Pharmacotherapeutics and drug interactions

Pharmacotherapeutics

it  is the use of drugs to treat disease.

types of drug therapies:-

• acute therapy, if the patient is critically ill and requires acute intensive therapy
• empiric therapy, based on practical experience rather than on pure scientific data
• maintenance therapy, for patients with chronic conditions that don’t resolve

• replacement therapy, to substitute for missing substances in the body
• supportive therapy, which doesn’t treat the cause of the disease but maintains other threatened body systems until the patient’s condition resolves
• palliative therapy, used for end-stage or terminal diseases to make the patient as comfortable as possible.
   
  -there are many Factors affecting a patient’s response to a drug Because no two people are alike physiologically or psychologically, such as
  ( age - gender - disease - drug interactions - infections -hepatic, renal and GIT functions - diet)
   
   drug dependence :-
    patient displays a physical or psychological need for the drug.
   Physical dependence produces withdrawal symptoms when the drug is stopped
  psychological dependence is based on a desire to continue taking the drug to relieve tension and avoid discomfort
  drug tolerance :-
    patient develops a decreased response to a drug over time. The patient then requires larger doses to produce the same response.
   

  Drug interactions

  Drug interactions can occur between drugs or between drugs and foods.The more drugs a patient receives, the greater the chances that a drug interaction will occur.

  1- additive action

   occur when two drugs with similar actions are administered to a patient .The effects are equivalent to the sum of the 2 drugs .

   advantages: lower doses of each drug, decreased probability of adverse reactions, and greater pain control than from one drug given alone 

   

   2- potentiation action
  also called synergistic effect occurs when two drugs that produce the same effect are given together and one drug enhances the effect of the other drug. This produces greater effects than when each drug is taken alone.

   

  3- antagonistic effect 
   occurs when the combined response of two drugs is less than the response produced by either drug alone.
   
  4- decreased or increased absorption
   two drugs are taken together can change the absorption of one or both of the drugs
  -  drugs can interact and form an insoluble compound that can’t be absorbed.
  -drugs that change the acidity of the stomach can affect the ability of another drug to dissolve in the stomach.
  it  can be avoided by administering the drugs at least 2 hours apart. 
  
  
   5-decreased or increased metabolism and excretion.
   When two drugs are given together, they can compete for protein-binding sites, leading to an increase in the effects of one drug as that drug is displaced from the protein and becomes a free, unbound drug.
   Toxic drug levels can occur when a drug’s metabolism and excretion are inhibited by another drug.
   

drug receptors

 drug receptors

receptor is target macromolecule present on the cell surface or intracellularly where the drug binds to.

After attachment to a receptor site, a drug may either initiate a response or prevent a response from occurring.

An agonist is a drug which produces a stimulation type response. The agonist is a very close mimic and "fits" with the receptor site and is thus able to initiate a response.

An antagonist drug interacts with the receptor site and blocks or depresses the normal response for that receptor because it only partially fits the receptor site and can not produce an effect.

Antagonists can be competitive or noncompetitive.

• A competitive antagonist competes with the agonist for receptor sites. Because this type of antagonist binds reversibly to the receptor site, administering larger doses of an agonist can overcome the antagonist’s effects.
  
  A noncompetitive antagonist
• binds to receptor sites and blocks the effects of the agonist. Administering larger doses of the agonist can’t reverse the antagonist’s action.
  
  

  -If a drug acts on a variety of receptors, it’s said to be non-selective and can cause multiple and widespread effects. In addition, some receptors are classified further by their specific effects. For example, beta receptors typically produce increased heart rate and bronchial relaxation as well as other systemic effects.

  Beta receptors, however, can be further divided into beta₁ receptors (which act primarily on the heart) and beta₂ receptors (which act primarily on smooth muscles and gland cells).

  -  Desensitization of receptors
  Repeated or continuous administration of an agonist (or an antagonist) may lead to changes in the responsiveness of  the receptor. To prevent potential damage to the cell (for example, high concentrations of calcium, initiating cell
  death), several mechanisms have evolved to protect a cell from excessive stimulation. When repeated
  administration of a drug results in a diminished effect, the phenomenon is called tachyphylaxis. 

  The receptor becomes desensitized to the action of the drug . In this phenomenon, the receptors are still present on the cell surface but are unresponsive to the ligand.

