Drug-Receptor Concepts (PDF)

**Drug-Receptor Concepts** **Outline of Lectures** - What is pharmacology? - Drug-Receptor Concepts - Drug-Receptor Interactions - Drug-Drug Interactions - Variation **Learning Outcomes** - Define and distinguish between 'pharmacology', 'pharmacodynamics' & 'pharmacokinetics'...

**Drug-Receptor Concepts** **Outline of Lectures** - What is pharmacology? - Drug-Receptor Concepts - Drug-Receptor Interactions - Drug-Drug Interactions - Variation **Learning Outcomes** - Define and distinguish between 'pharmacology', 'pharmacodynamics' & 'pharmacokinetics' - Explain how drugs act to produce their effects Describe the various types of drug targets or receptors - Define and distinguish between an agonist, a partial agonist & an antagonist - Describe how drug-receptor binding translates into a biological effect - Define & discuss the importance of therapeutic index **Basic Principles of Drug Action** - What is pharmacology? - Drugs & The Human Body - Drug taking initiates 2 processes 1. Actions of the drug on the body 2. Actions of the body on the drug consider it's harmful → try to metabolise - Study of this 'drug-body interaction' called '***pharmacology***' **Drug-Body Interactions** - "When we have a headache, we take for granted that after taking some aspirin, our headache will probably disappear within 15 to 30 minutes. We also take for granted that, unless we take more aspirin later, the headache may recur within a few hours. This familiar scenario reveals the primary events of pain relief: - The ***first*** is the **[administration]** and **[absorption]** of the drug into the body; the ***second*** is the **[distribution]** of the drug throughout the body; the ***third*** is the **[interaction]** of the drug with relevant functional components of the body, which are responsible for the drug's actions; and the ***fourth*** is the **[elimination]** of the drug from the body". - RM Julien 1. Absorption 2. Distribution 3. Metabolism 4. Excretion **Branches of Pharmacology (Traditional)** A diagram of a pharmacology Description automatically generated **Drug-Receptor Concepts** **How Do Drugs Act?** - Drugs interact with biological systems in ways that [mimic, or otherwise affect, the natural chemical messengers] ex) neurotransmitters, hormones [ or processes of the body] - **Two types of drug action** - **Non-specific drug action** a. **[Some]** drugs act in a simple ***physical*** or ***chemical*** manner -- e.g. antacids, osmotic diuretics, osmotic laxatives 1. **[Antacids]** -- anti+acids / basic alkaline compound neutralizes acid -- interact with H + 제산제 2. **[Osmotic diuretics]** -- 삼투압 이뇨제; 혈액 신장 삼투압 증가, 물 나트륨 재흡수 억제 / highly soluble micro molecules; 혈액에 쉽게 녹아 신장을 통해 빠르게 배출됨 / nephron에서 흡수되지 않고 배출, 수분과 나트륨 배출 3. **[Osmotic laxatives]** -- 삼투성 완하제 / does not digest, 장에 남아 장의 삼투압 높이고 increase solute content 장으로 물을 끌어들여 배변에 도움 b. Lack any specific structure-activity relationship 특정 수용체에 결합하지 않음 c. Require large doses of drug for effect - **Specific drug action** a. **[Most]** drugs act in a highly ***specific*** manner 특정 수용체에 결합해서 작용 - phenylephrine α receptor agonist / 혈관수축제 -- 혈압 낮을 때, 마취할 때 충혈억제 코막힘 완화 - salbutamol selective β-2 agonist / 천식-기관지 확장 - atropine muscarinic-acetylcholine receptor의 competitive antagonist - digoxin 심근 수축력 증가 -- 심부전, 비정상 심장리듬 치료 b. They interact with or bind to ***specific*** macromolecular or cellular targets in the body, called 'receptors' c. Show clear-cut structure-activity relationship d. Produce biological effects at very low doses **The Idea of the Drug 'Receptor'** - **The Drug Receptor Concept** - 'Most drugs produce their biological effects by interacting with specific macromolecules in the body, called receptors' - **The Receptor** - 'The specialised component of the cell or organism that interacts with a drug, and [initiates the chain of