PRINCIPLES OF PHARMACOKINE

TICS AND PHARMACODYNA

MICS

Sandeep KandelInstitute of Medicine Maharajgunj Medical Campus, Nepal

PRESENTATION LAYOUTI. Pharmacokinetics

Absorption Distribution Metabolism Excretion

II. Pharmacodynamics Signal Transduction Dose Response

Relationship Agonist and Antagonist

III.Ocular Pharmacology

Ocular Drug Absorption Drug Delivery System

PHARMACOKINETICS AND PHARMACODYNAMICSThe purpose of studying pharmacokinetics and pharmacodynamics is to understand the drug action, therapy, design, development and evaluation

Pharmacokinetics is what the Body Does To The Drug like how the drug is Absorbed, Distributed, Metabolized, and Excreted by the body – Drug disposition

Pharmacodynamics is what the Drug Does To The Body which may be the therapeutic effects or the adverse side effects - Drug action

PHARMACOKINETICS

PHARMACOKINETICSRefers to what body does to the drugDefined as the study of the time course of drug absorption, distribution, metabolism, and excretionThese four pharmacokinetic properties determine the:

•Speed of onset of drug action

•Intensity of drug’s effect

•Duration of drug action

Absorption

Distribution

Metabolism

Elimination

AbsorptionDrug absorption from the site of administration permits the entry of the therapeutic agent into the plasma

Distribution The drug may then reversibly leave the bloodstream and distribute into the interstitial and intracellular fluids

MetabolismThen the drug may be biotransformed by the metabolism in liver, or other tissues

Elimination Finally, the drug and its metabolites are eliminated from the body in the urine, bile, or feces.

I. ABSORPTION OF DRUGS

It is the transfer of a drug from its site of administration to the bloodstream via one of the several mechanismsThe rate and efficiency of absorption depend upon following factors:

The environment where the drug is absorbedThe drug’s chemical characteristicsRoute of administration (which influences the bioavialability)

MECHANISM OF ABSORPTION OF DRUGS FROM THE GI TRACT

Passive Diffusion: •The driving force for passive diffusion is the concentration gradient across a membrane separating the two body compartments

•Water soluble drugs penetrate the cell membrane through the aqueous channels or pores

•The lipid soluble drugs gain access to the cell across the biological membranes due to their solubility in the membrane lipid bilayers

Facilitated Diffusion:

Drugs enter the cell through specialized trans-membrane carrier proteins that facilitate the passage of large molecules

It requires carrier molecules and can be saturated

Active Transport:

• This mode of drug entry involves specific carrier proteins that span the membrane and energy-dependent active transport is driven by the hydrolysis of ATP

• It is capable of moving the drugs against the concentration gradient ie. from low concentration to high concentration

Endocytosis and Exocytosis:

• Transports the drug of exceptionally large size across the cell membrane

• Endocytosis involves the engulfment of a drug molecule by the cell membrane and transport into the cell by pinching off the drug filled vesicle.

• Exocytosis is used by cells to secrete many substances by similar vesicle formation process

• For instance, Vitamin B12 is transported across the gut by endocytosis and neurotansmitters like nor-epinephrine are released by exocytosis

DRUG DISPOSITION

FACTORS AFFECTING DRUG ABSORPTION

1. Effect of pH on drug absorption[

•Most drugs are either weak acids or weak bases•Acidic drugs (HA) release a proton (H+), causing a charged anion (A-) to form

HA H+ + A –

•Weak bases (BH+) can also release an H+ and loss of a proton produces the uncharged base (B)

BH+ B + H+

•A drug passes through membranes more readily if it is uncharged, thus for weak acid, uncharged protonated HA can permeate through the membranes and A- cannot•For weak bases, the uncharged B can permeate through the membranes but the protonated form BH+ cannot

•The ratio between the ionized and the non ionized forms is determined by the pH at the site of absorption and by the strength of the weak acid or base, represented by the ionization constant, pKa

2. Blood flow to the site of absorption•Because the blood flow to the intestine is much greater than that of stomach, the absorption of drug from intestine is more favored

3. Total surface area available for absorption•With surface rich in brush border containing micro-villi, the intestine has a surface area about 1000-fold that of the stomach, making absorption of drug across the intestine more efficient

