Biopharmaceutics lecture4(2)

Routes of Drug Routes of Drug AdministrationAdministration

Presented by:Presented by:

Marcia WilliamsMarcia Williams

Routes of Drug Administration Routes of Drug Administration IntroductionIntroduction

May be classified asMay be classified as– ENTERAL and ENTERAL and – PARENTERAL. PARENTERAL.

Enteral means has to do with the GI tract and includes Enteral means has to do with the GI tract and includes oral, buccal, and rectal. oral, buccal, and rectal. Parenteral means not through the alimentary canal and Parenteral means not through the alimentary canal and commonly refers to injections such as IV, IM, and SC; commonly refers to injections such as IV, IM, and SC; but could also include topical and inhalation. but could also include topical and inhalation. IV can be distinguished from the rest, as with all others IV can be distinguished from the rest, as with all others at least one membrane must be crossed, thus an at least one membrane must be crossed, thus an absorption process is involved in the administration and absorption process is involved in the administration and the pharmacokinetics. the pharmacokinetics.

Buccal/SublingualBuccal/SublingualRouteRoute

Drug is taken as smaller tablets which are held Drug is taken as smaller tablets which are held in the mouth or under the tongue.in the mouth or under the tongue.Buccal tablets are often harder tablets [4 hour Buccal tablets are often harder tablets [4 hour disintegration time], designed to dissolve slowly. disintegration time], designed to dissolve slowly. Nitroglycerin, as a softer sublingual tablet [2 min Nitroglycerin, as a softer sublingual tablet [2 min disintegration time] may be used for the rapid disintegration time] may be used for the rapid relief of angina. relief of angina. This ROA is also used for some steroids such as This ROA is also used for some steroids such as testosterone and oxytocin. testosterone and oxytocin. Nicotine containing chewing gum may be used Nicotine containing chewing gum may be used for cigarette smoking replacement. for cigarette smoking replacement.

Buccal/SublingualBuccal/SublingualRouteRoute

Factors affecting oral mucosal delivery:Factors affecting oral mucosal delivery:Lipophilicity of the drug: Lipophilicity of the drug: – Slightly higher lipid solubility required than for GI Slightly higher lipid solubility required than for GI

absorptionabsorption

Salivary secretionSalivary secretion::– Absorption is delayed if mouth is dryAbsorption is delayed if mouth is dry– Drug must be soluble in aqueous buccal fluid.Drug must be soluble in aqueous buccal fluid.

pH of the salivapH of the saliva– Usually around 5Usually around 5– Favourable absorption rate for unionized drugFavourable absorption rate for unionized drug

Factors affecting oral mucosal Factors affecting oral mucosal delivery (cont’d)delivery (cont’d)

Binding to oral mucosaBinding to oral mucosa– Binding decreases bioavailabilityBinding decreases bioavailability

Thickness of oral epitheliumThickness of oral epithelium– Sublingual faster than buccalSublingual faster than buccal

Advantages of buccal sublingual Advantages of buccal sublingual administrationadministration

First pass - The liver is by-passed thus there is First pass - The liver is by-passed thus there is no loss of drug by first pass effect for buccal no loss of drug by first pass effect for buccal administration. Bioavailability thus is higher. administration. Bioavailability thus is higher.

Rapid absorption - Because of the good blood Rapid absorption - Because of the good blood supply to the area absorption is usually quite supply to the area absorption is usually quite rapid. rapid.

Drug stability - pH in mouth relatively neutral (cf. Drug stability - pH in mouth relatively neutral (cf. stomach - acidic). Thus a drug may be more stomach - acidic). Thus a drug may be more stable. stable.

Disadvantages of buccal Disadvantages of buccal sublingual administrationsublingual administration

Holding the dose in the mouth may be Holding the dose in the mouth may be inconvenient. inconvenient.

If any is swallowed that portion must be If any is swallowed that portion must be treated as an oral dose and subject to first treated as an oral dose and subject to first pass metabolism. pass metabolism.

Only small doses can be accommodated Only small doses can be accommodated easily. easily.

Oral

Sublingual

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Isosorbide concentrations after a 5 mg oral or sublingual dose.Data from: Assinder et al. J Pharm Sci 66:775, 1977.

