Welcome to Drug Actions and Adverse Reactions Development Page

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The membrane barriers play a major role during any drug action or adverse reacton. Membrane barriers can either consist of a layer of closely packed cells or a cell membrane also known as the plasma membrane.The cell membrane is what surrounds and protects the living cells of our body. It must regulate what can enter from the extrinsic environment into the intrinsic envionment of the cell to cause an action or adverse reaction. It is important to understand what the cell membrane consist of since this is the membrane of choice used to explain drug interactions. It is made up of a lipid bilayer made up of phospholipids, cholesterol and proteins which expand from the outside to the inside of the cell allowing a gateway to the intracellular environment.


How do drugs cross cell membrane?

  • Passive diffusion:

Drugs diffuse across a cell membrane from a region of high concentration (eg, GI fluids) to one of low concentration (eg, blood). Diffusion rate is directly proportional to the gradient but also depends on the molecule's lipid solubility, size, degree of ionization, and the area of absorptive surface. Also, some degree of water solubility is needed for the passive diffusion. No matter how lipid soluble the drug is it will never cross the cell membrane unless it can dissolve in the extracellular fluid.
Because the cell membrane is lipoid, lipid-soluble drugs diffuse most rapidly. Small molecules tend to penetrate membranes more rapidly than larger one.

**http://www.youtube.com/watch?v=s0p1ztrbXPY**

  • Specialized transported processes.


  • Carrier mediated transport:


  • I.The passage of lipid insoluble substances through the cell membrane is mediated by carrier proteins in the cell membrane.

  • A. Carrier-mediated transport exhibits the properties of specificity, competition, and saturation.
    B. The transport rate of molecules reaches a maximum when the carriers are saturated. This maximum rate is called the transport maximum, or Tm.

II. The transport of molecules such as glucose from the side of higher to the side of lower concentration by means of membrane carriers is called facilitated diffusion.


  • A. Like simple diffusion, this is passive transport, cellular energy is not required.
    B. Unlike simple diffusion, facilitated diffusion displays the properties of specificity, competition, and saturation.

  • III. The active transport of molecules and ions across a membrane requires the expenditure of cellular energy (ATP).

  • A. In active transport, carriers move molecules or ions from the side of lower to the side of higher concentration.
    B. One example of active transport is the action of the Na+/K+ pump.
*
1. Sodium is more concentrated on the outside of the cell, whereas potassium is more concentrated on the inside of the cell.
2. The Na+/K+ pump helps to maintain these concentration differences by transporting
Na+ out of the cell and K+ into the cell.



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http://www.youtube.com/watch?v=_bmp2_T0c7k
Filtration
Passage of drug molecules through the endothelial lining of the capillaries as a bulk flow. Lipid insoluble substance (often the only mechanism for lipid insoluble) . Filtration is involved in the distribution and elimination of almost ALL drugs.

Endocytosis and exocytosis
Most complex method
Endocytosis= series of events in which substance is engulfed and internalized by the cell .

Exocytosis - is the durable process by which a cell directs the contents of secretory vesicles out of the cell membrane. These membrane-bound vesicles contain soluble proteins to be secreted to the extracellular environment, as well as membrane proteins and lipids that are sent to become components of the cell membrane.


**http://www.youtube.com/watch?v=4gLtk8Yc1Zc**

Here is a video that incorporates 4 different methods of diffusion all into one.

http://www.youtube.com/watch?v=8zYIEiXvSZY

How are drugs absorbed?


Absorption: transfer of the drug from its site of administration into the bloodstream.
The route of administration influences the rate and the extent of the drug absorption:



1- ORAL INGESTION::

Convenience, economic, safety
Allergic rx. Less likely to occur
Sudden high blood conc. Are less likely.
Low cost
painless
Most is absorbed by the stomach and small intestines


Drawbacks:
Patient Compliance is required.
Delayed absorption
Metabolic inactivation may occur before the drug reaches the blood
The spectrum of adverse rxn can extend from GI tract to the other.


What can affect absorption?
The duration of exposure, concentration of the drug, and surface availability can affect absorption.