4. Contact time at the absorption surface• If the drug moves across the GI tract very quickly, as can happen with severe diarrhea, it is not well absorbed

5. Expression of P-Glycoprotein•P-glycoprotein is a multidrug trans-membrane transporter protein responsible for transporting various molecules including drugs

BIOAVAILABILITYBioavailability is the fraction of administered drug that reaches the systemic circulation

Is important for calculating drug doses for non-intravenous routes of administration

It is determined by comparing the plasma levels of a drug after a particular route of administration with the plasma drug levels achieved by IV injection, in which the total agent rapidly enters the circulation

FACTORS INFLUENCING THE BIOAVAILABILITY

In contrast to IV administration, which confers 100% bioavailability, the oral administration of drug involves the first-pass metabolism A. First-Pass hepatic metabolismWhen the drug is absorbed across the GI tract, it first enters the portal circulation before entering the systemic circulationIf the drug is rapidly metabolized in the liver or gut wall during the initial passage, the amount of unchanged drug in the circulation is decreased

B. Solubility of the drug • Very hydrophilic drug are poorly absorbed

because of their inability to cross the lipid-rich cell membranes

• Paradoxically, drugs that are extremely hydrophobic are also poorly absorbed, because they are totally insoluble in the aqueous body fluids

• For a drug to be readily absorbed, it must be largely hydrophobic, yet have some solubility in aqueous solutions

• That’s why many drugs are either weak acids or weak bases

BIOEQUIVALENCETwo related drug preparations are bioequivalent if they show comparable bioavailability and similar times to reach the peak blood concentrations

THERAPEUTIC EQUIVALENCETwo similar drugs are therapeutically equal if they are pharmaceutically equivalent with similar clinical and safety profiles

II. DRUG DISTRIBUTION

Process by which a drug reversibly leaves the blood-stream and enters the interstitium (extracellular fluid) and then the cells of the tissues

A. Blood Flow: • The rate of blood flow to the different tissue

capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs

• Blood flow to the brain, liver and kidney is greater compared to that of adipose tissue, skin and viscera.

B. Capillary permeability: •In the liver and spleen, a large part of the basement membrane is exposed due to large, discontinuous capillaries through which large plasma proteins can pass•While in case of brain, the capillary structure is continuous that constitute the blood-brain barrier•So, to enter the brain, drugs must pass through the endothelial cells of the capillaries of the CNS or be actively transported•Lipid soluble drugs can readily penetrate into the CNS because they can dissolve in the membrane of the endothelial cells

C. Binding of drugs to plasma proteins and tissues: Binding to the plasma proteins:• Reversible binding to the plasma proteins sequester

drugs into the non-diffusible form and slows their transfer out of the vascular compartment

• Plasma albumin is a major drug binding protein and may act as a drug reservoir

Binding to the tissue protein:• Numerous drugs accumulate in the tissues, leading

to the higher concentration of drug in the tissues than in the ECF and blood

• Drugs may accumulate as a result of binding to the tissue proteins, lipid, or nucleic acids

VOLUME OF DISTRIBUTION

The apparent volume of distribution, Vd, can be thought of as the fluid volume that is required to contain the entire drug in the body at the same concentration measured in the plasma

Where, C0 = Plasma concentration at time zeroOnce the drug enters the body, it has the potential to distribute into any one of three functionally distinct compartments of body water or to become sequestered in a cellular site

Vd= (Amount of drug in the body)/C0

Plasma compartment: If a drug has a very large molecular weight or binds

extensively to the plasma proteins, it is too large to move out through the endothelial slit junctions of capillaries, thus is trapped within the plasma

Extracellular Fluid: If a drug is of low molecular weight but is

hydrophillic, it can move through the endothelial slit junctions of the capillaries into the interstitial fluid.