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101520253035

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Effect of buffer pH on the buccal absorption of nicotineAdapted from: Svensson CK. Clin Pharmacokinet 12:30, 1987.

Rectal Route of Administration Rectal Route of Administration

Most commonly used for suppository or enema. Most commonly used for suppository or enema. Some drugs given by this route include: Some drugs given by this route include: – aspirin, dipyrone, paracetamol, theophylline, chlorpromazine and aspirin, dipyrone, paracetamol, theophylline, chlorpromazine and

some barbituratessome barbiturates

Advantages: Advantages: By-pass liver - Some of the veins draining the rectum By-pass liver - Some of the veins draining the rectum lead directly to general circulation - by-passing the liver. lead directly to general circulation - by-passing the liver. Useful for patients unable to take drugs orally or with Useful for patients unable to take drugs orally or with younger children. younger children. Disadvantages: Disadvantages: Erratic absorption - incomplete and erratic. Erratic absorption - incomplete and erratic. Not well accepted.Not well accepted.

Availability (%) of lidocaine after IV, Availability (%) of lidocaine after IV, oral and rectal administrationoral and rectal administration

Data from: de Boer et al. Data from: de Boer et al. Clin Pharmacol TherClin Pharmacol Ther 26:701-709, 1979. 26:701-709, 1979.

SubjectSubject IVIV 11 100100 22 100100 33 100100 44 100100 55 100100 66 100100

100100

OralOral1717494953531313353537373434

RectalRectal595987878080313110010059597171

IntravenousIntravenousRoute of AdministrationRoute of Administration

Drugs may be given into a peripheral vein Drugs may be given into a peripheral vein over 1 to 2 minutes or longer by infusion. over 1 to 2 minutes or longer by infusion.

Rapid injections are used to treat epileptic Rapid injections are used to treat epileptic seizures, acute asthma, or cardiac seizures, acute asthma, or cardiac arrhythmias etc.arrhythmias etc.


Advantages: Advantages:

Rapid - A quick response is possible Rapid - A quick response is possible

Total dose - The whole dose is delivered Total dose - The whole dose is delivered to the blood stream. Large doses can be to the blood stream. Large doses can be given by extending the time of infusion. given by extending the time of infusion.

Veins relatively insensitive - to irritation by Veins relatively insensitive - to irritation by irritant drugs at high concentration in irritant drugs at high concentration in dosage forms. dosage forms.


Disadvantages: Disadvantages: It may be difficult to find a suitable vein. It may be difficult to find a suitable vein. May be toxic - Because of the rapid response, toxicity May be toxic - Because of the rapid response, toxicity can be a problem with rapid drug administrations, could can be a problem with rapid drug administrations, could then be given as an infusion while monitoring for toxicity. then be given as an infusion while monitoring for toxicity. Requires trained personnel - Trained personnel are Requires trained personnel - Trained personnel are required to give intravenous injections. required to give intravenous injections. Expensive - Sterility, pyrogen testing and larger volume Expensive - Sterility, pyrogen testing and larger volume of solvent means greater cost for preparation, transport of solvent means greater cost for preparation, transport and storage. and storage. Risk of infection.Risk of infection.


There are some preparations that, due to poor There are some preparations that, due to poor solubility of the drug, contain solvents that solubility of the drug, contain solvents that may produce rate-related toxicity. For may produce rate-related toxicity. For example, diazepam injection USP contains example, diazepam injection USP contains 40% propylene glycol, among other solvents. 40% propylene glycol, among other solvents. Injected rapidly, diazepam may induce Injected rapidly, diazepam may induce hypotension or arrhythmias. For this reason, hypotension or arrhythmias. For this reason, it is recommended that IV injections of it is recommended that IV injections of diazepam be given no more rapidly than 1 diazepam be given no more rapidly than 1 mL/min.mL/min.