biochemical events] leading to the drug's observed [biological effects]' **The Drug Target of 'Receptor'** - Drug receptors are protein or glycoprotein molecules **protein** **configuration** decides their roles 1차 -- amino acid chain 직선 모양: 수용체의 아미노산 서열 결정 2차, 3차: 수용체의 약물활성부위 형성 4차: 복잡한 수용체 형성 - Most drug receptors are located on **the cell membrane** hydrophilic drug와 상호작용 -- e.g. atenolol β1-adrenergic receptor를 차단하는 blocker -- 혈압 낮춤 / chlorphenamine Histamine H1 receptor 차단 -- 알레르기 증상 완화, cimetidine, codeine - Some drug receptors are located inside the cell -- **e.g. oestrogen, testosterone, vitamin D, etc** lipophilic drug와 상호작용 / in cytoplasm or nucleus (big restriction) **Drug Targets or Receptors are Protein or Glycoprotein Entities** [GABA~*A*~]{.math.inline} receptor: ion channel / Cl- ion 세포 안으로 들여보내 -- 뉴런의 흥분 억제 β1-adrenergic receptor: GPCR / G-Protein Connect Receptor / 심장 -- adrenaline (norepinephrine, epinephrine)이 결합하면 심장 수축력 증가 → 심장박동 빨라짐 **Drug Targets or 'Receptors'** - **Multiple types of Drug Targets or 'Receptors'** - **'Classical' receptors** -- regulatory protein or binding sites for endogenous (in the body) or natural chemical messengers, such as neurotransmitters & hormones - **Ion channels** the drug combines to close/open the channel -- e.g. lidocaine Na+ channel blocker -- 국소마취 효과, diazepam [GABA~*A*~]{.math.inline} blocker -- 진정 효과, amiodarone K+ channel blocker -- 부정맥 치료 - **Enzymes** -- e.g. NSAIDs Ibuprofen-COX enzyme (cyclooxygenase) inhibitor, Statins HMG-CoA enzyme inhibitor -- hyperlipidaemia 고지혈증, ACE inhibitors Angiotensin-Converting-Enzyme Inhibitor → lowers blood pressure - **Carrier or transport proteins** inhibit or promote activity -- e.g. digoxin, PPIs, SSRIs **\ ** **Drug-Receptor Interactions** **How do drugs and receptors interact?** Drugs bind to receptors because the drug's [molecular structure & shape] are similar to those of the natural chemical messengers the body produces to target those receptors - There must be a **[complementary fit]** interaction with the binding site → chemical reaction between the drug molecule & the binding site on the receptor - Drug & receptor interact to form a drug-receptor (D-R) complex ***via*** a reversible chemical reaction - The drug-receptor interaction is governed by **the Law of Mass Action** a. We can relate **[drug concentration]** & **[biological effect]** to the **[fraction of receptors]** occupied by the drug - **The 'Lock and Key' Relationship** - Basis of **[selectivity]** of drug action fitting is the *basic* requirement a. ***Chemical* selectivity** Only drugs with the correct shape and properties bind to the right receptors b. ***Biological* or tissue selectivity** If the drug that binds into the cell which does not have its receptor, NO EFFECT on that cell The drug only works in tissues or cells that actually express the receptor it targets **Drug-Receptor Interactions** - Drug & receptor interact to form a D-R complex via a reversible chemical reaction **Drug + Receptor ⇔ Drug-receptor complex**  - The fraction of receptors occupied by the drug is a function of: - the concentration of drug in the biophase - the equilibrium dissociation constant ([*K*~*D*~]{.math.inline}) for drug -- receptor complex **\ ** **Drug Concentration-Receptor Occupancy Curve** A graph of a drug Description automatically generated **Drug-Receptor Interactions** - **The 'Receptor Occupancy Theory'** - Assumptions a. drug effect is proportional to the **[fraction]** of receptors occupied b. maximum drug effect ([*E*~max~]{.math.inline}) occurs when **[all]** receptors in the system are occupied by the drug **Drug Concentration-Effect Curve**  **\ ** **Log Drug Concentration-Effect Curve** A graph of a drug concentration Description automatically generated **Drug-Receptor Interactions** **What happens when a drug binds to its receptor?