However, the hydrophillic drugs cannot move across the lipid membrane of cell to enter the water phase inside the cell

Hence these drugs distribute into a volume that is sum of plasma water and the interstitial fluid which constitute about 20% of total body weight ie. 14L in a 70kg individual

Total Body Water If the drug has low molecular weight and is hydrophobic, it moves into interstitium through the slit junctions as well as through the cell membranes into the intracellular fluid

Into a volume of about 60% of total body weight ie. 42L of a 70kg individual

III. DRUG CLEARANCE BY METABOLISM

The major routes involved in drug elimination are• Hepatic Metabolism• Elimination in Bile• Elimination in Urine

Metabolism leads to products with increased polarity, which will allow the drug to be eliminated Clearance(CL): It estimates the amount of drug cleared from the body per unit of time

CL= 0.693 × Vd/t1/2 Where, t1/2 = The drug’s elimination half time Vd = Apparent volume of distribution

KINETICS OF METABOLISM:

First Order Kinetics:

• When the rate of drug metabolism and elimination is directly proportional to the concentration of free drug, and first order kinetics is observed

• Hence, with every half life the drug concentration reduces by 50%

Zero Order Kinetics:

• With few drugs like aspirin, ethanol and phenytoin, the doses are very large• Therefore, the rate of metabolism remains constant over time. This is called

zero order kinetics, clinically referred to as Non-linear kinetics

REACTIONS OF DRUG METABOLISM

The kidney cannot efficiently eliminate lipophillic drugs that readily crosses cell membrane and are reabsorbed in the distal convoluted tubules.

Therefore, the lipophillic agents must be metabolized into more polar substances in the liver using two general sets of reactions:

Phase I Phase II

PHASE I REACTIONConverts lipophilic molecules into more polar molecules by introducing or unmasking a polar functional group such as –OH or –NH2

Most frequently catalyzed by the Cytochrome P450 system

Various reactions like, Amine oxidation, alcohol dehydrogenation and etc, do not involve P450 systems

PHASE II REACTIONConsists of the conjugation reactions

Subsequent conjugation of Phase I metabolites with an endogenous substrate, such as Glucuronic acid, Sulfuric acid, Acetic acid or an amino acid results in polar and therapeutically inactive compounds

Glucuronidation is the most common and most important conjugation reaction

IV. DRUG CLEARANCE BY THE KIDNEY

Involves three processes:

GLOMERULAR FILTRATION

Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexusFree drug flows through the capillary slits into the Bowman’s Space as part of the glomerular filtrate

Lipid Solubility and pH do not influence the passage of drugs into the glomerular filtrate

PROXIMAL TUBULAR SECRETION

Drugs that were not transferred into the glomerular filtrate leave the glomeruli through the efferent arterioles, which divides to form capillary plexus around the proximal tubule

Secretion primarily occurs in the proximal tubules by two energy-requiring active transport systems:

One for Cations One for Anions

DISTAL TUBULAR REABSORPTION

As drug moves toward the distal convoluted tubule, its concentration increases and exceeds that of peri-vascular areaIf the drug is uncharged then it may diffuse out of the nephric lumen into the systemic circulation

ION TRAPPINGThe manipulation of the pH of urine to increase the ionized form of drug to minimize the amount of back diffusion and hence increasing the clearance of the undesirable drug

Weak acids can be eliminated by method of Ion Tapping by alkalinization of urine while weak base can be eliminated by the acidification of the urine

DRUG CLEARANCE BY OTHER ROUTESOther routes of drug elimination mainly include via intestines, the bile, the lungs, and the breast-milk in the lactating mother

The feces are primarily involved in elimination of unabsorbed orally ingested drugsThe lungs are primarily involved in the elimination of anesthetic agents

Excretion of drugs into milk, sweat, saliva, tears, hair, and skin occurs only to a small extent

TOTAL BODY CLEARANCEThe total body clearance, CLtotal, is the sum of the clearances from various drug metabolizing and drug eliminating organs.

CLtotal= CLhepatic+ CLrenal+ CLpulmonary+ CLother

BIOLOGICAL HALF-LIFE OF A DRUGThe time required for one-half of an administered drug to disappear from the blood plasma

 As the drug molecule leaves plasma it can be eliminated from the body, or it can be translocated to another body fluid compartment such as the intracellular fluid or it can be destroyed in the blood

As repeated doses of a drug are administered its plasma concentration builds up and reaches the steady state

STEADY STATEWhen the amount of drug in the plasma has built up to a concentration level that is therapeutically effective and as long as regular doses are administered to balance the amount of drug being cleared the drug will continue to be active The time taken to reach the steady state is about five times the half life of a drugSometimes a loading dose may be administered so that a steady state is reached more quickly then smaller maintenance doses are given to ensure that the drug levels stay within the steady state

