Desensitization of receptors

Desensitization of receptors

Repeated or continuous administration of an agonist (or an antagonist) may lead to changes in the responsiveness of the receptor

-repeated administration of a drug results in a diminished effect  وده تعريف  الtachyphylaxis

يعنى استمرار اعطاء الAgonist او ال Antagonist  بيقلل استجابة الreceptor  ليهم

وبالتالى التأثير بتاعهم هيقل.

                         

Dose Response Relationships

حجم تأثير الدواء بيعتمد على كمية او تركيز الدواء عند receptors  اللى بدورها بيتم تحديدها  بجرعة الدواء اللى داخلة الجسم  وpharmacokinetics الخاص  بالدواء.

فى الرسم البيانى  اللى جاى(اسم الرسم البيانى ده  ( graded dose response curves

 رسمنا  effect  على المحور ص مرة مع  ال dose  على المحور س.

ومرة مع ال log doseعلى المحور س وواضح ان العلاقة بينهم طردية.

Ec50 هى drug dose that shows fifty percent of maximal response

وكلما كانت ال Ec50  صغيرة كل مكان  ال drug more potent  .

وفى الرسم واضح ان drug A more potent than drug B))

ال curve  ده بنعرف منه حاجتين مهمين جدا

1-potency

a measure of the amount of drug necessary to produce an effect of a given  magnitude

2-efficacy

the ability of a drug to give a physiologic response when it interacts with a receptor.

the maximal response (Emax) or efficacy is more important than drug potency 

                          

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)

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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

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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.

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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