  - Dose Response Relationships 

  -The magnitude of the drug effect depends on the drug concentration at the receptor site.
  

   -Drug potency refers to the relative amount of a drug required to produce a desired response. Drug potency is also used to compare two drugs. If drug X produces the same response as drug Y but at a lower dose, then drug X is more potent than drug Y.

   -efficacy

   This is the ability of a drug to illicit a physiologic response when it interacts
  with a receptor.
  

  - a dose-response curve is used to graphically represent the relationship between the dose of a drug and the response it produces.

  

  
  

  Maximum effect

  On the dose-response curve, a low dose usually corresponds to a low response. At a low dose, a dosage increase produces only a slight increase in response. With further dosage increases, the drug response rises markedly. After a certain point, however, an increase in dose yields little or no increase in response. At this point, the drug is said to have reached maximum effectiveness.

  - therapeutic index

  it is The relationship between a drug’s desired therapeutic effects and its adverse effects . It’s also referred to its margin of safety.

  The therapeutic index usually measures the difference between:

  • an effective dose for 50% of the patients treated
  • the minimal dose at which adverse reactions occur.

  
  

Pharmacodynamics

Pharmacodynamics

 
it is the effect of drug on the body .
-drugs exert their effects by interacting with receptors (present on the cell surface or intracellularly) leading to change in cell activity.

what is the receptor ?

it is any biologic molecule to which a drug binds and produces a measurable response. Thus, enzymes and structural proteins can be considered to be pharmacologic receptors

-Drugs may interact with receptors in many different ways
Drugs may bind to( enzymes , nucleic acid or membrane receptors ) forming drug-receptor complex that makes biologic response.
- not all drugs exert their effects by interacting with a receptor; for example, antacids chemically
neutralize excess gastric acid, reducing the symptoms of the heartburn.
-Interaction of receptors with drug involves the formation of chemical bonds ( electrostatic, hydrogen bonds and van der Waals forces) (non-covalent bonds) The bonds are usually reversible, except some drugs (which form covalent bonds)
-the successful binding of a drug requires an exact fit of the drug atoms with the complementary receptor atoms.
-In the presence of a ligand, the receptor undergoes a conformational change to bind the ligand. The change in conformation of the receptor caused by binding of the agonist activates the receptor.

-Major Receptor Families

1- ligand-gated ion channels
2- G protein coupled receptors
3- enzyme-linked receptors
4- intracellular receptors


translation into Arabic

بعد مخلصنا الpharmacokinetics  اللى هى تأثير الجسم على الدواء ، هنتكلم دلوقت عن الpharmacodynamics واللى هى تأثير الدواء على الجسم

Pharmacodynamics

it is the effect of drug on the body .

طيب ازاى الدواء بيدى التأثير المطلوب ؟
لازم الدواء يرتبط بمكان معين عشان يدى التأثير العلاجى المكان ده اسمه Receptor و مستقبلات الدواء دى بتبقى موجودة على جدار الخلية ودى الغالبيه العظمى منها او بتبقى داخل الخلية
لما الدواء بيرتبط بالمستقبل بتاعه بيكون حاجه اسمها drug-receptor complex وبعدها بيحصل signal transduction  وبعدين الدواء يدى التأثير المطلوب .
نتكلم شوية عن الreceptors
هو عبارة عن جزئ موجود على او داخل الخلية وهو المكان اللى الدواء برتبط بيه عشان يدينا التأثير المطلوب.

بس مش كل الادوية بتدى التأثير بتاعها عن طريق الارتباط بالمستقبلات ، على سبيل المثال مضادات الحموضة بتزود ال PH  فبتالى بتعادل الحموضة من غير مترتبط بمستقبلات.

-الانزيمات وبعض البروتينات اللى فالجسم تعتبر من انواع المستقبلات.

-الدواء بيرتبط بالمستقبل الخاص بيه عن طريق تكوين روابط كيميائية زى (electrostatic , Hydrogen bonds and van der waals forces)
ودى بتبقى غالبا روابط ضعيفة ونادر لما تتكون بينهم روابط covalent  قوية .

