Basic Principles of Pharmacology

What is pharmacodynamics vs pharmacokinetics?

- pharmacodynamics: what the drug does to the body

- pharmacokinetics: what the body does to the drug

what is pharmacotherapeutics?

- use of drugs to prevent and treat diseases

- indication as to why you are using the drug

what is posology?

- science of drug dosing

what is a drug?

- a medicine or other substance which has a physiological effect when ingested or otherwise introduced into the body

what is a receptor?

- binding site w/ biological effect

what is affinity?

- potential for drug-receptor binding

- some drugs really want to bind to a receptor, but some drugs do not, doses are adjusted accordingly

- how well a drug binds to a receptor

what is Intrinsic activity?

- capacity to produce (vs inhibit) a biological effect

- basically means how well the drug activates the receptor once it is bound

what is intrinsic activity also called?

- efficacy

what is an agonist?

- substances that stimulate a receptor to produce a physiologic reaction

what is an antagonist?

- substances that oppose or interfere with the activity of a receptor and its endogenous substrate without producing a physiologic effect itself

which have both affinity and intrinsic activity, agonist or antagonist?

- agonist

which has only affinity but no intrinsic activity, agonist or antagonist?

- antagonist

what is specificity?

- ability to act at a specific receptor

what happens when a drug has low specificity?

- it binds everywhere

- low specificity drugs cause lots of side effects

ex: antihistamines

what is selectivity?

- the tendency to act on more than one specific receptor

- how much more strongly a drug acts on one receptor compared to another

What is EC50?

- Concentration of drug that produces 50% of maximal response

- in vitro

what is ED50?

- 'effective' dose to illicit a 50% response (in vivo)

what is maximum dose?

- minimum amount of drug producing maximum therapeutic effect

- sometimes called ED95 on graph

what is potency?

- biological response to a given dose

- C has the highest potency out of all of the others

what is efficacy?

- the ability of a drug to produce a maximum response

- A and B have the equivalent efficacy, C has the lowest

- A is also more potent compared to B

what is toxicity?

- the degree to which a substance can harm humans or animals

what is therapeutic index?

- TD50 / ED50

is higher or lower therapeutic index better?

- high

- on graph, further away from each other is better.

what is IC50?

- 'inhibitory' concentration is needed to inhibit, in vitro, a given biological process or biological component by 50%

what is tolerance?

- a decrease in response to a drug that is used repeatedly

- can be overcome by increased concentration

what is Tachyphylaxis?

- rapidly decreasing therapeutic response, cannot be overcome by increased concentration

what are the types of receptors?

A. Ligand-gated ion channels

B. G protein-coupled receptors (most common in ocular pharm)

C. Enzymatic

D. Calcium Release

E. Nuclear

what are the different modes of action for agonist?

−Direct

−Indirect

−Mixed

−Inverse

−Partial

what is a direct agnost?

- binds directly to the binding site and activates it

- ex: phenylephrine

what is an indirect agnost?

- does not bind to binding site

- causes release of something that does bind to the binding site

- ex: cocaine, causes release of norepinephrine to bind to alpha one receptor

what is a mixed agonist?

- it can be an agonist or an antagonist depending on the concentration in the body

- ex: tamoxifen

What is an inverse agonist?

- Agonist that binds to the same site as an agonist however produces an opposite response

- ex: antihistamines

What is a partial agonist?

- A drug that binds to its receptor but produces a smaller effect at full dosage than a full agonist

- used to reduce dependency on a drug

how can antagonist be classified?

- binding integrity

- binding site selectivity

- mode of action

what are the type of binding integrity of antagonist?

- reversible

- irreversible

what are the types of binding site selectivity of antagonist?

- competitive

- non-competitive (allosteric)

- Uncompetitive (allosteric binding in presence of substrate slows ligand dissociation and response rate)

what are competitive antagonist?

- antagonist that bind to the receptor site of the agonist

What is a non-competitive antagonist?

- A non-competitive antagonist binds to a different receptor (allosteric) and causes the receptor of the agonist so it can no longer bind

- can be either reversible or irreversible

- if irreversible, then there is formation of covalent bonds at the receptor

what is an uncompetitive antagonist?

- uncompetitive antagonist are unable to bind to allosteric site until there is an agonist that is bound, once agonist is on receptor, it binds and locks agonist in so other agonist can not bind to the receptor

- usually reversible

what are the different modes of action of antagonist?

- biological

- chemical

- physiological

what is ADME?

- absorption

- distribution

- metabolism

- excretion

what influences a medications ability to get absorbed?

- first pass metabolism

- barriers: degree of vascularity at site of administration

- patient age, gender, weight, pregnancy, health

what is distribution influenced by?

- Volume of Distribution (Vd) = dose/[drug in plasma]

− Influenced greatly by route of administration

what is metabolism influenced by?

− Reflected by drug half life

− Influenced greatly by health of metabolizing organ(s)

what is elimination?