** **Consequences of Drug-Receptor Interaction** - One of [four] possible things can happen - The drug may mimic a [natural, endogenous chemical messenger] hormones, neurotransmitter ⇒ produce the same effect as the natural chemical messenger **(called an 'Agonist' drug** SAME binding site**)** - The drug may 'block' the receptor, i.e. prevent the natural chemical messenger from binding ⇒ produce no effect **(called an 'Antagonist' drug** SAME binding site**)** - The drug may bind to a site near the binding site for a natural, endogenous chemical messenger & influence its binding ⇒ ↑ enhance or ↓ inhibit/reduce the effect of the natural chemical messenger **(called an 'Allosteric modulator'** POSITIVE/NEGATIVE allosteric modulator**)** - The drug may bind to the site normally occupied by a natural, endogenous chemical messenger ⇒ produce an opposite effect to the natural chemical messenger **(called an 'Inverse Agonist' drug** 별로 없음**)** **\ ** **Types of Drug-Receptor Interaction**  **Drug Agonism & Antagonism** - **What is the basic distinction between 'Agonist' & 'Antagonist' drugs?** - Both have '**[affinity]**' for their receptors ㄴ 약물의 친화력: 약물이 수용체에 얼마나 쉽게 결합하는지 / 약물-수용체 복합체를 형성할 확률 a. 'a measure of the ease with which a drug binds to its receptor' b. *'a measure of the probability that a drug molecule will interact with a receptor to form a drug-receptor complex'* c. 'Affinity' expresses the chances of the drug binding to its receptor **(By analogy, a key fitting into a lock)** -- chemical selectivity d. Affinity is measured by the [*K*~*D*~]{.math.inline} of the drug ㄴ [**K**~**D**~]{.math.inline} (해리상수)와 반비례 / 약물-수용체 복합체 결합이 끊어지는 경향 **Affinity = 1/**[**K**~**D**~]{.math.inline} - Agonist drugs have '**[efficacy]**', whereas antagonist drugs have no '**[efficacy]**' ㄴ 약물의 효능: 생리적 반응을 일으키기 위해 수용체를 활성화하는 능력 / 약물이 수용체를 활성화시키고 신호전달경로가 작동해 생물학적 반응을 일으킴 a. *'a measure of the ability of the drug-receptor complex to couple or transduce the drug binding into a biological response'* b. 'Efficacy' expresses the ability of the drug to 'activate' or cause a conformational change in the receptor that will lead to a biological response. **(By analogy, the key turning the lock)** c. 'Efficacy' (e) may be *0*, low or very high ㄴ **Full Agonist**: VERY HIGH -- leads to MAX biological response **Partial** **Agonist**: LOW -- leads to LESS than MAX biological response **Antagonist**: 0 -- FAILS to biological response / binding site에 맞는데 reaction이 일어나지 않음 **Agonist Drug Action** - **Agonist** - ' a drug that binds to its receptor, activates the receptor, and elicits (bring out) a biological response' - **Two types of Agonists** - **Full agonist** 결합한 수용체를 100% 완전히 활성화시킴 a. binds to its receptor, activates the receptor & is capable of eliciting the **[maximum]** possible response b. has high efficacy (*e*) -- **e.g. dobutamine, salbutamol** c. Full + Partial agonist 같이 복용하면 Partial Agonist가 Full Agonist의 결합을 방해해 antagonist처럼 행동함 - **Partial agonist** a. binds to its receptor and activates the receptor, but can only elicit **[less than]** the **[maximum]** possible response 결합한 수용체가 다 반응하긴 하는데 각각 반응 강도가 낮음 -- 80% 정도 ㄴ 따라서 약을 아무리 많이 먹어도 maximum effect 나타나지 않음 b. intermediates efficacy (*e*) c. reduces the response elicited by the full agonist -- **e.g. buprenorphine, oxymetazoline** - **Full vs Partial Agonist** A graph of a normal distribution Description automatically generated with medium confidence **Antagonist Drug Action** - **Antagonist (*pharmacological*)** - 'a drug that binds to its receptor but fails to activate the receptor, and so fails to elicit a response' - it has an efficacy (*e*) of 0 NO biological effect - it competes with the agonist drug (or natural chemical messenger) for binding to the receptor - its biological 'effect' results from preventing the agonist drug (or natural chemical messenger) from binding to its