-Major Receptor Families

1- ligand-gated ion channels

ودى من ضمن الreceptors  الموجودة على جدار الخلية ودى بتتحكم فى دخول وخروج الايونات ، والاستجابة هنا بتبقى سريعه جدا ( أجزاء من الثانية ) ، ومن ضمن العمليات اللى بتنظمها المستقبلات دى:-

  ( cardiac conduction , neurotransmission)

-----------------------------------------

2- G protein coupled receptors

وده موجود على جدار الخلية وهو ده النوع الغالب من المستقبلات ، والاستجابة لتأثيره بيبقى من ثوانى لدقايق

ومن ضمن العمليات اللى بتنظمها :- neurotransmission

----------------------------------------

3- enzyme-linked receptors

النوع ده برضه موجود على جدار الخلية والاستجابة  هنا بتبقى من دقايق لساعات ومن ضمن ودى بتتحكم فى :-

النمو وال الmetabolism  وعمليات حيوية  اخرى.

------------------------------------

4- intracellular receptors

النوع ده بقى موجود داخل الخلية وطبعا عشان الدواء يدخله جوه لازم يكون بيدوب فى الدهون عشان يقدر يعدى من جدار الخلية الدهنى  ، الاستجابة هنا بتوصل من ساعات لأيام

kinetics of drug elimination

kinetics of drug elimination

 

-Plasma clearance

it is the volume of plasma from which all drug appears to be removed in a given time.
clearance = rate of elimination (Roe) \C

-extraction ratio = C2/C1.

C1 is concentration of drug enters the kidney
C2 is concentration of drug exits the kidney

-Excretion rate =clearance * plasma concentration

        mg/min          ml/min               mg/ml

Total body clearance

The total body (systemic) clearance, CLtotal or CLt, is the sum of the clearances from the various drug-metabolizing
and drug-eliminating organs.

CLt = CL hepatic   +    CL renal    +   CL pulmonary   +   CL other

CLt  can be derived from the steady-state equation:

CLt = ke Vd
where ke = the first-order rate constant for drug elimination from the total body.
           Vd  is the volume of distribution

-half-life time  t½

 t½ =0.693Vd/CL
 This is the period of time required for the concentration or amount of drug in the body to be reduced by one-half.
it depends on how quickly the drug is eliminated from the plasma.

drugs that are cleared from the blood more rapidly than others need to be given in regular doses to build up and maintain a high enough concentration in the blood to be therapeutically effective.
as repeated doses of a drug are administered its plasma concentration builds up and reaches what is known as a steady state. This is when 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 drug.
(a steady-state is achieved when the plasma concentration of drug remains constant)
Roe =CLt)(C)
Css ( the steady-state concentration) =Ro /keVd = RoCLt     

Ro      is the infusion rate
ke     is the first-order elimination rate constant
Vd      is the volume of distribution (constant for most drugs )

 i hate  equations :(

Drug elimination

 Drug elimination

Drugs are cleared primarily by the liver and kidneys. Excretion into the urine is a major route of elimination for metabolites and unchanged drug.


organs that excrete drugs eliminate water soluble  .

Lipid soluble drugs are not readily eliminated until they are metabolized to more polar compounds.

Possible sources of excretion include:

Breath -Urine -Saliva -Perspiration -Feces -Milk -Bile-Hair.

- kidney is the most important organ that eliminate drugs and their metabolites.

-Substances excreted in the feces are the orally ingested unabsorbed drugs or metabolites excreted in the bile that are not reabsorbed from the intestinal tract.

- Pulmonary excretion  is important as it pertains to the elimination of anesthetic gases and vapors, as well as alcohol.

 

 A. Renal elimination of a drug

1- Glomerular filtration:

Drugs enter the kidney through renal arteries, which divide to form a glomerular capillary plexus.
 no bound to albumin drugs flows through the capillary slits into Bowman's space as part of the glomerular filtrate . 
The glomerular filtration rate (125mL/min) is normally about twenty percent of the renal plasma flow (600 mL/min). 
(it is not affected by PH and lipid solubility.)

 

2- Proximal tubular secretion:

Drugs that were not transferred into the glomerular filtrate leave the glomeruli through efferent arterioles,
 which divide to form a capillary plexus surrounding the nephric lumen in the proximal tubule. 
Secretion primarily occurs in the proximal tubules by two energy-requiring active transport (carrier-requiring) systems, one for anions
 (for example, deprotonated forms of weak acids) 
and one for cations
(for example, protonated forms of weak bases). Each of these transport systems shows low specificity and can
transport many compounds; thus, competition between drugs for these carriers can occur within each transport
system . [Note: Premature infants and neonates have an incompletely developed tubular secretory mechanism and, thus, may retain certain drugs in the glomerular filtrate.]

