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BIOM2402 > Week 5/6 > Flashcards

Week 5/6 Flashcards

1
Q

Drug disposition*

A

*Disposition = the way something is placed or arranged in relation to other things

  1. Absorption
    - How a drug gets into the body (the plasma)
  2. Distribution
    - How a drug moves around the body
  3. Metabolism
    - How a drug is changed in the body
  4. 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..

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2
Q

Absorption

A

passage of drug from site of administration to plasma

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3
Q

Routes of Administration

A

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

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4
Q

Enteral Administration

A

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

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5
Q

Sublingual

A
  • 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)
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6
Q

Rectal

A

ADVANTAGES
* avoids ‘first-pass’ metabolism
* reduces vomiting/nausea
* good when patient is unconscious/seizures
* local inflammation (e.g. haemorrhoids)

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7
Q

Parenteral Administration

A

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)

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8
Q

Intravenous - i.v.

A
  • 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
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9
Q

Subcutaneous - s.c.

A
  • 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
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10
Q

Intramuscular - i.m.

A
  • 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
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11
Q

Intrathecal - i.t.

A

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

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12
Q

Inhalation

A

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
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13
Q

Topical

A
  • 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
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14
Q

Absorption across membranes (lipid barrier)

A
  • GI tract
  • Blood-brain barrier
  • Cell membrane
  1. Passive diffusion – passage
    along concentration gradient.
  2. Facilitated transport –
    involves carriers or transporters.
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15
Q

Passive diffusion

A

(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

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16
Q

Characteristics of drug molecules that affect passive diffusion (Partition coefficient)

A
  1. NON-IONISABLE – no charge on molecule (e.g. ethanol).
    Usually diffuse readily across membranes.
  2. 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

17
Q

Dissociation constant pKa - Henderson-Hasselbalch equation

A

pKa = pH + log [HA]/[A]

pKa = pH at which a molecule is 50% ionised

18
Q

Absorption from the GI Tract is dependent on:

A
  1. Concentration gradient
  2. Lipophilicity (R value)
  3. Blood flow to site of absorption
  4. Surface area - Most absorption of
    drugs occurs in the small intestine
    (large surface area) – including weak
    acids like aspirin.
  5. Formulation – Liquid/solid,
    size of granules
  6. GI tract contents (tetracyclines)
  7. Gut motility (transit time?)
19
Q

Where is aspirin (weak acid, pKa ~ 3.5) mostly absorbed?

A

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

20
Q

Bulk flow

A

drugs are delivered from site of
injection/absorption to site of action via the blood (also via lymph / cerebrospinal fluid - CSF)

21
Q

What is the ‘driving force’ for drugs to diffuse into peripheral
tissues?

A

“Plasma concentration”

22
Q

Plasma

A
  • Proteins (albumin)
  • Lipids
  • Lipoproteins
  • Other constituents

k1 x Cp = k2 x Ct
**Free drug
concentration

23
Q

Principle points to understanding plasma protein binding:

A
  1. Only unbound drug is available to diffuse into peripheral tissues
  2. Albumin is the most abundant and important protein for drug binding
  3. Albumin mainly binds acidic drugs
  4. Plasma protein binding can be
    saturable for some drugs
  5. Drugs can compete for plasma protein binding
24
Q

Why is protein
binding important?

A
  • 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…)
25
Q

Body Fluid Compartments – volume of distribution

A

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)

26
Q

Blood-Brain Barrier

A

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

27
Q

Blood-Brain Barrier in disease

A

Blood brain barrier can “open” during injury or inflammation / infection

28
Q

Is adipose tissue important?

A

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

29
Q

Metabolism

A

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

30
Q

Two major types of enzymatic reactions

A
  1. Phase I reactions
    = Functionalisation (make more reactive). Liver
    CLASS: Catabolic Reactions

e.g.
Oxidations (cytochrome P450, CYP)
Reduction (reductases)
Hydrolysis (esterases)

  1. 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

BIOM2402 (9 decks)

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