Basic Principles of Pharmacology II Flashcards
Drug Transport
- drugs must cross multiple membrane barriers to reach the receptor in target tissue
- ability of drug to reach the receptor will influence the effectiveness of the drug
Single Membranes
-cell membrane
Double Membranes
- capillary endothelial cells- cross through entire cells or around them
- multiple- various tissues
Transport Processes
- most drugs that will be dissolved in the GI fluid or carried by plasma need to be somewhat water soluble and many are highly water soluble
- ultimately to reach the target receptor the drug will have to cross multiple membrane barriers which are substatially lipid
Passive Processes
- follow a concentration gradient or hydrostatic pressure
- don’t require metabolic energy
- simple diffusion, facilitated diffusion, filtration
Simple Diffusion
- most common
- affected by: lipid solubility (oil/water partition coefficient), size (smaller is better), degree of ionization (nonionized is best)
Facilitated Diffusion
- uses a carrier protein
- masks drug characteristics that may impede simple diffusion
- selective, can be inhibited, can be saturated
Filtration
- driven by hydrostatic pressure and drug dissolved in the moving fluid is transported through pores in a membrane or channels between cells
- drug molecule size will be limiting
Active Processes
- use metabolic energy in the form of high energy phosphates such as ATP or electrochemical gradients, transport against a concentration gradient, rapid, selective, can be inhibited, can be saturated
- active transport, micropinocytosis
Active transport
-uses carrier
Micropinocytosis
-drug is transported in pinched off packets of single layer membrane
Different Drug Characteristics
- small molecule
- lipid-soluble
- lipid-insoluble
- large molecule
- protein bound
Weak Electrolyte Drugs
- many drugs
- non-ionized forms- diffuse
- lipid soluble
- concentration gradient
- weak acids (diffuse in HA form) or weak bases (diffuse in B+H form)
pKa
- ionized vs nonionized forms
- pka is a physical characteristic
- determines ratio of ionized to nonionzed forms at a particular pH
Henderson-Hasselbach Equation
pH = pKa +log A-/HA
or
log A-/HA = pH - pKa
-if the ratio can be estimated then the ease of absorption at a particular pH can be predicted
Absorption of drug in stomach
- a weak acid drug can be easily absorbed in stomach because it will favor HA form in low pH so it will be able to diffuse to the plasma
- a weak base drug is not absorbed in the stomach well because it will favor the BH + form which does not diffuse to plasma easily
Enteral
drugs that are absorbed through a portion of the GI tract
Parenteral
-drugs that are not absorbed through a portion of the GI tract
Considerations for the Routes of Administrations of Drugs
- Planned use of the medication- for patients to give themselves at home vs clinical setting
- Clinical setting- acute vs chronic- may want to closely monitor the drug effect and titrate the dose vs daily dosing for long term effects
- Rapidity of onset of desired action- e.g. treating a headache vs a seizure
- Specific target organ that the drug is intended to reach
Oral Route
Advantages: ease, safety, self-administration, cheap, prolonged absorption causing prolonged effect
Disadvantages:
- absorption may be too slow,
-absorption often variable and unpredictable,
-drug may be too irritating,
-drug may be destroyed by gastric acid enzymes,
-drug may be completely metabolized on first pass through liver
-not available for comatose or vomiting patients
First Pass Effect
1) Drug is administered by mouth
2) Drug enters GI tract
3) Active drug is absorbed from stomach and small intestine
4) High blood concentration of free drug is in hepatic portal vein (before liver metabolism)
5) Low blood concentration of free drug is in systemic arterial or venous circulation (after liver metabolism)
Rectal Route
Advantages:
- useful for infants, comatose, vomiting patient
- useful for foul-smelling, distasteful drugs
- useful for drugs destroyed in upper GI tract
- avoids immediate metabolism in liver
- for local action in rectum
Disadvantages:
- Nuisance- poor compliance
- Absorption may be erratic, incomplete
- Possibility of rectal irritation
Sublingual Route
Advantages:
- by-passes liver when first absorbed
- rapid absorption
Disadvantages:
- drugs must be soluble in saliva, not too distasteful, have appropriate pKA for rapid absorption
- tablets must be small
IV Route
Advantages:
- Rapid effect
- Can watch response and titrate dose
- all of dose enters circulation
- when oral route not available
- for drugs too irritating when given i.m. or s.c.
- for drugs given in large volumes of fluid
- for infusion and continuous monitoring
- parenteral administration of hypertonic solutions possible
Disadvantages:
- cost
- skill in administration
- danger of infection
- possible anaphylactic reaction
- danger of embolus formation due to air, drug precipitation, RBC agglutination
- danger of adverse cardiovascular effects if administration too rapid
- pain
Intraarterial Route
Advantages:
- administration of radioopaque material for visualization of circulatory tree- specialized stuff to dissolve clots
- high concentration of drug going to local area when desirable
Disadvantages:
-as for IV administration
Intramuscular Route
Advantages:
- when oral route not available
- absorption less variable than with oral
- may be less painful than with s.c. route
- absorption more rapid than with s.c. route
- possibility of slowing absorption to prolong effect
Disadvantages:
- pain
- sterile technique
- possible local necrosis
- lag period before effect onset
- accidental IV injection possible
- not to be used after anticoagulant administration
Subcutaenous Route
Advantages:
- absorption usually slower than after i.m. and effect more prolonged
- as for i.m. advantages
- example- insulin
Disadvantages:
-as for i.m. administration
Intrathecal Route
Advantages:
-when local effect on CNS required and other route unsatisfactory
Disadvantages
- skill
- danger of spinal cord injury
Topical Route
Advantages:
- for local action on or under skin
- for local action on or under membrane
- non-invasive
Disadvantages:
- difficulty of absorption through skin
- danger of excessive absorption through membranes and systemic toxicity
Inhalation Route
Advantages:
- rapid absorption for systemic action (nicotine, general anesthesia)
- high concentration attainable for local effect
- self administration possible
Disadvantages:
- possible excessive absorption and systemic toxicity
- poor regulation of dosage
- irritation of pulmonary
Pharmacokinetics of plasma levels by route of administration
- IV- all of the dose is in the plasma very quickly, it also falls off very quickly
- Inhalation- just underneath
- then it does to IM where the blood flow is very high
- then it does SC
- then PO- which rises slow, persistence of drug is slower
Bioavailability
- fraction of dose available for biologic action
- usually pertains to oral drug administration where variable absorption or “first pass” effects will decrease the amount of drug which reaches the circulation
- measured by comparing the AUC (area under the curve) for the oral dose form vs the IV dose form
- AUC oral/AUC injected x 100
- this will impact the size of the dose given orally to achieve a desired plasma level
- to predict plasma concentration usual Cp= Dose/Vd but if significant limitations in bioavailability then Cp= (F x Dose)/Vd where F is the fraction absorbed
- chemical equivalence does not equal biological equivalence
- most common for drugs given orally-dissolution is often the limiting step
-important for: drugs that are potent in small doses, drugs given for serious illnesses, changes in drug manufactureer
Other factors affecting absorption
- enteral- form of drug, food in stomach, illness, blood flow
- solution > suspension > capsule > tablet > timed release
-parenteral- blood flow, heat, cold, illness, etc.
form of drug- wafer, rods, injection in soil, transcutaneous patch