3-Distal tubular reabsorption:

drug concentration increases when it  moves toward the distal convoluted tubule, and exceeds that of the perivascular space.
  if The drug is uncharged, may diffuse out of the nephric lumen, back into the systemic circulation. to minimize the amount of back-diffusion, increasing the ionized form of the drug in the lumen may be used , and hence, increase the clearance of an undesirable drug. As a general rule, weak acids can be eliminated by alkalinization of the urine, whereas elimination of weak bases may be increased by acidification of the urine.

4- Role of drug metabolism:

 Most drugs are lipid soluble and without chemical modification would diffuse out of the kidney's tubular lumen when the drug concentration in the filtrate becomes greater than that in the perivascular space. 
To minimize this reabsorption, drugs are modified primarily in the liver into more polar substances using two types of reactions:

- Phase I reactions.

  that involve either the addition of:-
hydroxyl groups( or) the removal of blocking groups from hydroxyl, carboxyl, (or) amino groups.
 
and

 -Phase II reactions .

 that use conjugation with sulfate, glycine,( or) glucuronic acid to increase drug polarity.
 The conjugates are ionized, and the charged molecules cannot back-diffuse out of the kidney lumen.

Drug Metabolism

Drug Metabolism

 Drug metabolism is transforming drugs, so they can be excreted from the body. They can interact with other drugs and foods, . Interactions can lessen or magnify the desired therapeutic effect of a drug, or may cause unwanted  side effects. There are thousands of possible drug-to-drug and drug-to-food interactions, and many medications and supplements are contraindicated  under certain conditions or in patients with specific diseases and disorders. This is why it is important that patients told their physician fully informed about all drugs and dietary supplements including herbal remedies they are taking.
Most drugs are treated by the body like foreign substances, also known as xenobiotics. Humans have evolved a complex system for xenobiotic metabolism. It is thought that exposure to the many toxic compounds in plants has facilitated the development of enzyme systems to detoxify foreign substances. Occasionally, though, the enzymes make an intermediate more toxic than the parent compound. This can happen with some of the compounds in cigarette smoke.
The metabolism of drug depend on many factors
 Physiological factors
AGE
in neonates & infants ==>LMEs (liver microbial enzymes) are immature meaning not well-developed
in geriatric ==>LMEs are impaired meaning their activity decrease
SO we can say that we must adjust drug dose for pediatrics & geriatrics carefully
sex
males have higher activity of LMEs than females WHY
because male sex hormones are microsomal enzyme inducers but female  sex hormones are microsomal enzyme inhibitors.

NUTRITION

malnutrition decreases activity of LME

Genetic factors
due to species & individual differences

Environmental factors
STRESS
leads to increased metabolism HOW
stress increases blood level of glucocorticoids which are LME inducers
FOREIGN COMPOUNDS
as insecticides & preservatives ==> LME inducers
DRUGS
  some drugs are LME inhibitors but most drugs are LME inducers.

Drug metabolism usually consists of two phases.

 Phase 1 

non synthetic reactions
for all types of drugs
involve metabolic modifications which may give more active compounds than original
EX
Oxidation : methyl alc. is oxidized to formic acid==> toxic
phenacetin is oxidized to paracetamol
tremorine is oxidized to oxotremorine==>tremor inducing drug
Reduction : trichloroethanol is reduced to chloral hydrate
Hydrolysis : Acetyl salicylate is hydrolyzed to acetate & salicylate

Phase 2

 synthetic reactions
for only some drugs
involve conjugation to give water sol. subs. easily to be excreted
Conjugation is done with glucoronic acid (mainly) ,acetic acid ,glycine ,or sulphate
Ex
Benzoic acid + Glycine =====> Hippuric acid

 

Drug Distribution

Drug Distribution

 It is the process by which the drug  reversibly leaves the bloodstream and enters tissues.