PHARMACODYNAMICS

PHARMACODYNAMICS

Pharmacodynamics describes the actions of a drug on the body and the influence of drug concentrations on the magnitude of the response

Drug-receptor complex initiates alterations in the biochemical and/or molecular activity of a cell by a process called signal transduction

I. SIGNAL TRANSDUCTION

Drugs act as signals and their receptors act as signal detectors A. The Drug Receptor Complex:Cells have different types of receptors, each of which is specific for a particular ligand and produce an unique responseReceptors has ability to recognize a ligand and couple or transduce this binding into a response by causing a conformational change or a biochemical effectRecognition of drug by receptor is analogous to the Lock and key principle

B. Receptor State:Classically, the binding of a ligand was thought to cause receptors to change from an inactive state to an activated state

However, recent studies suggest that receptors exist in two states, inactive and active, that are in reversible equilibrium with one another

In absence of agonist, the equilibrium mainly favors the inactive state

Drugs acting as agonists bind to the active state of receptor and thus rapidly shift the equilibrium from inactive to activated state

C. MAJOR RECEPTOR FAMILIES

Pharmacology defines receptor as any biologic molecule to which a drug binds and produce a measurable response

Thus, enzymes, nucleic acids and structural proteins can be considered to be pharmacologic receptors

However, the richest source of therapeutically exploitable pharmacologic receptors are the proteins

PHARMACOLOGIC RECEPTORS

Ligand-Gated Ion Channels

G Protein-Coupled Receptors

Enzyme-Linked Receptor Channels

Intracellular Receptors

TRANSMEMBRANE LIGANDGATED ION CHANNELS

It is responsible for the regulation of the flow of ions across the cell membranesResponse to these receptors is very rapidThese receptors mediate diverse functions including neurotransmission, cardiac conduction, and muscle contractionFor example: generation of an action potential and activation of contraction in the skeletal muscle

TRANSMEMBRANE G PROTEIN-COUPLED RECEPTORS

Comprises a single alpha-helical peptide that has seven membrane-spanning regionsImportant processes mediated by G Protein-Coupled Receptors include neurotransmission, olfaction and visionThe extracellular domain of this receptor usually contains the ligand binding areaIntracellularly, these receptors are linked to a G Protein having three subunits, an α subunit that binds GTP and a beta-gamma subunit

Binding of appropriate ligand activates the G protein so that GTP replaces GDP on the α subunit

Dissociation of G protein occurs, and both the α -GTP subunit and beta-gamma subunit interact with other cellular effectors which further activates second messengers responsible for other actions within the cell

SECOND MESSENGERS

These are essential in conducting and amplifying signals coming from G-Protein Coupled receptors

A common pathway turned on by Gs and other types of G proteins, is the activation of adenyl cyclase by α GTP subunits, which results in the production of cAMP- a second messenger that regulates protein phosphorylation

ENZYME LINKED RECEPTORS

Consists of a protein that spans the membrane once and may form dimers or multisubunit complexes

Also have cytosolic enzyme activity as an integral component of their structure

Metabolism, growth and differentiation are important biological functions controlled by these receptors

INTRACELLULAR RECEPTORS

Ligand must be sufficiently lipid soluble so as to diffuse into the cell to interact with this receptorSteroid hormones exert their action on target via this receptor mechanismBinding of the ligand to its receptor activates the receptor and the activated ligand-receptor complex migrates to the nucleus, where it binds to specific DNA sequence, resulting in the regulation of gene expressionOther targets of intracellular ligands are structural proteins, enzymes, RNA and ribosomes

PHARMACOLOGIC RECEPTORS

CHARACTERS OF SIGNAL TRANSDUCTION

1.Ability to amplify small signals:Firstly, a single ligand-receptor complex can interact with many G proteins, thereby multiplying the original signal by manyfold

Secondly, the activated G proteins persists for a longer duration to amplify the signals

2. Desensitization of Receptors:When the repeated administration of a drug results in a diminished effect, the phenomenon is called tachyphylaxis

In this process, the receptors are still present on the cell surface but are unresponsive to the ligand

