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Drug administration (Dr Browns lectures) (Factors Affecting Drug Action,…
Drug administration (Dr Browns lectures)
Introduction to pharmacology & basic mechanisms of drug action
carrier proteins (transporters):
proton pumps in stomach to produce acid
4 receptors:
These are usually located on the cell membrane and include:
Antagonists such as:
Histamine type 2 receptors (H2)
Cimetidine for gastric ulcers
Muscarinic (M1 receptors)
Hyoscine (scopolamine) for motion sickness
β1-adrenergic receptor antagonists
Propranolol (β-blocker)
Agonists, such as:
Beta adrenergic receptors:
Salbutamol for asthma (β2-receptor agonist)
Note: different receptor types are found in different tissues.
β1-adrenergic in heart
β2-adrenergic in lungs
3 transport systems ion channels (Na):
e.g sodium channels in nerve fibres
calcium channels in heart muscles
other receptors:
Heart & Lungs
Beta adrenergic receptors:
Note: different receptor types are found in different tissues.
β1-adrenergic in heart
Propranolol β1-receptor antagonist to reduce heart rate
β2-adrenergic in lungs
Salbutamol, a β2-receptor agonist for asthma.
2 enzyme inhibitors
Cyclo-oxygenase (produces prostaglandins) inhibitor
Aspirin for inflammation
Phosphodiesterase (breaks down cAMP or cGMP)
Caffeine stimulant.
Sildenafil for MED.
factors affecting drug action:
Dependent upon adequate concentration in fluid surrounding the target tissue.
Concentration will depend upon:
Absorption from site of administration
Distribution of drug molecules around body
Metabolism
Excretion
ADME: also referred to as pharmacokinetics.
Concentration of drug in target tissue/organ determines pharmacodynamics (how well a drug functions) which is determined by ADME rates.
Different types of ligands:
AGONIST: A ligand which, when bound to its receptor, elicits an observable response. May be endogenous or exogenous.
e.g. salbutamol (asthma β2-agonist)
ANTAGONIST: A ligand which inhibits the response to an agonist. May act at the receptor, an associated site or a site distant to the receptor.
e.g. propranolol (to treat fast heart rate β1-antagonist)
How do drugs work:
Drugs cause a change in physiological function by interacting with the organism at the chemical level.
Loosely, this defines pharmacodynamics.
A small number of drugs work by means of their physicochemical properties:
e.g. general anaesthetics and antacids.
Most drugs target specific cellular macromolecules referred to as RECEPTORS which are usually proteins.
Alter DNA/RNA transcription or function
Enzymes
Transport systems
Receptors
Pharmacology encompasses study of the
Actions,
Mechanisms,
Uses,
Adverse effects.
A drug is “any natural or synthetic substance which alters the physiological state of a living organism”.
Broadly speaking, drugs can be divided into two group:
Medicinal drugs, for prevention, treatment and diagnosis of disease.
Non-medicinal – cannabis and cocaine but also caffeine, nicotine and alcohol (recreational).
Alter DNA/RNA Function
Lipid-Soluble Drugs & Hormones
Hormone diffuses through phospholipid bilayer & into cell
Binds to receptor turning on/off specific genes
New mRNA is formed & directs synthesis of new proteins
New protein alters cell’s activity
Routes of Administration & Pharmacokinetics
Distribution (kinetics)
Metabolism & Excretion (Elimination)
& Personalised Medicine
Routes of Administration & Pharmacokinetics
Factors Affecting Drug Action, Therapeutic Window & Bioavailability
size of molecule:
Diffusion through gaps between cells (glomerulus = 68KDa; capillary 30KDa)
Size of molecule (<0.5 nm Ø),
Aqueous diffusion will only occur through aqueous pores if the drug is smaller than 0.5nm Ø
OTHERWISE, simple lipid diffusion or facilitated/active transport determines if a drug is going to be absorbed.
