Pharmacodynamics, posology, drug interactions (trans 7) Flashcards
Proteins that have been classified as receptors:
- enzymes
- regulatory proteins
- transport proteins
- structural proteins
Enymes
- Participate in crucial metabolic pathways
- May be inhibited/activated by binding a drug
e.g. dihydrofolatereductase - found in folic acid synthesis, blocked by trimethoprim.
dihydropteroatesynthetase - blocked by sulphonamide.
Regulatory proteins
- Mediate actions of endogenous chemical signals. Change the activity of cellular enzymes.
e.g. neurotransmitters, autocoids, hormones
Transport proteins
- involved in transport processes.
e.g. H-K ATPase, Na/K ATPase (membrane receptor for cardioactive digitalis glycoside)
Structural proteins
- Serve structural roles, form cell parts
e.g. tubulin (receptor for colchicine an anti-gout drug)
REMEMBER
There are also nucleic acids that act as receptors
- Partially for chemotherapeutic approaches to control malignancy
e.g. dactinomycin, one of the first drugs used in treatment of tumors
REMEMBER
lipids of cell membranes may also interact with drugs (which need to be water-soluble)
best examples are general anesthetics
types of regulatory proteins
- Ligand‐Gated Ion Channels
- G‐protein Coupled Receptors
- Enzyme‐linked Receptors
Ligand‐Gated Ion Channels
- Binds hydrophilic ligands
- Receptor is on the surface of the cell membrane and transmits signal across the membrane
- Ligand binds to receptor, opening an ion channel transmembrane conductance of the relevant ion, thereby altering the electrical potential across the membrane
- Shortest duration of response, RAPID (in milliseconds)
e. g.
1. nicotinic Ach receptor (nAChR): causes Na+ influx, action potential and skeletal ms. contraction
- GABA receptors for Benzodiazepines: allows chloride influx, hyperpolarization
G‐protein Coupled Receptors
- Serpentine‐type receptor that binds hydrophilic ligands
- Involve activation of the G‐protein (which uses a molecular mechanism that involves binding and hydrolysis of ATP) to activate a 2nd messenger (e.g. cAMP, cGMP, Ca2+, phosphoinositides)
- Found on every type of cell in the body
- RAPID RESPONSE (seconds to minutes)
Adrenergic receptors Muscarinic, dopaminergic, serotonergic
Enzyme‐linked Receptors
- Contain the enzyme Tyrosine Kinase
- Consists of an extracellular hormone‐binding domain and a cytoplasmic enzyme domain; binds hydrophilic ligands
- response: minutes to hours
e.g.. Receptors for endothelium-derived growth factor (EDGF), insulin, macrophage colony‐stimulating factor 1 (CSF1), platelet-derived growth factor (PDGF), insulin‐like growth factor 1 (IGF‐1), Atrial Natriuretic Peptide (ANP)
Cytosolic‐Nuclear Receptors
- Binds Hydrophobic ligands/drugs (lipid soluble), receptor inside cell
REGULATORY: change the activity of cellular enzymes
- Regulation of gene expression
- Response: HOURS TO DAYS
- Best exemplified by steroid hormones
Some tissues have more receptors than are necessary to produce a maximal response. These tissues thus have so-called “spare receptors”
o Receptors are said to be “spare” when a maximal biologic response is elicited at a concentration of agonist that does not result in full occupancy of available receptors.
o Present when the concentration for 50% maximal effect is less than the concentration for 50% maximal binding (Kd> EC50)
o Insulin has plenty of available spare receptors (99%) and occupies only 1%, a big functional reserve for entry of glucose into the body in contrast to α- and adrenoceptors of the heart (5‐10%), which gives a limited reserve.
REMEMBER
Drug mechanism can also occur through non-receptor mediated processes
- Pumps
- ion-channels
- physical activity
- chemical interaction
- altering metabolic processes
Physical property of drug that refers to adhesion of atoms, ions, or molecules from a gas, liquid, or dissolved solid to a surface
Adsorption
**e.g. treatment of poisoning by activated charcoal where toxins bind to charcoal for excretion
REMEMBER
Physical property of drugs such as its mass can serve a certain purpose
e.g. in the use of bulk laxatives that will serve as a stimulant for defecation in the treatment of constipation
COLLIGATIVE EFFECT
- Depends mainly on the relative numbers of particles of ions and molecules (not the nature of substances) in a particular area and not on the detailed properties of the molecules themselves
e.g. Action of magnesium sulfate (purgative) which is a lipid soluble substance that is able to saturate the ion channels in plasma membrane.