While it is generally viewed that 100% of drug While it is generally viewed that 100% of drug administered intravenously is bioavailable, prodrug administered intravenously is bioavailable, prodrug administration via this route may result in less than administration via this route may result in less than

100% bioavailability100% bioavailability..DrugDrug BioavailabilityBioavailability

Chloramphenicol succinateChloramphenicol succinate ~70%~70%Dexamethasone phosphateDexamethasone phosphate ~90%~90%Dexamethasone sulfateDexamethasone sulfate ~40%~40%Prednisolone phosphatePrednisolone phosphate ~90%~90%Prednisolone phthalatePrednisolone phthalate ~50%~50%

Comparative bioavailability of IV chloramphenicol Comparative bioavailability of IV chloramphenicol succinate and oral chloramphencol palmitatesuccinate and oral chloramphencol palmitate IVIV POPOMean C90-min (mg/L)Mean C90-min (mg/L) 22.622.6 27.527.5Mean AUC (mg/hr/L) Mean AUC (mg/hr/L) 7878 110110

Subcutaneous Route of Subcutaneous Route of AdministrationAdministration

This involves administration of the drug dose just under This involves administration of the drug dose just under the skin.the skin.

Advantages:Advantages:

Can be given by patient, e.g. in the case of insulin Can be given by patient, e.g. in the case of insulin Absorption slow but usually complete. Absorption rate Absorption slow but usually complete. Absorption rate can be improved by massage or heat. can be improved by massage or heat. Vasoconstrictor may be added to reduce the absorption Vasoconstrictor may be added to reduce the absorption of a local anesthetic agent, thereby prolonging its effect of a local anesthetic agent, thereby prolonging its effect at the site of interest. at the site of interest.


Disadvantages: Disadvantages:

Can be painful Can be painful

Irritant drugs can cause local tissue Irritant drugs can cause local tissue damage damage

Maximum of 2 ml injection thus often small Maximum of 2 ml injection thus often small doses limit use. doses limit use.

D. D. SubcutaneousSubcutaneous

Advantages:Advantages:

•prompt absorption from aqueous solnsprompt absorption from aqueous solns•little training necessarylittle training necessary•avoid harsh GI tract environmentavoid harsh GI tract environment•can be used for suspensionscan be used for suspensions

Disadvantages:Disadvantages:

•cannot be used for large volumescannot be used for large volumes•potential pain and tissue damagepotential pain and tissue damage•variability in absorption from various sitesvariability in absorption from various sites


Methods of increasing the rate of absorptionMethods of increasing the rate of absorptionEnhancing blood flow to the site of Enhancing blood flow to the site of injectioninjection– By massaging, application of heat, co-By massaging, application of heat, co-

administration of vasodilators locally or by administration of vasodilators locally or by exercise.exercise.

Increasing the drug-tissue contact area:Increasing the drug-tissue contact area:– By co-administering the enzyme By co-administering the enzyme

hyaluronidase that breaks down the hyaluronidase that breaks down the connective tissue - permits the drug to spreadconnective tissue - permits the drug to spread


Methods of decreasing the rate of Methods of decreasing the rate of absorptionabsorption

VasoconstrictionVasoconstriction– By local coolingBy local cooling– Co-injection of a vasoconstrictor such as Co-injection of a vasoconstrictor such as

adrenalineadrenaline– Immobilization of limbImmobilization of limb

Sites for SC injectionSites for SC injection

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Disappearance of IDisappearance of I125125-insulin from subcutaneous injection-insulin from subcutaneous injectionat different sites. at different sites. Data from Koivisto & Felig, Data from Koivisto & Felig, Ann Intern MedAnn Intern Med 92:59, 1980 92:59, 1980..

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Disappearance of IDisappearance of I125125-insulin from subcutaneous injection-insulin from subcutaneous injectionat different sites. at different sites. Data from Koivisto & Felig, Data from Koivisto & Felig, Ann Intern MedAnn Intern Med 92:59, 1980. 92:59, 1980.

Intramuscular Route of Intramuscular Route of AdministrationAdministration

IntramuscularIntramuscularInjection is administered into the gluteal muscle of the Injection is administered into the gluteal muscle of the buttock or the deltoid muscle of the upper arm and the buttock or the deltoid muscle of the upper arm and the vastus lateralis muscle of the thigh.vastus lateralis muscle of the thigh.Larger volume than SC can be given by IM Larger volume than SC can be given by IM A depot or sustained release effect is possible with IM A depot or sustained release effect is possible with IM injections, e.g. procaine penicillin injections, e.g. procaine penicillin The site of injection will influence the absorption, The site of injection will influence the absorption, generally the deltoid muscle is the best site generally the deltoid muscle is the best site Absorption is sometimes erratic, especially for poorly Absorption is sometimes erratic, especially for poorly soluble drugs, e.g. diazepam, phenytoin. soluble drugs, e.g. diazepam, phenytoin. The solvent may be absorbed faster than the drug The solvent may be absorbed faster than the drug causing precipitation of the drug at the site of injection. causing precipitation of the drug at the site of injection.