receptor - **e.g. atenolol** β1 adrenaline receptor antagonist / lowers heart rate & blood pressure - **chlorphenamine** anti-histamine / Histamine1 receptor antagonist - **naloxone** 마약의 진통효과 억제 / opioid receptor에 결합 - **The 'Spare Receptor' / 'Receptor Reserve' concept** Maximum effect without full receptor occupancy: 수용체가 일부만 만들어져도 최대의 약효가 남 ⇔ the Law of Mass Action / abundant of receptors to produce maximum response - exceptions to the 'receptor occupancy theory' - full agonists may elicit maximum response ***[without]*** full receptor occupancy - system is said to have ***['spare receptors']*** or a ***['receptor reserve']*** a. enables economy of hormone / transmitter secretion some metabolise in the bloodstream or break down by an enzyme, 그 이후에도 response에 필요한 만큼 남아있음 → 적은 양으로도 충분한 효과 b. allows low affinity drugs to elicit maximum possible response 약하게 결합해도 충분한 수의 spare receptor가 있으면 최대 반응을 일으킬 수 있음 = 결합할 확률 ↑ **Characteristics of the Graded Dose-Response Curve**  - **Potency** 약효가 나는 minimum amount - A measure of **[amount]** of drug needed to elicit a specific response - reflected in the location of D-R curve along dose axis experimentally expressed as [ED~50~]{.math.inline} or [EC~50~]{.math.inline} 50% of MAX effect - clinically expressed as ***[absolute]*** 1g or ***[relative]*** (compared to other drugs) potency - **[NOT]** a critical characteristic of the drug 약효발휘를 위한 용량을 주면 효과는 같음 - **e.g. morphine vs diamorphine (heroin)** same effect -- diamorphine is just 3 times more potent than morphine = **control dosage** - **Maximal efficacy** - maximal response / effect produced by the drug - reflected as a plateau in the log D-R curve - the **[most]** important characteristic of drug How much pain? What kind of pain? -- **e.g. paracetamol** 두통 **vs morphine** 출산 진통 - maximal efficacy may be *[determined]* or *[limited in clinical practice by the onset of adverse side effects!]* - **Slope** - slope of curve [varies from drug to drug] - reflects **the magnitude of change in response** per unit change in dose - the slope may be an important consideration in clinical practice under certain circumstances! ㄴDose increase might cause S/E - **Biological variability** - ***[different]*** responses to same dose of drug in ***[different]*** individuals - ***[different]*** responses to same dose of drug in ***[same]*** individual 복용하는 시간 등에 따라서도 다르게 나타남 - possible sources of variation in drug response a. Age b. Gender c. Genetic factors d. Polypharmacy e. Pathological state **Drug-Drug Interactions** - **Drug Antagonism** - 'Interaction between two drugs such that the effect of [one is diminished or completely abolished] in the presence of the other' - **Type of drug antagonism** 1. **Competitive antagonism (pharmacological / receptor)** 2. **Non-competitive antagonism** 3. **Chemical antagonism** 4. **Pharmacokinetic antagonism** 5. **Physiological or Functional antagonism** **Competitive antagonism** - The **[agonist]** & **[antagonist]** drugs compete for the **[same]** receptor binding site - Antagonist drug binding reduces chances of agonist binding ⇒ **[agonist effect ↓]** - 2 subtypes, depending on nature of antagonist-receptor interaction 1. **Reversible or surmountable** 극복 가능한 / MANY drugs follow this mechanism -- cardiovascular and other diseases - Both the agonist & antagonist drugs bind **[reversibly]** to the receptor 길항제가 수용체에 결합하지만, 더 높은 농도의 작용제를 투여하면 길항제를 극복 - The fraction of receptors occupied depends on 2 drugs' relative **[receptor affinities]** & **[concentrations]** Increase agonist molecules → agonist drugs produce bigger response until it completely replace antagonist drug - Antagonism **[can be]** overcome by increasing concentration of agonist drug - This leads to **[two]** effects on the agonist log D-R curve (in the presence of an effective dose of the antagonist drug) a. a parallel shift