Pharmacokinetics Flashcards
(30 cards)
Is the drug getting into the patient?
PHARMACEUTICAL PROCESS
Is the drug getting to its site of action?
PHARMACOKINETIC PROCESS
Is the drug producing the required pharmacological effect?
PHARMACODYNAMIC PROCESS
Is the pharmacological effect being translated into a therapeutic (or toxic) effect?
THERAPEUTIC PROCESS
What your body does to the drug is called
Pharmacokinetics
The quantitative analysis of the time course of drug:
Absorption
Distribution
Metabolism
Excretion
Routes of Administration
Oral
Sublingual
Rectal
Parenteral : Intravenous, Intramuscular, and Subcutaneous
Inhaled
Topical : Intranasal, Eye, and Cutaneous
In oral administration, mechanism of absorption can be of 2 types
enteral:
1. Mechanism of absorption
* Passive non-ionic diffusion
-Majority of drugs
2. Specialised transporters
* Large neutral amino acid transporter
-L-dopa, Methyldopa, Baclofen
- Oligopeptide transporter (PEPT-1)
-Amino beta lactams, ACE inhibitors - Monocarboxylic acid transporter
-Salicylic acid, pravastatin
Enteral: absorption from mouth, stomach and small intestine
Mouth and stomach: minority
Small Intestine: majority
Passive > Active
- Rate ~ 75% in 1-3 hours. Depends on:
Motility e.g. diarrhoea decreases absorption
Blood flow
Food: Enhances or impairs
Particle size and formulation
Physico-chemical factors: Unionised/Lipid soluble - Rate of gastric emptying is a rate limiting step
Effects of Food on Oral Drug Absorption
1. Poor acid stability
Prolonged gastric exposure Degradation
E.g. isoniazid
**2. Require acid environment **
E.g. ketoconazole
3. Fat or bile acids enhance absorption
E.g. tacrolimus,
4.Bind to fibre, reducing absorption
E.g. digoxin
5. Bind to calcium (chelate), reducing absorption
E.g. tetracyclines,
Effect of Formulation on Absorption
** Rate of disintegration of tablet**
-Tablet compression
-Bulk excipients
Rate of dissolution of drug particles in intestinal fluid
-Particle size: smaller dissolve quicker
Modified Release
-Reduce frequency of oral administration
E.g. morphine
-Deliver contents to site of action
E.g. mesalazine: pH sensitive coating – 5-ASA (5-aminosalicylic acid) released in distal small bowel and colon; used for ulcerative colitis
Sublingual Administration
From blood vessels at base of tongue
Lipid soluble drugs only
-E.g. Nitroglycerin [used for angina (chest pain)]
Small surface area
-Potent drugs only
Avoids first pass metabolism
Rapid absorption: minutes
Rectal Formulations
Avoid first pass metabolism
Erratic absorption because of rectal contents
Acceptable to patients?
Useful if unable to take oral medications. E.g. paracetamol
Useful if unable to get IV access. E.g. diazepam in status epilepticus
Direct effect on large bowel. E.g. Corticosteroids in Inflammatory Bowel Disease
Parenteral: Subcutaneous
Very small injection volume
Drug absorbed very slowly into blood through capillaries
Larger drug molecules such as protein drugs reach blood through lymphatic system
E.g., insulin
Parenteral: Intramuscular
Slow absorption, but faster compared to subcutaneous due to better supply of blood vessels than skin
Larger injection volume compared to subcutaneous
Less invasive compared to IV
Painful
Parenteral: Intravenous
Direct delivery to plasma : No absorption required
Rapid effect
Avoids first pass metabolism
Risks: Infection, embolism (blockage due to clot formation)
Inhaled Medications
- Formulations
Powders, Aerosol solutions, Nebulised solutions - Delivery to bronchioles
~10%
Depends on type of inhaler and how it is used - Local effects
E.g. infections - Some systemic absorption
Salbutamol: Used for Asthma. Can cause tremor (Tachycardia)
Corticosteroids: Used for Asthma. Can cause osteoporosis
Ipratropium bromide: Used for bronchitis. Can cause anticholinergic ‘dry mouth’
Topical: Intranasal Formulations
- Direct therapeutic effect
Sodium chromoglycate for rhinitis - Systemic effect
Sumatriptan in migraine - Local toxicity
Cocaine: Necrosis of nasal septum
Topical: Eye Drops
Absorption through conjunctival sac epithelium
Local effects in eyes with minimal systemic effects
Some systemic absorption
E.g. Timolol for glaucoma may precipitate bronchospasm in asthma
Topical: Cutaneous Administration
- Local effect on skin
Steroids - Slow systemic absorption (patch)
Lipid soluble drugs only
-Oestrogen
-Opioids – Fentanyl
First Pass Metabolism of Oral Drugs
Gut
Liver
First Pass Metabolism in Gut Lumen
- Gastric acid
E.g. Inactivation of benzylpenicillin - Proteolytic enzymes
E.g. Inactivation of insulin - Microbial enzymes
First Pass Metabolism in Gut Wall
-
Monoamine oxidase: Metabolises monoamines
* Irreversible MAO inhibitors + amine-containing foods
-Tyramine not metabolised by MAO in gut wall
Enters systemic circulation
Releases NAD from stores in nerve endings causing hypertensive crisis
** 2. CYP 3A4**
Many drugs act as inducers, inhibitors or substrates
Blocked by grapefruit juice
3. P-glycoprotein (enterocytes of gut lumen)
Interactions b/w inhibitors (e.g. verapamil, macrolides) and substrates (e.g. digoxin)
Hepatic First Pass Metabolism
- Reduced amount of parent drug
- Metabolites
-More water soluble: Facilitates excretion
-Activity
Decreased
Increased: Pro-drugs
- Inactive precursors, metabolised to active metabolites
-E.g. Cyclophosphamide, simvastatin, ramipril, perindopril
-Reduced first pass metabolism ->Reduced bioavailability of pro-drugs
Bioavailability
The percentage of an ingested dose of a drug that enters systemic circulation
Implications for oral and parenteral dosing
-High bioavailability -> Dose same for IV and p.o. routes
E.g. Metronidazole
-Low bioavailability -> Higher dose for PO than parenteral routes
E.g. Morphine: 10 mg s/c or IM 30 mg PO
