MT1 Flashcards
Define Drugs
Therapeutic agent;
Any substance, other than food, used in the prevention, diagnosis, alleviation, treatment or cure of a disease
Pharmacodynamics is…
what drugs do to the body;
The study of the relationship of drug concentration to drug effects
Pharmacokinetics is…
The quantitative study and characterization of the time course of drug concentrations in the body;
Describes the time course of drug concentrations in the body;
Potency
Related to the amount of agonist needed to produce an effect of a given magnitude;
Usually expressed as ED50 where low ED50 = high potency
ED50
dose to achieve 50% of the maximum effect achievable with that agonist
Efficacy
related to the maximum effect that can be achieved with a particular agonist;
Usually expressed as Emax where high Emax = high efficacy
Emax
The maximum effect that can be achieved with that drug
Maximum efficacy is defined as
the maximum effect achieved with the endogenous receptor agonist
Inverse agonists
stabilize inactive state of a receptor or destabilize the active state.
Their effect is to reduce constitutuve receptor activation
Chemical antagonism
direct interaction of two substances in solution such that the effect of one or both is lost.
Physiological antagonism
Indirect interaction of two substances with opposing physiological actions
Pharmacological antagonism
blockage of interaction of one substance with receptor by another substance
Competitive Antagonists (3)
Bind reversibly to the receptor;
Inhibition can be overcome by increasing [agonist];
Primarily affect agonist potency;
Non-Competitive Antagonists (3)
Bind irreversibly (eg. covalently) to the receptor or reversibly/irreversibly to an allosteric site;
Inhibition cannot be overcome by increasing [agonist];
Primarily affect efficacy;
What kind of antagonist reduces the number of receptors available for activation by agonists?
Non-competitive antagonists
Superagonists
Rare;
>100% Emax;
Drug desensitization
The effect of a drug often diminishes when given continuously or repeatedly
Receptor mediated desensitization
Loss of receptor function;
Reduction in receptor number;
Non-receptor mediated drug desensitization
REducation of receptor-coupled signalling components;
Reducation of drug concentration;
Physiological adaption
ADME
Absorption
Distribution
Metabolism
Excretion
Routes of administration
SYSTEMIC: enteral, parenteral
LOCAL: topical
Enter drug administration
Desired effect is systemic (non-local), substance is given via digestive tract;
Ex. Oral route
Oral route of drug admin
Enteral route;
Most common and convenient route;
Subject to FIRST PASS EFFECT (metabolism by intestine/liver enzymes);
So not suitable for drugs that are rapidly metabolized, acid labile, known to cause GIT irritation;
First pass effect
Metabolism of drug that reduces amount of drug that ultimately reaches the systemic circulation (bioavailability)
Parenteral drug admin
desired effect is systemic (non-local), drug is given by route other than digestive tract;
Transmucousal druf admin
A parenteral form of drug admin; Includes: Buccal - under tongue Insufflation - snort Inhalation
Injection drug admin
A parenteral form of drug admin;
Usually intravenous, intramuscular, or subcutaneous;
Intravenous is rapid to bloodstream because it is direct and give 100% bioavailability;
By-pass first pass effect;
Suitable for acid labile drugs;
But may require professional admin, high costs, sterile preparation;
Oral drug absorption
the process by which a drug moves from the site of admin to the site of measurement (usually blood)
Drug Distribution
The process by which drug REVERSIBLY leaves the blood and is distributed throughout the tissues of the body
Drug distribution depends on (4)
1 - blood flow (lung, kidney, liver > brain, skeletal muscle > adipose, bone)
2 - Ability of drug to transverse cell membranes
3 - degree of binding to blood proteins
4 - unique proterties of drug/tissue
Why is volume of distribution ‘apparent’?
It assumes equal partitioning throughout body (eg pl concentration is equal to that of all other volumes)
Factors contributing to a high volume of distribution
Physiological properties of drug:
- high lipophilicity, low polarity, low ionization and low MW
- Increased ability to traverse pl membranes
Physiological properties of tissues:
- iodine containing drugs transported to thyroid
- adipose can accumulate large amounts of lipid-soluble drugs
factors contributing to a low volume of distribution
- low lipophilicity, high polarily, high ionization, high MW
- ability to bind to blood proteins (eg blood serum albumin)
Binding of drug to blood proteins (albumin)
Contributes to a low volume of distribution.
Albumin-bound drugs are generally therapeutically inactive;
Binding is reversible - can be displaced by another drug, Displacement can lead to a dangerous increase in blood concentration of drug
Concerning for highly bound drugs with narrow therapeutic window
Major determinant of action of drugs in the body
Elimination - metabolism and excretion.
Elimination of lipophilic drugs
Most drugs are lipophilic and only partially ionized at physiological pH
- poorly excreted by kidney and liver
- Metabolism increases their polarity, ionization and water solubility
Why are lipophilic drugs poorly excreted by kidney and liver
- bind to plasma proteins, inhibiting glomerular filtration
- reabsorption at renal tubules and biliary epithelium
- partitioning into lipid-rich tissues (adipose)
Bioavailability - define
the amount of administered drug that reached the systemic circulation in unchanged form
Cytochrome P450
CYP Gene Superfamily
- 57 individual genes
- Multiple physiological roles
- Families 1, 2, 3, are most relevant to drug metabolism
- Major contributors to Phase 1 metabolism
- Extremely broad substrate range (multiple isoforms, low specificity for substrates)
- Expression levels vary among individuals - so diff pharmacokinetics
- Enzymatic activity can be inhibited by drugs and diet components (decreases rate of metabolism of co-administered drugs / most common cause of adverse drug interactions)
- Expression levels can be induced by drugs and diet components resulting in increased rate of metabolism of co-administered drugs
CYP 3A4
- most relevant enzyme to human drug metabolism
- most abundant CYP in intestine and liver (first-pass effect)
- very broad substrate specificity
- metabolizes 50-70% of drugs
Interindividual differences in drug metabolism
1 - diet + env (incl. co-administered drugs, smoking, job)
2 - Age (generally drug, metabolism is reduced in elderly and children are different)
3 - Disease (generally reduces metabolism)
4 - Genetic Factors (polymorphisms for drug metabolizing enzymes)