to the right antagonist가 있으면 agonist 더 넣어야 효과 O b. **[NO]** reduction in the maximal response A graph of a number of different colored lines Description automatically generated with medium confidence 0 -- control (**[NO]** antagonist) / 1-1000 -- fit doses of antagonists antagonist drug ↑ to the system -- curve moves to right agonist ↑ - same 100% response (antagonism is completely reversible) Ex) β1-receptor, α-receptor & adrenaline, anti-histamine & H1 receptor 2. **Irreversible or in surmountable** 극복 불가능한 / antagonist just stay on the receptor, bound & permanently block agonist drugs from binding - The antagonist drug binds **[irreversibly]** to the receptor (due to ***high affinity*** or ***covalent bonding*** which is hard to break) - A fraction of receptors rendered permanently unavailable for agonist drug binding - The antagonism **[cannot]** be overcome by increasing the concentration of the agonist drug - This leads to **[two]** effects on the agonist log D-R curve (in the presence of an effective dose of the antagonist drug) a. a reduction in the slope of the curve b. a reduction in the maximal response receptors are not available for agonist drug -- 100% bind required to get MAX response **System Without Spare Receptors** 100개 receptor 중에 antagonist가 100개 occupy  **System With Spare Receptors** A graph showing the difference between an individual and an individual Description automatically generated Ex) ibuprofen -- COX enzyme, α-receptor adrenaline, **phenoxybenzamine**- α-adrenoceptor antagonist → the resulting insurmountable block manages **phaeochromocytoma**, a **tumour** releases large amounts of **adrenaline** (epinephrine), but 붙을 receptor 없음 **Non-competitive Antagonism (= irreversible)** - The antagonist drug **[does not compete]** with agonist drug for **[same]** receptor binding site - The antagonist drug may bind to a **[different site]** on the receptor or **[interfere]** with response coupling - The antagonism **[cannot]** be overcome by increasing concentration of agonist drug irreversible - This leads to **[two]** effects on the agonist log D-R curve (in the presence of an effective dose of the antagonist drug) very similar w/ irreversible competitive antagonism -- no spare receptor / mechanism 차이임 a. a reduction in the slope of the curve b. a reduction in maximal response antagonism cannot be overcome Ex) picrotoxin -- derived from plant, acts on GABAa receptor (ion channel), flow into the channel and block it from the inside  **Chemical Antagonism** - Results from [***direct*** **interaction**] between the **[antagonist]** & **[agonist]** drugs - The '*antagonist*' drug binds to / combines with the active drug '*agonist*' in **[solution]** make it inactive complex -- cannot bind to receptor → The active drug is rendered ***[inactive]*** or ***[unavailable]*** to interact with its target receptors - Typical examples a. **Protamine** positive charge / ionic interaction and prevent heparin from activating **vs Heparin** negative charge / treat cardiovascular conditions / prevent blood clotting? overdose 피 안 멈춤 b. **Dimercaprol** bind to heavy metals **vs Heavy metals (Hg, Cu, Pb)** 중금속 노출되었을 때 cause mutation in long term **\ ** **Pharmacokinetic Antagonism** ADME (absorption, distribution, metabolism, and excretion) - The '*antagonist*' drug acts to reduce the effective concentration of the active drug '*agonist*' at its site of action active drug concentration 줄이면 / 길항제가 작용제의 농도를 감소시켜 효과를 억제 - Possible mechanisms a. **Reduced absorption from the GIT** - Ferrous salts vs Tetracycline antibiotics 2-3hrs after taking salts -- so that we can get antibiotic effects → reduce effect of ferrous salts 분해 시켜 흡수되지 않도록 함 b. **Increased metabolic degradation** - Phenobarbital liver produce large amount of cytochrome \*P450 enzyme -- promotes metabolism vs Warfarin 대사 촉진시켜 효과 억제 / 용량 중요 adjust