II. DOSE RESPONSE RELATIONSHIPAs the concentration of drug increases, the magnitude of its pharmacologic effect also increses

Plotting the magnitude of the response against the increasing dose of drug produces the graded drug-dose response curve, that generally has a shape of a rectangular hyperbola

The two important properties of the drug defined in the graph are its efficacy and potency

1. Potency It is an amount of drug required to produce an

effect of a given amplitudeThe concentration of drug producing an effect of

50% of the maximum is commonly designated as EC50

2. Efficacy It’s the ability of the drug to elicit a response

when it interacts with a receptorA drug with greater efficacy is more important

than drug potencyMaximal efficacy assumes that all the receptors

are occupied by the drug and no increase in the response will be observed if more drugs is added

III. AGONISTS Binds to a receptor and produces a biological response which may mimic the response of an endogenous ligand A. Full Agonist:

If a drug binds to a receptor and produces a maximal biological response it is known as a full agonist

B. Partial Agonist: Have efficacies greater than zero but less than that

of full agonist The unique feature of partial agonist is that, under

appropriate conditions, a partial agonist may act as an antagonist of a full agonist

C. Inverse AgonistThey reverse the constitutive activity of receptors and exert the opposite pharmacological effect of receptor agonist

IV. ANTAGONISTS

Antagonist are the drugs that decrease or oppose the actions of another drug or endogenous ligand

An antagonist has no effect if an agonist is not presentIf both the antagonist and the agonist bind to the same receptor then they are said to be competitive

An antagonist may act at a completely separate receptor, initiating effects that are functionally opposite to those of the agonist

V. THERAPEUTIC INDEX

The therapeutic index of the drug is the ratio of the dose that produces toxicity to the dose that produces a clinically desired response in the population of the individuals

Where , TD50=the drug that produces toxic effect in half the population

ED50=the drug that produces a therapeutic effect in half the population

TI=TD50/ED50

OCULAR PHARMACOLOGY

MECHANISMS OF OCULAR DRUG ABSORPTION

Drugs can be administered in many different topical forms, including solutions, gels and ointments. The efficacy of treatment is usually dependent on intraocular penetration, which depends on:

1) Permeability of the drug across the cornea

2) Anatomical and physiological influences of the local environment, including lacrimation, tear drainage and the composition of the precorneal tear film.

ROUTES OF ADMINISTRATION

Conjunctiva

Topical administration into the inferior fornix of the conjunctiva is by far the most common route of ocular drug delivery

Both lacrimation and blinking profoundly influence the residence time of fluid in the fornix.

CLINICAL CORRELATIONThe conjunctival sac has a capacity of approximately 15–30 μL (dependent on blinking) and the natural tear film volume is 7–8 μL The tears turn over at approximately 16% per minute during a normal blink rate of 15–20 blinks per minute Most solution applicators deliver between 50 and 100 μL per drop, so a substantial amount of drug will be lost through overspill on administration

After its transport through the epithelium, in the subconjunctival stroma, which is a highly vascular conjunctiva owing to the rich superficial venous plexus and lid margin vessels, drugs may be absorbed in significant concentrations into the circulation

After administration into the inferior fornix, drugs drain directly through the nasolacrimal duct into the nose, where measurable systemic absorption of drugs via the nasal and nasopharyngeal mucosa occurs

Restricting the entry of a topically applied ophthalmic dose into the nasal cavity by nasolacrimal occlusion for 5 min, or by making appropriate alterations to the vehicle (i.e. from solution to ointment) increases ocular absorption

PRECORNEAL TEAR FILM AND CORNEA

The pH of normal tears varies between 6.5 and 7.6, while many drug delivery systems are often formulated at pH of less than 7

Any alteration in the components of the tear film will result in instability of the tear film and a reduced conjunctival residence time of the drug.

At the same time alteration in the pH of the tear film may affect the ionization of the drug and thus its diffusion capacity.

TRANSPORT OF DRUGS ACROSS CORNEA

The epithelium of the cornea represents the most important barrier to the drugs via this route. First, the stratified cellular epithelium is bound by desmosomes between the lateral borders of the superficial cells. Second, the corneal epithelium is hydrophobic so will allow only lipid-soluble drugs to pass through.