Influence of the PH:
The pH of the environment effects the degree of the ionization-- which effects the absorption rate.:
Ex: Aspirin is an organic acid that remain unionized in the stomach and its passage through the stomach mucosa is favored. But because the plasma has a PH of 7.4 aspirin become ionized to such extent. Then equilibrium is established… unequal distribution of drug molecules based on pH across the gastric membrane is known as” ions tapping “

EX: codeine is a base that is completely ionized in the stomach. At equilibrium the drug remains in the stomach .. Only very weak bases are non-ionized in the stomach and available for absorption

In the small intestine basic drugs are favored for absorption more than acidic


Mucosal surface area:

Stomach has a thick mucosa layer
Small intestine as Kerckring, villi, microvilli that increase the effectiveness of absorption



Gastric emptying:

Organic bases that are not absorbed at all in the stomach
Occurs 3 x/ min
Presence of fat delay the process
Presence of fat promotes the drug absorption of a drug that is highly soluble in lipid ex; antifungal agents
Latency period= lag phase b/w the ingestion and the onset effect of the drug



Influence of dosage form

Dissolving of the soln control the drug absorption
Dissolution of the drug particles occur by a diffusion -limited mechanism
Mercerization promotes solubilization
Decrease particle size 85% ( compensating increase in the # of particles) will double the rate of dissolution
To avoid release of the drug in the stomach they are often prepared in a form of enteric coated tablets but it does break down in the alkaline environment such as the intestine.


Drug inactivation

Inactivation of the drug before reaching the blood is one of the drawbacks of the oral injection
Gastric acid causes break down of the drug
Enzymatic activity ..ex; pancreatic and intestinal peptidase
Enteric bacteria enzymes
Intestinal contents
Formation of insoluble salts
Lidocaine is destroyed during its pass ( if taken orally) because it’s metabolized in liver



2- INHALATION

alveolar membrane = highly permeable to agents in gaseous state, fine powder, and droplets.
First category- therapeutic gases (carbon monoxide, inhalation anesthetics, and volatile organic solvents)
Second category- aerosols (liquid or solid particles, include bacteria, viruses, smoke, pollen, and dust)
rapid onset effect
-rapid absorption may produce toxic effect
many drugs are prepared in an aerosol form because they're highly effective while minimizing systemic exposure.



3- PARENTAL INJECTION

  • Intravenous :
directly into the blood stream
used when blood concentration is required
controlling of drug administration
must be administered at slow rate
disadvantage:
1- hard to remove from the blood stream
2- instant toxic reaction, and severe
3- threatening anaphylactic events ( antigen-antibody)
4- embolism
5- infection
6- hematoma formation


  • intramuscular route
given in cases where patient is not cooperative , can't give drug orally, or high percent of drug inactivation is required.


4- TOPICAL APPLICATION

skin, mucous membrane, Iontophoresis
drugs applied to epithelial surfaces for loc al effects
the absorption of the drug depends on the degree of kertanization


1. Describe the characteristics of a drug including the log dose-effect curve, potency, efficacy and chemical signaling between cells.
A) Log dose effect curve
i) Relationship between dose administered and effect attained.
ii) Below minimum threshold there can be no incremental effect from a drug.
iv)Above a certain ceiling, even a large dose will exert no demonstrable
influence b/c max effect has been reached.
B) Potency
i) Potency of a drug is the dose required to elicit an arbitrarily determined level
of response.
ii) Usually of little regard b/c a drug that is very potent regarding its desirable effects is often equally potent regarding those that are undesirable.
iv) Influences by affinity of drug for its receptor its intrinsic activity, and its ability to reach the receptor.
v) Active drug will appear to have low potency if not well absorbed, becomes bound to nonspecific sites or cannot reach target organ.
C) Efficacy
i) Number of receptors that must be activated to yield a maximal response.
ii) Drug with high efficacy needs to stimulate only a small % of receptors.
D) Chemical signaling between cells
i) At a chemical synapse a narrow gap or synaptic cleft, separates the presynaptic cell from the postsynaptic cell. Due to the cleft the cells are not electrically coupled and an action potential occurring in the presynaptic cell cannot be transmitted directly to the membrane at the postsynaptic cell. Instead, a series of events converts the electric signal arriving at the synaptic terminal in to a chemical signal that travels across the synaptic cleft where it is converted back into an electrical signal in the postsynaptic cell. This is done by neurons sacs called synaptic vesicles that exist in the cytoplasm at the tip of the presynaptic axon. The vesicles contain neurotransmitters, the substance is released as an intercellular messenger into the synaptic cleft to the post synaptic membrane where synaptic receptors will uptake it.