Common excipients added to tablets:
Why add excipients?
Ease of administration.
Improved compliance.
Consistency and control of bioavailability.
Enhance / maintain / enable bioavailability.
Ensure a robust reproducible product.
Divided into functional classifications:
Diluents e.g. lactose, microcrystalline cellulose
Disintegrants e.g. sodium starch glycolate
Binders e.g.PVP, HPMC
Lubricants e.g. magnesium stearate
Glidants e.g. colloidal SiO2
Summary:
Majority of aspirin SHOULD be absorbed in the stomach?
Q. Why is this not the case?
A. Small intestine has much larger surface area due to microvilli.
Why does aspirin irritate stomach cells?
Large amounts of aspirin enters the cells due to the favourable pH but gets trapped due to the higher pH in the cells.
Useful to help increase excretion by making urine alkaline, thereby trapping the weak acid.
Bioavailability:
the proportion of the drug in a dosage form available to the body
other factors:
Stereochemistry:
important if membrane carriers are involved
eg L-DOPA absorbed by aromatic amino acid carriers such as phenylalanine.
Metabolism:
if a prodrug is administered this becomes important,
eg aspirin converted to salicylic acid, azathioprine converted to 6-mercaptopurine
Diamorphine conversion to morphine
Codeine to morphine
intestinal metabolism may limit bioavailability
concentration gradient
Dependent upon:
concentration of free lipid soluble form if transport is via lipid diffusion or concentration of total amount if by active transport or facilitated diffusion. (Remember pKa).
Blood flow through the tissue (intestine)
Speed of transit through the GI-tract
eg oral contraceptives with diarrhoea
Extent of ionization
Drugs are absorbed more readily if they are non-ionised.
This depends upon the pH of the environment the drug is in:
Q? How can we predict the proportion of ionised to non-ionised drug:
A. Henderson-Hasselbach equation:
pKa = “The pH at which 50% of the drug is ionised”.
plasma protein binding:
Certain drugs bind readily to plasma proteins (albumin and -globulin)
eg. Heparin, warfarin, tetracycline
Forms a circulating depot preparation,
Important when considering giving other drugs in combination with highly protein bound drugs
eg phenytoin + tetracycline
FRIABILITY
Only important with oral or rectal dosing.
Rate at which drug disintegrates in gastric juice or rectum.
surface area of absorbing surface:
Most mucous membranes have a relatively small surface area.
bucal mucosa (oral cavity)
vaginal mucosa,
nasal.
Other mucous membranes have:
Secretory function:
Stomach
Others have secretory and absorptive function
Small intestine. Surface area of ~200 m2 (tennis court)
Factors affecting oral absorption:
Compliance: Taking medication regularly.
Drug formulation - disintegration/ dissolution rates (particle size) Tablets, elixir, slow release
Presence of food - penicillin
pH of gastric contents - antacids etc
Gastrointestinal motility
Migraine, diabetic neuropathy cause stasis and slow drug absorption
Diarrhoea: increases motility and reduces absorption (oral contraceptives!)
Partition Coefficient
Greater the partition coefficient, greater the amount of drug absorbed.
Further excipients:
Solvent / co-solvents
Buffering agents
Antimicrobial preservatives
Anti-oxidants
Wetting agents
Anti-foaming agents during manufacture
Thickening agents
Sweetening and flavouring agents
Reasons for using a loading dose?
Highly plasma protein bound.
Accumulation in body compartments.
Slow rate of elimination.
What can we do if drug has a narrow therapeutic window?
Therapeutic Drug Monitoring (TDM)
Titrate dose/infusion rate based on patients body weight?
e.g. Propofol (general anaesthetic; induction)
Measure plasma concentration?
e.g. Lithium citrate (mood stabilizer)
Measure biochemical parameter?
e.g. Warfarin (anti-coagulant)
INR = International normalisation ratio
Prothrombin time (blood clotting time)