Bowman’s membrane, an acellular collagenous sheet, shows similar drug penetration characters with the stromaIn contrast, the stroma, which accounts for 90% of the corneal substance, permits ionized water-soluble drugs to pass more efficiently than lipid-soluble drugs.Finally, transport across the single-layer endothelium of the cornea is relatively free because it contains gap junctions that permit good penetration of most drugs into the aqueous humour. Hence to exhibit better ocular penetration many topical eye medications are weak bases, for example tropicamide, cyclopentolate and atropine

CILIARY BODYDrugs are usually limited by the apically tight junctions of the non-pigmented cells of the ciliary epithelium

Systemic drugs enter the anterior and posterior chambers largely by passing through the ciliary body vasculature and then diffusing into the iris, where they can enter the aqueous humor

The ciliary body is the major ocular source of drug metabolizing enzymes

LENSThe lens can be viewed primarily as a barrier to rapid penetration of drugs from aqueous to vitreous humor

Hydrophilic drugs of high molecular weight cannot be absorbed by the lens from the aqueous humor, because the lens epithelium is a major barrier to entryLipid-soluble drugs, however, can pass slowly into and through the lens CortexAfter the lens removal following cataract surgery more rapid exchange can occur between aqueous and vitreous contents and various ocular components

VITREOUSVitreous can serve both as a major reservoir for drugs and as a temporary storage depot for metabolites

RETINA AND OPTIC NERVETight junctional complexes (zonula occludens) in the retinal pigment epithelium prevent the ready movement of antibiotics and other drugs from the blood to the retina and vitreousThe barrier protects against the entry of a wide variety of metabolites and toxins and is effective against most hydrophilic drugs, which do not cross the plasma membrane

REMOVAL OF DRUGS AND METABOLITESThe bloodstream is responsible for removing drugs and drug metabolites from ocular tissuesThe two circulatory pathways in the eye—the retinal vessels and the uveal vessels—are fairly differentThe retinal vessels can remove many drugs, metabolites, and such agents as prostaglandins from the vitreous humor and retina, apparently by active transportThe uveal vessels remove drugs by bulk transport from the iris and ciliary body

BIOAVAILABILITY OF OCULAR DRUGS

Precorneal fluid dynamics

Drug binding to tear proteins

Conjunctival drug absorption

Systemic drug absorptionResistance to corneal penetrationDrug binding to melanin

Intraocular drug metabolism

OCULAR DRUG DELIVERY SYSTEM

The corneal epithelium presents a considerably greater barrier to hydrophilic than to lipophilic drugs (10 : 1)Corneal epithelial permeability increases during ocular inflammation increasing the absorption of drugs, like dexamethasonePenetration of anionic sodium fluorescein, a hydrophilic agent, only in cases epithelial breakdown is also suggestive of lipophilic nature of corneal eptheliumPreservatives such as benzalkonium chloride have also been shown to enhance the ocular absorption of drugs

[

For a drug to penetrate optimally, it must be able to exist in both ionized and un-ionized forms. Drugs will be buffered by the precorneal tear film and any alteration in the pH will change the ratio of ionized to un-ionized forms of the drug

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Once absorbed into the eye, drugs may be bound to melanin within the pigment epithelium of the iris and the ciliary body, which may in turn reduce its bioavailability and also retard its clearanceSimilarly, after penetrating into the eye, drugs may be rendered inactive by intraocular metabolism which is mainly carried out by the ciliary body

DRUG VEHICLES AFFECT DRUG DELIVERY

1. SolutionsSolutions are a common mode of delivery because they cause less blurring of vision than ointmentsThey are easily administered and achieve high intraocular concentrationsPossess a short contact time and are quickly washed away at a rate proportional to the volume instilled Polyvinyl alcohol or methylcellulose added to the solution increases the viscosity and/or lowers the surface tension, and will thus prolong contact time. Ophthalmic suspensions, particularly steroids, are assumed to have the drug particles that persist in the conjunctival sac which gives rise to a sustained-release effect

2. Semisolids (ointments)Ointments consist of any one or a combination of hydrocarbons, mineral oils, lanolin and polymers such as polyvinyl alcohol, carbopol and methylcelluloseDrugs applied by this method provide an increase in the duration of action because of reduced dilution, reduced drainage and prolonged corneal contact timeGive rise to blurring of the vision and an increased incidence of contact dermatitis