Factors That Influence Drug Effects:

There are differences between people that affect the variation of individual response to a drug from person to person. Even with a standardized dose, pharmacodynamic differeences, are evident within a test group. Along with those differences, Pharmacokinetic differences, differences in standardized dose, can play a major factor in drug responsiveness. A third component of this variance is the failure of patients to take their medication correctly, as prescribed by their physician.

Patient Factors:

Many factors such as a person's size, age, weight, and genetic background can be factors that influence drug effects. These factors should always be taken into consideration when therapeutic drug treatment is planned.

Patient Body Weight:

A patient's body weight can vary exponentially from person to person , creating a challenge for a physician to achieve the correct so called, "standard dose." Body composition or "Mass" is an extremely important fluctuating factor in the successful therapeutic use of a drug. Two different factors can be seen within person of the same weight that produce completely different outcomes. Firstly, a person of high adipose, or excessive body fat, may not be as responsive to a drug that a person of highly muscularized body tissue may be. Because of this biological make-up, an expansive knowledge of lipophillic and hydrophillic drugs is critical.


Types of reactions


Allergic- Administration of the drug causes an undesirableimmunologic response, i.e., rash, anaphylaxis, which is often unpredictable.Side effect- Undesirable effect occurs which is expected orpredictable at therapeutic doses, i.e., nausea, dry mouth.Side effects are the most common adverse effects.Drug toxicity- Occurring most commonly in children and frail elders,this is when a physiologic system is damaged fromdoses over therapeutic levels, i.e., nephrotoxicity fromover ingestion of NSAIDs. Toxicity is usually predictable. Drug-drug interaction- The absorption, distribution, metabolism, and/or excretion of one drug is altered by the administration of another drug, i.e., erythromycin taken with digoxin increases the digoxin level or NSAIDs and methotrexate interactions are usually predictable.Drug–physiology interaction- The presence of a drug at therapeutic levels adversely alters a physiologic system – can overlap with a side effect, i.e., administration of Clindamycin can result incolitis and diarrhea. Such interactions are usually predictable.Drug-laboratory test interaction -There is no effect on the physiologic system being tested, but a false positive or false negative test result,i.e., amoxicillin can cause a false-positive urine glucose test. Such interactions are usually predictable.Idiosyncratic- By definition these are unpredicted physiologic, or, psychological responses occurring at therapeutic doses.These are unique to an individual.

Describe and compare the pharmacologic effects, adverse reactions and uses of cholinergic and anticholinergic agents.

How Are Drugs Distributed?


Distribution refers to the movement of drugs throughout the body. The first layer to be crossed is the capillary membrane tissue. Once the drug enters the systemic circulation it is then diluted by the plasma volume. Depending on the molecular weight of the drug, this will affect its passing across the capillary membrane. Such as lipophilic drugs, they cross the membrane quickly. Another factor that influences passage across the cell membrane is their pH. Intracellular pH is 7.0 and extracellular pH is 7.4. Acidic drugs maintain outside the cell whereas the acidic drugs remain within.
Central Nervous System- Entry into the CNS is dependent on lipid solubility, cellular sheath surrounding brain capillaries, and abundant amount of membrane transporters exporting drugs gaining entry into the endothelial cells.
Drugs can enter the oral cavity through passive diffusion across the alveolar and ductal cells of the salivary glands, passive diffusion across the oral epithelium, or through the gingival crevice.
Distribution of drugs isn’t equal throughout the body. The volume of distribution can be used to figure out drugs are distributed among the different parts of the body. The quantity of the drug given is divided by the plasma concentration of the drug at equilibrium. This then gives you the volume of distribution. This is the amount of water by which a particular dose would have to be diluted to produce a given plasma concentration assuming no drug has been lost through incomplete absorption, metabolism or excretion.