− Routes may include fecal, urinary, sweat, respiration and saliva

− Drug clearance = [drug volume eliminated] ÷ [time]

what is the volume of the tear film?

- 10 microliters

what is the max surface volume of the tear film?

- 30 microliters

what is the volume of a drop of medication?

- 25-50 microliters

what are the three layers of the tear film?

- Lipid, aqueous, mucin

where is most of a drop of medication eliminated in the eye?

- 80% is eliminated in the nasolacrimal drainage with first 2 minutes

what is done to help reduce elimination of a drop of medication?

- punctal occlusion

what kind of medication can pass through the corneal epithelium?

- epithelium has tight junctions, which are barriers to drugs (helps to keep bacterial/infection out)

- barrier to hydrophilic drugs

- favors absorption of lipophilic

what must a drop of medication be to absorbed by corneal epithelium?

- lipophilic

- small

how does the cornea play a role in the pharmacokinetics of a medication?

- major barrier to ocular penetration

- major site of absorption for topical drugs

- corneal esterase metabolizes lipophilic prodrugs

- reservoir (distribution)

epithelium: lipophilic

stroma: hydrophilic

how do larger/hydrophilic molecules get absorbed in the eye?

- get absorbed through conjunctiva or sclera

- less than 20% of drug passage to iris and ciliary body due to high vascularization and blood vessels

what percentage of medication reaches the anterior chamber?

- 1-7%

- cornea is a good barrier

how often is the aqueous recycled?

- about every 50 minutes, especially hydrophilic drugs

- aqueous humor = 200 microliters

how does the iris affect pharmokinetics?

- pigment granules of the iris epithelium absorb light and also can absorb lipophilic drugs

- tropicamide is a lipophillic drug, patients with darker iris are dilated less bc the pigment granules absorb more

- most anti-cholinergics are lipophillic

who dilates easier blue or brown eyes?

- blue eyes bc there is less pigment for the medication to attach onto

does the crystalline lens act as a barrier to medication?

- yes, especially to hydrophilic and large molecules (hydrophobic barrier meaning it does not allow hydrophilic in and allows hydrophobic)

- prevents drug penetration from anterior chamber to posterior chamber

(we do not want things to reach the posterior chamber and the vitreous is mainly made up of water)

- lens epithelium is hydrophobic/lipophilic, this is significant bc some of the lens absorbs steroids leading to PSC.

how would you get medication into the posterior chamber?

- injections

what part of the eye is the blood-aqueous barrier?

- ciliary body

- entry point for systemic drug

- primary drug metabolism site major ocular source of drug metabolizing enzymes

what is the role of the vitreous in medication?

- can serve both as a major reservoir (distribution) for drugs and as a temporary storage depot

• Elimination −anterior chamber−choroid

what is the outer blood retinal barrier?

- tight junction complexes (zonula occludens) in the RPE

what is the inner blood retinal barrier?

- capillaries of the retina are lined by continuous, close-walled, endothelial cells

- helps prevent blood from leaking, but also does not let medications leave

what is the function of the blood retinal barriers?

- barrier to metabolites and toxins and is effective against most hydrophilic drugs

when would zero order kinetics be more advantageous for a medication when compared to first order?

- when there is a small dosage of the drugs

- eliminates at a constant rates

when would first order kinetics be more advantageous for a medication when compared to zero order?

- when there is a large amount of the drug

- left is low dose

- right is high dose

is alcohol consumption first or zero order kinetics?

- zero, there is a fixed rate at which we can eliminate alcohol

- reason as to why we get drunk

what is posology based off?

- first and zero order kinetics

what is a steady state of a drug?

- first order kinetics

- achieved when rate of intake equals rate of elimination

- the rate of elimination depends on the concentration of the drug

how does zero order kinetics affect dosing schedules?

− Greater demand for dose modification: loading vs maintenance

− Doubling a dose calls for twice the time to be metabolized

what must be done in order to achieve a steady state?

- Dosing intervals need to achieve a steady state

• The steady state must approach the therapeutic drug level for the given condition

• Adjustments may be required to dosing frequency

• To reach new therapeutic levels

• To improve compliance

- in this picture, after the first dose, it temporarily reaches a therapeutic level, but then decreases due to elimination

- additional doses are needed to maintain steady states

what would be done if an increase in therapeutic level in needed to treat a disease?

- increase the concentration, increase in dosing is not needed

- increase frequency of dosing, keep concentration the same

- in some cases, certain concentrations are not available

what can be done to improve compliance?

- increase concentration, lower the frequency of dosage the patient has to take

what is polypharmacy?

- use of 5 or more medications

what is resistance?

- loss of pharmacological effect especially to bacteria

what is Teratogenesis?

- congenital malformation

what is Bioavailability?

- amount of active drug reaching target tissue

what does DPA stand for?

- diagnostic pharmaceutical agent

what does TPA stand for?

- therapeutic pharmaceutical agent