doses c. **Increased renal excretion** elimination - NaHCO3 vs Aspirin weak acid니까 ionization을 억압해 ㄴnon-ionized molecules are more easily absorbed to plasma membrane (lipid -- hydrophobic) compared to ionised -- fully ionized and not re-absorbed -- 소변으로 방출 anti-pyretic (reduces fever) -- potentially dangerous → speed-up excretion of aspirin **Physiological / Functional Antagonism** - Interaction of two **[opposing]** agonist effects in a single biological system ⇒ **[cancelling]** out of each other's effect no direct interactions - The two drugs elicit **[opposing]** responses by acting on **[different]** receptors - Typical examples a. **Acetylcholine** neurotransmitter which decreases in heartrate **vs Noradrenaline (heart rate)** β1 receptor -- increase heartrate → balance of two effects (NOT reduce each other's effects) b. **Glucocorticoids** mobile glucose; liver to bloodstream & block blood stream **vs Insulin (blood sugar levels)** more insulin uptake -- glucose ↑ in bloodstream **Summation / Additivity** simple addition - **Summation** (SAME drug mechanism → drug effects = addition) - When the combined effect of two drugs which elicit the same overt response, ***[regardless of their mechanism of action]***, is equal to the algebraic sum of their individual effects Paracetamol + codeine → co-codamol (SAME pain relief drugs) - **Additivity** (DIFFERENT drug mechanism, drug effects = addition) - When the combined effect of two drugs, ***[which act by the same mechanism]***, is equal to that expected by simple addition of their individual effects **\ ** **Synergism / Potentiation** - **Synergism or Potentiation** (one -- very little effect, administer with another drug -- enhanced drug effect) - When the conjoint effect of two drugs is greater than the algebraic sum of their individual effects - The ***[synergist]*** may act to a. **Increase the concentration of the other drug at its receptor sites** (pharmacokinetic) - Tyramine monoamine (similar to adrenaline, noradrenaline) from cheese / indirectly acting sympathomimetic drug (**sympathetic**) & MAO inhibitors Mono Amine Oxidase / okay in the liver / inhibitor of enzyme is used to treat CNS diseases b. **Increase the responsiveness of the other drug's receptor-effector protein** - Benzodiazepines relieve anxiety Ex) Diazepam -- increasing GABA channel by binding acts on GABA ([GABA~*A*~]{.math.inline} receptor) **receptor ion channel** -- more channel open, more chloride ions go through the channel A diagram of a cell membrane Description automatically generated  **\ ** **Variation in Drug Responsiveness** - **Definitions, Types & Mechanisms** - **Drug Tolerance** - Definitions - Mechanisms **Variation in Drug Responsiveness** - **Scope** - ***Inter***-patient variation - ***Intra***-patient variation - **Possible consequences** - Lack of efficacy since effective for some patients, some not (undesirable) - Unexpected side effects common S/E / take into serious conditions (?) - **Possible mechanisms** - Pharmacokinetic smtg affects ADME mechanism - Pharmacodynamic how drugs interact with the body - **Possible types of variation** - Qualitative variations completely different/unexpected response in nature we normally would expect ㄴpotentially serious Ex) antibiotic -- **chloramphenicol** S/E in 1/50,000 - Quantitative variations all **SAME** response in patients, but the **amount** of response is different - **Quantitative variations** - ***Hyper***-responsiveness SAME/BIGGER response compared to others - ***Hypo***-responsiveness or tolerance (most common phenomena) - **Tolerance** - **[Innate]** inborn -- reduce responsiveness of drugs / Ex) atropine -- antagonist, digoxin -- treat heart failure (doses can acc kill human being) vs **[acquired]** tolerance person initially have response → develop reduce drug responses - **[Tolerance]** **slowly** developing