Backgroud: Adrenergic vasoconstrictors are commonly used by dentists to enhance the pain relieving action of local anesthetics and to control local bleeding. Although normally considered safe forthese applications, vasoconstrictors can participate indrug interactions that potentially are harmful topatients.

Methods: The faculty of a March 1998 symposiumentitled “Adverse Drug Interactions inDentistry: Separating the Myths From the Facts” extensivelyreviewed the literature on drug interactions.
They then established a significance rating of alleged adverse drug interactions pertaining to dentistry, based on the quality of documentation and
severity of effect. The author of this article focused on the adrenergic vasoconstrictors epinephrine and levonordefrin.

Results: Vasoconstrictor drug interactions involving tricyclic antidepressants, nonselective β-adrenergic blocking drugs, certain general anesthetics and cocaine are well-documented in both humans and animals as having the potential for causing serious morbidity or death. Evidence for adverse interactions involving adrenergic neuronal blocking drugs, drugs with α-adrenergic blocking activity, local anesthetics
and thyroid hormones is much less compelling, suggesting for the most part that clinically significant reactions may occur only when both the
vasoconstrictor and the interacting drug are used in excessive doses. In the case of monoamine oxidase inhibitors, there is no credible evidence of a significant interaction with epinephrine or levonordefrin.
Conclusions: Potentially serious adverse drug interactions involving adrenergic vasoconstrictors can occur in dental practice. In most circumstances, careful administration of small doses of vasoconstrictors and avoidance of gingival retraction cord containing epinephrine, coupled with monitoring of vital signs, will permit these drugs to be used with no risk or only minimally increased risk. Only in the case of cocaine intoxication must adrenergic vasoconstrictors be avoided completely.
Clinical Implications. For optimal patient safety, dentists must recognize potential drug interactions involving adrenergic vasoconstrictors
and modify their use of these agents accordingly.


ADVERSE DRUG INTERACTIONS IN DENTISTRY: VASOCONSTRICTORS


POSSIBLE DRUG INTERACTION

Vasoconstrictor with tricyclic antidepressant
(levonordefrin with imipramine)
Vasoconstrictor with nonselective

adrenoceptor antagonist (epinephrine

with propranolol)
Vasoconstrictor with general anesthetic
(epinephrine with halothane)
Vasoconstrictor with cocaine
(epinephrine with cocaine)
Vasoconstrictor with antipsychotic or
other α-adrenoceptor blocker
(epinephrine with chlorpromazine)
Vasoconstrictor with adrenergic neuronal
blocker (levonordefrin with guanadrel)
Vasoconstrictor with local anesthetic
(lidocaine with epinephrine)
Vasoconstrictor with thyroid hormone
(epinephrine with thyroxine)
Vasoconstrictor with monoamine oxidase

inhibitor (epinephrine with phenelzine



MECHANISM AND CLINICAL
PRESENTATION

Sympathomimetic effects may be
enhanced. Epinephrine should be
used cautiously; use of levonordefrin
should be avoided.
Hypertensive and/or cardiac reactions
are possible. Vasoconstrictor
should be used cautiously; blood
pressure and heart rate should be
monitored.
Increased possibility of cardiac arrhythmias
exists with some general
anesthetics. Consultation with
anesthesiologist is recommended.
Arrhythmias and hypertensive
responses possible. Concurrent
use should be avoided.
Hypotension resulting from overdose
of antipsychotic agent may
be worsened. Vasoconstrictor
should be used cautiously.
Sympathomimetic effects may be
enhanced. Vasoconstrictor should
be used cautiously.
Multiple effects on systemic toxicity,
which may be self-limiting.
Summation of effects possible
when thyroid hormones are used
in excess. Vasoconstrictor should
be used cautiously if signs of
hyperthyroidism are present.
No substantial evidence of an
interaction