Lid Scrub: After several drops of the antibiotic solution or detergent, such as baby shampoo, are placed on the end of a cotton-tipped applicator, the solution is applied to the lid margin with the eyelids either opened or closed

3. Slow-release preparations Ocular InsertsControlled-release delivery systems deliver a bioactive agent to the target site at a controlled concentration over a desired time course. Ocular inserts are flexible, elliptical devices, consisting of three layers. The two outer coats of ethylene vinyl acetate enclose an inner coat of drug/alginate mix.

Collagen shieldsThe collagen bandage shields prolong contact between drug and corneaDrugs can be incorporated into the collagen matrix, absorbed on to the shield during rehydration, or applied topically over a shield when in the eye and the shield releases the drugs gradually into the tear film

Soft contact lens In this case the polymer of the contact lens is hydrophilic and thus water-soluble drugs are absorbed into the lens The lens is hydrated once placed on to the cornea and so releases the drug until equilibrium is reached between drug concentration in the contact lens and in the conjunctival sac

Intravitreal insertsHas gained increasing impetus following the successful trial evidence supporting intravitreal drug administration for macular degeneration, vascular occlusions and CMV viral retinitis

INTRACAMERAL AND INTRAVITREAL ADMINISTRATION

The treatment of many ocular disorders is hampered by poor penetration into the eye

Intracameral administration involves delivering a drug directly into the anterior chamber of the eye

The treatment of bacterial endophthalmitis is often inadequate unless vitrectomy and intravitreal antibiotics are used

PERIOCULAR ADMINISTRATIONWhen higher concentrations of drugs, particularly corticosteroids and antibiotics, are required local injections into the periocular tissues can be considered Includes subconjunctival, sub- Tenon’s, retrobulbar, and peribulbar administration

Subconjunctival Injection:Offer an advantage in the administration of drugs, such as antibiotics, with poor intraocular penetrationSub-conjunctival injection involves passing the needle between the anterior conjunctiva and Tenon’s capsule

Greatest clinical benefit of the sub-conjunctival route is in the treatment of severe corneal disease, such as bacterial ulcers

Sub- Tenon’s Injection:Anterior sub-Tenon’s injections of corticosteroids are occasionally used in the treatment of severe uveitis Posterior sub-Tenon’s injection of corticosteroids is most often used in the treatment of chronic equatorial and mid-zone posterior uveitis, including inflammation of the macular region Cystoid macular edema after cataract extraction and diabetic macular edema are treated occasionally with sub-Tenon’s repository steroids

Retrobulbular Injection:Originally developed to anesthetize the globe for cataract extractionHowever antibiotics, vasodilators, corticosteroids, and alcohol have also been administered through this routeCurrently, retrobulbar anesthetics are frequently used, retrobulbar corticosteroids are used occasionally and retrobulbar alcohol or phenol is rarely administered for intractable ocular pain in blind eyes

Peribulbular Injection:The procedure consists of placing one or two injections of local anesthetic around the globe but not directly into the muscle cone

ADVANCED OCULAR DELIVERY SYSTEM

New Ophthalmic Delivery System(NODS) is a method of administering a drug as a single unit volume within a water-soluble preservative-free form Particulates: Microspheres and nanoparticles represent promising particulate polymeric drug delivery systems for ophthalmic medications Liposomes are vesicles composed of lipid membranes enclosing an aqueous volume Iontophoresis is a method of drug delivery that utilizes an electric current to drive a polar drug across a semipermeable membrane

DRUGS ADMINISTERED SYSTEMICALLY ALSO PENETRATE THE EYE

Carbonic anhydrase inhibitors (acetazolamide and dichlorphenamide), are administered orally or intravenously to reduce intraocular pressure. Systemic antibiotics, like ciprofloxacin, are found to have the ability to reach intraocular infections. Similarly, both non-steroidal anti-inflammatory drugs and steroids penetrate the eye when given orally.Conversely, drugs applied topically may also reach the systemic circulation and affect the contralateral eye.

INSTILLING TOPICAL OCULAR SOLUTIONS

PRESCRIPTION

REFERENCES