it depends on:-

1- capillary permeability

determined by capillary structure and chemical nature of the drug.
-The capillary wall consists of an endothelial cell layer and abasement membrane enveloping the endothelial cell layer .Capillary structure varies widely in terms of the basement membrane that is exposed by slit (tight) junction between endothelial cells In the brain, the capillary structure is continuous, and there are no slit junctions The capillaries of the brain are surrounded by a thick lipid membrane. Polar and ionic hydrophilic drugs cross this barrier slowly In order to enter the brain, drugs must be actively transported through the endothelial cell so repass through the endothelial cells of the capillaries of the central nervous system (brainand spinal cord).
Ionized or polar drugs generally fail to enter the CNS, since they are unable to pass through the endothelial cells of the CNS.
-drug  structure
The chemical nature of the drug strongly influences its ability to cross cell membranes. Hydrophobic drugs (lipophilic drugs),readily move across most biological membranes. The major factor influencing the hydrophobic drug's distribution is the blood flow to the area. By contrast, hydrophilic drugs, do not readily penetrate cell membranes and must go through the junctions of endothelial cells in capillary beds .Small drug molecules can freely diffuse out of the blood vessel while large drug molecules are confined to the plasma

2- blood flow

The rate of blood flow to the tissue capillaries varies widely as a result of the unequal distribution of cardiac output to the various organs.

3- the degree of binding of the drug to plasma proteins

Albumin is the major drug-binding and may act as a drug reservoir , when the drug eliminated by metabolism or excretion the bound drug dissociate from protein.

-volume of distribution

The volume of distribution is  is the ratio of the amount of a drug in the body to its concentration in the plasma or blood.
                                          Amount of drug in the body (Q)
  volume of distribution (Vd)=  ------------------------------
                                           Plasma drug concentration(C)
-large molecular weigh drug or extensively bind to plasma proteins drugs are too large to pass through capillaries and trapped within the plasma . in this case the drug distributes in plasma which is about 6% of the body weight ( 4L in 70 kg individual )
-low molecular weight & hydrophilic can move through capillaries slit junctions into interstitial fluid
however hydrophilic cannot pass through the lipid cell membrane to enter the water phase of the cell so this drugs  distribute in the volume  ( plasma water + interstitial fluid) (extracellular fluid ) about 20 % of the body weight ( 14 L in 70 kg individual)
-low molecular weight & hydrophobic can move through the endothelial slit junction into interstisial fluid and can pass through the cell membrane into the intracellular fluid the drug, therefore, distribute in the total body water about 60% of body weight (42L in 70kg individual)
-in pregnancy extremely lipid soluble drug  distribute to placenta and thus increase Vd .
sometimes drug(2) can take the place of drug(1)that binds to the plasma proteins so the concentration of drug 1 will increase and may reach the toxic concentration .
-ex:-
1-Chloral hydrate ,clofibrate ,phenybutazone can displace coumarin which is anticoagulant so if we take any drug of this  3 drugs with Coumarin it will cause bleeding.
2-Salicylates can displace Tolbutamide which is a hypoglycemic drug so Hypoglycemic shock will happen if we take both drugs with each other.
-drugs of high Vd have high half-life .

4- the degree of binding of the drug to tissue proteins.

some drugs prefer to accumulate in specific tissues for ex:-
Chlorpromazine prefer Brain
Digitoxin prefer Liver ,Kidney & Heart
Tetracycline prefer Bones & Teeth
Calcium prefer Collagen
Arsenic prefer Keratin
Iodine prefer Thyroid gland .... and so on

5- hydrophobicity of the drug. 

 

translation into Arabic

Drug Distribution

انتشار الدواء و بيعرف على انه عملية انتشار الدواء من الدم الى الخلايا و العكس والعملية دى بتعتمد على

1- capillary permeability

ودى فيها نقطتين اول نقطة تركيب الشعيرة الدموىة وتانى نقطة اللطبيعه الكيميائية للدواء

الشعيرة بيبقى فيها basement membrane  محاط بطبقة من indothelial cell   الطبقة دى بيبقى فيها فتحات اسمها slit junctions  فبالتالى بيبقى فى جزء من ال basement membrane  ظاهر(الجزء الظاهر ده بيختلف من شعيرة دموية لشعيرة أخرى حسب مكان وجودها فى الجسم )المهم ان الجزء الظاهر ده هو اللى بيمر منه الplasma proteins ،  لكن فال brain  مفيش slit junctions  وفى طبقة سميكة من الدهون فبالتالى lipid drugs هتمر لل brain لكن ال charged drugs  مش هتعرف تمر ولازم تدخل على  carriers بال Active transport   

تانى عامل بيأثر على الانتشار هو

2- blood flow لانه بيختلف من مكان لمكان لان ال Cardiac output  بيختلف من عضو لعضو يعنى مثلا بيبقى كتير للكبد والكلية و المخ لكن بيبقى قليل للخلايا الدهنيه والجلد وهكذا.