Chemical interaction of drugs:
Neutralization
Best exemplified by antacids neutralizing gastric acidity
Chemical interaction of drugs:
Chelation
- Binding of ions and molecules to heavy metal ions
Seen in the use of antacids which chelate with tetracyclin; penicillamine antidote for Wilson’s disease or copper poisoning; Dimercaprol (BAL) an antidote for heavy metal poisoning such as Hg, arsenic, and lead toxicity; works through the oxidation of potassium permanganate
Properties of drug
AFFINITY:
o The ability of the drug molecule to bind to a receptor, not necessarily producing a biological effect (or intrinsic activity)
o Varies in degrees, others have strong affinity which may cause displacement of other drugs
o Competitive or non-competitive
**
Agonist - has affinity
Partial agonist - has affinity
Antagonist - has affinity
Properties of drug
EFFICACY:
o (most important property of a drug) -Clinical effectiveness
o Ability of a drug to produce maximal response
o Agonist - binds to a receptor, it produces an effect; therefore it has both affinity and efficacy. Partial agonist - has affinity and causes a similar effect but only half the efficacy of a full agonist. Antagonist - has affinity to a receptor but does not produce an effect therefore it has no efficacy.
Properties of drug
INTRINSIC ACTIVITY:
o Agonist-receptor coupling that brings about a response
o Capacity of a single drug‐receptor complex to evoke an effect
Full Agonist = intrinsic activity of 1
Partial Agonist = intrinsic activity of 0.5
Antagonist = NO intrinsic activity
POTENCY
o A range of doses over which a drug produces increasing responses
o Minimum effective concentration to produce effect.
o Median effective concentration= concentration required to produce 50% of a drug’s maximal response.
o A drug can have absolute or relative potency
NOTE: If the drug is potent, it does not necessarily mean that it is also the more efficacious, better or stronger.
Drug concentration which induces a specified clinical effect in 50% of the subjects to which the drug is administered
EC50 (Median Effective Concentration 50%)
Concentration of a drug which induces death in 50% of the subjects to which the drug is administered; Used in animals
LD50 (Median Lethal Dose for animals and Median Toxic Dose for humans)
**In humans, we follow the median toxic dose: illicit toxicity in 50% of subjects to which drug is administered
Ratio of LD50 to ED50
TI (Therapeutic Index)
- *Rough estimate of the margin of safety of a drug
- *The higher the TI, the wider the margin of safety
Margin between therapeutic and lethal
doses of a drug
Margin of Safety
Classical Occupation Theory (by Clark)
D + R DR Effect
o The drug is directly proportional to number of receptors occupied
o Based on the laws of mass action, maximum effect achieved if all receptors are occupied
o Number of bound receptors is in turn directly proportional to the concentration of the drug
o The produced biological effects depends on the concentration of the drug-receptor complexes formed
o Relates to affinity
Receptor theory which postulates that a drug does not just modify or bind, it also activates the receptor to increase or produce the response (intrinsic activity)
Modified Occupation Theory
- *Concept of “spare receptors”
- A drug has more receptors than it needs. These excess or reserve site have the same quality/function as those that have been activated
Rate theory
**refer to trans for equation
o Response is directly proportional to the rate of the receptor binding
o Intrinsic activity is a function of the association (k1) and dissociation (k2) rates
o The k2 determines the number of encounters per unit time
o Agonists have a fast k1 and slow k2; Antagonists have slow k1 and fast k2
Receptor theory which postulates that receptors are either in the resting or active state
Two-state/Allosteric Model
o Agonists bind to the active state of the receptor
o Antagonists bind to the receptors in the resting state
o Partial agonists: can bind to either resting or active state producing an effect with “intermediate efficacy”
Involves a conformational change at the level of the receptor leading to a proper alignment of system or molecules to produce an effect
Induced Fit Theory
REMEMBER
The study of pharmacodynamics entails quantifying drug actions by studying the drug dose-response relationship seen in the DR curve
o Dose response: hyperbolic; log dose curve: sigmoidal
**the steeper the slope of the graph, the narrower the margin of safety.
Uses of a dose-response curve:
Quantitate drug action
Tells us the type of drug by its mode of action, potency, therapeutic dose, efficacy, and relative drug safety
Can be used as a rational basis for drug therapy
What are the two types of dose-response curve?
