue
- good vascularisation
- rapid absorption into bloodstream
- no ‘first-pass’ metabolism in the liver
- e.g. anti-anginal drug nitroglycerin (vasodilator)
- absorbed rapidly - straight to the heart
- can’t be given orally (90% cleared by 1st pass)
Rectal
ADVANTAGES
* avoids ‘first-pass’ metabolism
* reduces vomiting/nausea
* good when patient is unconscious/seizures
* local inflammation (e.g. haemorrhoids)
Parenteral Administration
Injections
- Intravenous (i.v.)
- Intramuscular (i.m.)
- Subcutaneous (s.c.)
- Intraperitoneal (i.p.)
- Intrathecal (i.t.)
ADVANTAGES
* rapid onset, compared to oral
i.v. > i.m. > s.c.
* drugs are not broken down by
by acid/enzymes as in the gut
* ‘first-pass’ metabolism in the liver
is less of a problem
DISADVANTAGES
* less convenient (skilled person)
* risk of infection
* more toxicities (higher peak blood
levels)
Intravenous - i.v.
- desired blood level can be reached quickly
- very good in emergencies
- once injected, no retreat
- can overdose very rapidly and die very quickly
- irritating (GI) solutions can be given this way
- repeated injections require usable veins
Subcutaneous - s.c.
- used to extend the time of pharmacological effect
- give with oily solution to bind up drug
- add vasoconstrictors to reduce blood flow
- only used when drug does not irritate s.c. tissues
e.g. can’t use for barbiturates- pain, necrosis, tissue sloughing
Intramuscular - i.m.
- also used frequently for drugs
(e.g. penicillin and vaccines) - more rapid absorption than s.c. (better blood perfusion to muscle)
- slow constant absorption can be produced by using oily vehicle
- oil doesn’t mix well with tissue water
- used for hormone injections
Intrathecal - i.t.
Injected into the spinal cord between the membranes (meninges) covering the cord
- e.g. spinal anaesthesia
(epidural for childbirth)
- rapid onset, slow recovery
- safer than general anaesthesia
Inhalation
Good absorption of drugs into bloodstream
- very large surface area
- thin barrier to diffusion
- very large blood supply
=> high levels of agents in short period of time - e.g. cigarette smoking (… vaping), about 15 sec
- volatile general anaesthetics given this way
- some drugs inhaled to have local effects in the lungs
- e.g. anti
-asthmatic drugs
Topical
- Direct application to diseased or injured site - e.g. eyes, ears, nose, vagina, anus - require lower overall doses - reduced systemic toxicity
- Skin - few drugs penetrate skin readily
- Patches work well- nicotine, fentanyl
Absorption across membranes (lipid barrier)
- GI tract
- Blood-brain barrier
- Cell membrane
- Passive diffusion – passage
along concentration gradient. - Facilitated transport –
involves carriers or transporters.
Passive diffusion
(most important mechanism for most drugs)
Rate of diffusion is dependent on:
1. Surface area of membrane (A)
2. Concentration gradient (DC) -drug
3. Partition coefficient (R) -drug
4. Diffusion coefficient (D) -memb
5. Thickness of membrane (Dx)
Rate of diffusion = (D.R.A.DC)/Dx
Characteristics of drug molecules that affect passive diffusion (Partition coefficient)
- NON-IONISABLE – no charge on molecule (e.g. ethanol).
Usually diffuse readily across membranes. - IONISABLE – drug charged to some extent (most drugs)
Ionisable drugs are either:
1. acids (give up a hydrogen ion)
- become negatively charged
2. bases (accept a hydrogen ion)
- become negatively charged
Dissociation constant pKa - Henderson-Hasselbalch equation
pKa = pH + log [HA]/[A]
pKa = pH at which a molecule is 50% ionised
Absorption from the GI Tract is dependent on:
- Concentration gradient
- Lipophilicity (R value)
- Blood flow to site of absorption
- Surface area - Most absorption of
drugs occurs in the small intestine
(large surface area) – including weak
acids like aspirin. - Formulation – Liquid/solid,
size of granules - GI tract contents (tetracyclines)
- Gut motility (transit time?)
Where is aspirin (weak acid, pKa ~ 3.5) mostly absorbed?
Stomach: pH = 1-2
Aspirin = mostly unionized
Crosses membrane easily
=> Aspirin can be easily
absorbed in stomach…
Small intestine
- pH = 8
- Aspirin = mostly ionized
- Less able to cross membrane
BUT: Very large surface area
Bulk flow
drugs are delivered from site of
injection/absorption to site of action via the blood (also via lymph / cerebrospinal fluid - CSF)
What is the ‘driving force’ for drugs to diffuse into peripheral
tissues?
“Plasma concentration”
Plasma
- Proteins (albumin)
- Lipids
- Lipoproteins
- Other constituents
k1 x Cp = k2 x Ct
**Free drug
concentration
Principle points to understanding plasma protein binding:
- Only unbound drug is available to diffuse into peripheral tissues
- Albumin is the most abundant and important protein for drug binding
- Albumin mainly binds acidic drugs
- Plasma protein binding can be
saturable for some drugs - Drugs can compete for plasma protein binding
Why is protein
binding important?
- Acts as a reservoir – displaced by other drugs (=> drug interactions).
- Change in plasma proteins (elderly) -> changes in pharmacology.
- Change in blood volume (severe bleeding) -> changes in pharmacology.
- Species dependence (drug development / translational considerations…)
Body Fluid Compartments – volume of distribution
Plasma compartment: large drugs e.g. heparin (~ 14 kDa), therapeutic antibodies (150 kDa)
Extracellular compartment = plasma + interstitial
E.g. Gentamicin / penicillin (highly polar drugs)
Total body water = plasma + interstitial + intracellular
E.g. Ethanol (unionized, polar yet lipophilic => readily cross membranes)
Blood-Brain Barrier
For drugs to enter the central nervous system:
1. Preferably small (low MW)
2. Must be very lipophilic, or
3. Must be a substrate for specific transporters
4. Not substrates for MDRs (see below)
Transporters are also used to remove from/prevent entry of drugs to the brain:
- ‘Multi-drug resistance proteins’ =
P-glycoproteins from MDR genes
(Multi drug resistance genes)
- non-selective drug transporters.
- also found in GI tract and liver
Blood-Brain Barrier in disease
Blood brain barrier can “open” during injury or inflammation / infection
Is adipose tissue important?
Drug partitioning into adipose tissue (fat).
* Non-polar environment.
* Site of accumulation of highly lipophilic drugs.
* Can act as a reservoir for slow release into body
Metabolism
how a drug is changed by the body
Drugs (mostly) are foreign compounds (xenobiotics)
The purpose of metabolism of xenobiotics is to:
1. Increase the rate of excretion
2. Decrease likely toxicity
Two major types of enzymatic reactions
- Phase I reactions
= Functionalisation (make more reactive). Liver
CLASS: Catabolic Reactions
e.g.
Oxidations (cytochrome P450, CYP)
Reduction (reductases)
Hydrolysis (esterases)
- Phase II reactions
=Conjugation (-OH, -SH, -NH2)
Enzymes often transferases.
Liver, lungs & kidney
CLASS: Anabolic Reactions
e.g.
Add water-soluble moiety to drug
* glucuronyl
* glutathione
* sulfate
* acetyl
* methyl