Advantages:Advantages:•less skill necessary for administrationless skill necessary for administration•can be used to administer oily vehiclescan be used to administer oily vehicles•prompt absorption from aqueous sol’nprompt absorption from aqueous sol’n

Disadvantages:Disadvantages:•painfulpainful•cannot be used in presence of cannot be used in presence of abnormal clotting timeabnormal clotting time•drug may ppt at the site of drug may ppt at the site of administrationadministration•variability in bioavailabilityvariability in bioavailability

Z-track method for IM injections

Injection siteInjection site deltoiddeltoidvastus lateralisvastus lateralisgluteus maximusgluteus maximus

MalesMales11.711.7 9.89.811.111.1

FemalesFemales 10.210.2 9.49.4 4.34.3

Data from: Vukovich et al. Data from: Vukovich et al. Clin Pharmacol TherClin Pharmacol Ther 18:215, 1975. 18:215, 1975.

Peak plasma cephradine concentrations Peak plasma cephradine concentrations (mcg/mL) after IM administration to (mcg/mL) after IM administration to

different sites in male and female subjectsdifferent sites in male and female subjects

InhalationInhalation Route of Administration Route of Administration

Drugs administered as fine particles of liquids or solids or Drugs administered as fine particles of liquids or solids or as aerosols or spray. The drug may be required for local as aerosols or spray. The drug may be required for local or systemic effects.or systemic effects.Local effect - bronchodilators Local effect - bronchodilators Systemic effect - general anesthesia Systemic effect - general anesthesia Rapid absorption, by-passing the liver Rapid absorption, by-passing the liver Absorption of gases is relatively efficient, Absorption of gases is relatively efficient, Solids and liquids are excluded if larger than 20 micron Solids and liquids are excluded if larger than 20 micron and even then only 10 % of the dose may be absorbed. and even then only 10 % of the dose may be absorbed. Cromolyn is taken as a powder with 50 % of the particles Cromolyn is taken as a powder with 50 % of the particles within the range of 2 to 6 micron. If particles are larger within the range of 2 to 6 micron. If particles are larger than 20 micron they will impact on the mouth and throat than 20 micron they will impact on the mouth and throat and if smaller than 0.5 micron, they will not be retained. and if smaller than 0.5 micron, they will not be retained.

C. C. NasalNasal

•Historically utilized only for local effects•Growing number of compounds administered intranasally that are intended for systemic effects

•For drugs that are destroyed in the GI environment (or first-pass effect)•As an alternative to intravenous administration – better safety and patient acceptanceDrugs include anticonvulsants (midazolam),

narcotic antagonists (naloxone), peptides (calcitonin, insulin), and smoking cessation agents (nicotine)

Mucosal Atomizer Device

From: www.ofmaa.org

Intranasal naloxone administration in the field by paramedics

Factors that influence absorptionFactors that influence absorption from the nasal mucosafrom the nasal mucosa

pHpH

ConcentrationConcentration

Molecular weightMolecular weight

FormulationFormulation

Condition of nasal mucosaCondition of nasal mucosa

Figure from: http://www.drugdeliverytech.com/cgi-bin/articles.cgi?idArticle=61

Nasal to brain delivery of drugsNasal to brain delivery of drugs

TopicalTopical Route of Administration Route of Administration

Local effect - eye drops, antiseptic, Local effect - eye drops, antiseptic, sunscreen, callous removal, etc. sunscreen, callous removal, etc. Systemic effect - e.g., nitroglycerin Systemic effect - e.g., nitroglycerin ointment. ointment. Absorption through the skin, especially via Absorption through the skin, especially via cuts and abrasions but also intact, can be cuts and abrasions but also intact, can be quite marked. This can be a real problem quite marked. This can be a real problem in handling toxic materials in the laboratory in handling toxic materials in the laboratory or pharmacy. or pharmacy.

Health & Medicine

Biopharmaceutics lecture4(2)