تالت عامل بقى هو درجة ارتباط الدواء ببروتينات الدم

3- the degree of binding of the drug to plasma proteins

الالبيومين هو اكتر بروتين بترتبط بيه الادوية لدرجة انه ممكن يكون مخزن للدواء ( لما كمية الدواء الغير مرتبطة ببروتينات تقل بسبب تكسيره فالكبد او اخراجه يروح الالبيومين مطلع شوية

هنتكلم بقى دلوقت عن حاجه اسمها

-volume of distribution

وهو عبارة عن النسبه بين كمية الدواء اللى دخلت جسمنا وتركيز الدواء اللى وصل للبلازما وبتتحسب بالمعادلة دى

                                         ( Amount of drug in the body ( Q

                                               ------------------------------     =  volume of distribution Vd

                                         (  Plasma drug concentration ( C

large molecular weight drugs-  بترتبط ببروتينات البلازما وبالتالى بتنتشر فالبلازما بس اللى هى حوالى 6% من وزن الجسم يعنى  4 ليتر فى شخص وزنه 70 كيلو

low molecular weight  hydrophilic drugs-  بتقدر تعدى من ال slit gunction وتوصل لل extracellular fluid لكن مش بتقدر توصل لل  intracellular fluid وبالتالى بتنتشر فى حجم ( البلازما + السوائل اللى خارج الخلية )

بيكون تقريبا 20 % من وزن الجسم يعنى 14 ليتر فى شخص وزنه 70 كيلو

low molecular weight  hydrophobic drugs- بتقدر تعدى وتدخل جوة الخلية يبقى هتكون منتشرة فالبلازما والسوائل خارج الخلية والسوائل داخل الخلية (كل سوائل الجسم )يعنى تقريبا 60 % من وزن الجسم تقريبا 42 ليتر فى شخص وزنه 70 كيلو

- فى الحوامل ال Vd بيزيد فى حالة الادوية اللى هى extremely lipid soluble  لانه بينتشر وبيوصل الplacenta  .

-فى بعض الاحيان بيبقى عندنا دواء مثلا (2) بيبقى مرتبط ببروتينات البلازما وناخد دواء  تانى هنسميه (1) ييجى بقى الدواء  رقم(1 ) ياخد مكان الدواء (2) على البروتين ويخلى الدواء (1) حر فالدم وبالتالى تركيزه هيزيد وممكن يوصل لل toxic concentration

طيب نشوف أمثله على كده

1-Chloral hydrate ,clofibrate ,phenybutazone can displace coumarin which is anticoagulant

,وبالتالى لو خدنا اى دواء من التلاته دول مع الcoumarin  هيحصل نزيف.

2-Salicylates can displace Tolbutamide which is a hypoglycemic drug  يعنى هيحصل غيبوبة سكر لو خدنا النوعين دول مع بعض

- لما بيكون  Vd  كبيرة بيبقى الhalf-life بتاعة الدواء عاليه واى عامل بيزود ال Vd  اكيد هيزود ال half-life بتاعة الدواء.

4- the degree of binding of the drug to tissue proteins.

رابع عامل بيأثر على انتشار الدواء هو درجة ارتباط الدواء ببروتينات الخلية لان بعض الادوية بتفضل تتجمع فى بعض الخلايا مثلا

Chlorpromazine prefer Brain

Digitoxin prefer Liver ,Kidney & Heart

Tetracycline prefer Bones & Teeth

Calcium prefer Collagen

Arsenic prefer Keratin

Iodine prefer Thyroid gland .... and so on

خامس حاجه بقى بتأثر على الانتشار هى

5- hydrophobicity of the or drug  structure

Hydrophobic drugs (lipophilic drugs) بتقدر تمر من اى جدار وتدخل جوة الخلية لكن ده  بيعتمد على ال blood flow  لمنطقة الانتشار

لكن hydrophilic drugs مش بتقدر تدوب فى جدار الخلية الدهنى عشان تدخل الخلية ، لكن ممكن تمر من ال slit junctions  .