acquisition of tolerance (exposure to drug) / takes weeks to months vs **[tachyphylaxis] rapidly** developing tolerance (set of protection) / matter of hours or days **Acquired** **Tolerance** - **Definitions** - 'An acquired state of progressively decreasing responsiveness to a drug as a result of ***[prior]*** or ***[repeated]*** exposure to the drug or another drug with a similar action' cross-tolerance: develop tolerance to a specific drug → have tolerance to drugs in same class - **Mechanisms** - **Pharmacodynamic** a. Receptor 'down-regulation' expose to particular drug → interact to protect themselves ㄴReduce the density/number of receptors so that interact with fewer drugs - Reduction in receptor density -- e.g. β1-adrenergic receptor interact with heart b. Receptor 'uncoupling' -- e.g. β2-adrenergic receptor signalling Receptors are coupled -- binding to the cell surface → trigger to change the chemical of cells / drug can still bind, but coupling is impaired → chemical activity is reduced - **Metabolic** a. Enhanced metabolism of the drug increases its own metabolism Ex) P450 enzyme b. Due to induction of metabolising enzymes -- e.g. alcohol 1) psychological adaptation 2) alcohol will induce enzyme to digest alcohol, barbiturates, etc. - **Exhaustion / Depletion of mediators** a. Common with indirectly-acting drugs need mediator to produce effects b. Due to depletion of endogenous stores of **[mediators]** of the drug's action - Amphetamine concentrate well / stay late night -- stimulates sympathetic nerve system → regularly taking SAME dose would blunt/reduce effects, nitrates - **Physiological adaptation** a. Evoked compensatory or homeostatic mechanisms b. Blunts or cancels out the drug's effects - Diuretics increase urine -- reduce plasma volume, nitrates **Clinical Selectivity** - **[Absolute]** vs **[Relative]** Selectivity - **[Therapeutic]** or **[Desirable]** effects vs **[Adverse]** or **[Undesirable]** or **[Side]** effects - Concept of Therapeutic Index **[Absolute]** vs **[Relative]** Selectivity - No drug has only one single, specific effect - Drugs produce a **[spectrum]** of effects - Hence '***[relative]***', not '***[absolute]***', selectivity of drug action - Relative selectivity - ***'The degree to which a drug acts upon a given site relative to all possible sites of interaction'*** **[Therapeutic]** or **[Desirable]** effects vs **[Adverse]** or **[Undesirable]** or **[Side]** effects - Drug effects split into **[therapeutic]** & **[undesirable (s/e)]** - Undesirable effects may be **[minor]** (nausea, vomiting, etc) or **[serious]** Ex) thalidomide -- pregnancy women, statin -- reduce plasma pressure (destroying skeletal muscle) - How do undesirable effects come about? - Both effects may be mediated via **[same]** receptor-effector mechanism - **e.g. nitrates** serious troubling headaches -- dilate blood vessels -- sensory neurons get stretched -- cause tension headache**, insulin, warfarin** - Both effects may be mediated via **[identical]** receptors located in **[different]** tissues - **e.g. haloperidol** Dopamine D2 receptors - antipsychotic drugs are used to treat psychotic disorders, such as schizophrenia ㄴmight cause symptoms of Parkinson diseases**, verapamil** - Both effects may be mediated via **[different]** types of receptors - **e.g. salbutamol** selective β2-adrenergic receptor agonist used in the treatment of asthma and COPD **, propranolol** **Concepts of Therapeutic Index** - **Therapeutic Index** - Determined by the ratio of **[toxic]** to **[therapeutic]** dose - Therapeutic Index = [\$\\frac{median\\ toxic\\ dose\\ (\\text{TD}\_{50})}{median\\ effective\\ dose\\ (\\text{ED}\_{50})\\ }\$]{.math.inline} - Provides a useful measure of a. The **[margin of safety]** of the drug b. The **[benefit]** to **[risk]** ratio of the drug - **e.g. penicillin vs warfarin**