- Graded or Quantitative Dose-Response Curve (GDRC)
2. Quantal Dose-Response Curve
GDRC
- Relates a given dose of the drug to a quantitatively gradable effect of the drug in a given population
USED TO:
1. Classify drugs into agonist, partail agonist and antagonist
2. differentiate between competitive and non-compe
3. classify drugs according to moa
4. to determine the relative potency of drug analogs
**DRUG EFFICACY
QDRC
- Frequency of occurrence, either inhibition or stimulation, in a given population (not efficacy as in GDRC)
- all-or-none prinicple
USED TO:
1. To determine the median therapeutic dose and toxic dose (LD50) of a drug for patient population
2. To evaluate the drug safety by determining the minimum therapeutic dose and optimal dose before toxic effects (range of doses)
3. to determine drug selectivity
ED50 in GDRC: dose that produces 50% of maximum response
ED50 in QDRC: median effective dose that can produce a response in 50% of the population
Efficacy
o Clinical effectiveness
o Maximum desirable ceiling effect
o Reflected as the plateau – limit of the dose-response relation on the response axis (y-axis)
o Determined mainly by the nature of drug and the receptor and its associated effector system
o Maximum response of a drug
o Response-related
Potency
o Location of the dose response curve along the horizontal or dose axis (x-axis)
o A range of doses over which the drug produces increasing responses
o Depends also on affinity (Kd) of receptors for binding the drug
**the clinical effectiveness of a drug depends not on its potency (EC50) but on its maximal efficacy and its ability to reach the relevant receptors
2 types of potency
Absolute Potency
o refers to the biologic unit of weight or dosage units needed to produce the desired response in terms of a
particular therapeutic end point
o location of the dose response curve along the x-axis
o weight is the basis of comparison
o e.g. morphine vs meperidine = 10mg vs 100mg (same effect, morphine is more potent)
Relative Potency
o Ratio of equi-effective dose of a drug to a given standard (innovator vs new drug)
o Comparison of 2 drug analogs based on their ED50
o Compare a dose of the new drug w/ a reference or standard drug in their ability to produce same effect (relative potency = ED50new/ED50std)
o Used by drug companies
The normal variation observed in a range of doses that may be needed to give the desired response
Biologic variability
o Differences in responses of people even in the same drug
o Affected by sex, age, diet, concurrent drugs taken in, polypharmacy, drug interaction, etc.
Competitive Equilibrium Antagonists
Aka surmountable antagonism
Binds reversibly to the same pharmacologic site as the agonist
Causes the DR curve to shift to the right, meaning higher dose of the drug still produces the same effect
Classical examples:
Acetylcholine vs atropine
Morphine vs naloxone
Competitive Non-equilibrium Antagonists
The degree of inhibition does not depend on the concentration of the unbound antagonist but on the turnover rate of the receptors (rate of new receptors)
E.g. epinephrine/ norepinephrine vs α blocker phenoxybenzamine
Non-competitive Antagonists
It does not compete at binding w/ the receptor, it binds to a different receptor
It affects the activity and has no effect to the receptors since they can bind at other receptor sites
E.g. epinephrine vs verapamil
Chemical antagonists
One drug will bind to another drug and it will affect the chemical structure and activity of that drug
E.g. protamine which will bind to heparin
Functional/Physiologic Antagonists
Two drugs bind to two different receptors producing opposing effects
E.g. in the bronchial smooth muscles: histamine and epinephrine (histamine causes bronchoconstriction and epinephrine causes relaxation)
Drug safety determination is determined by the:
- Therapeutic index (TI)
- Certain Safety Factor (CSF)
- Standard Safety Margin (SSM)
Therapeutic index (TI) o Relative measure of the drug’s toxicity or safety
For humans: TI = TD50/ED50 For animals: TI = LD50/ED50 **higher TI means safer
Certain Safety Factor (CSF)
CSF = LD1/ED99
o Indicates overlapping of the desirable and undesirable effects of the drug
o Overlapping signifies that at a dose that would cause 99% of the population that responds with the desired effect would at the same time cause a certain percentage of population to die
o Non-overlapping curves ensure that the dose would cause 99% of the population to produce the desired response, as well as not cause any deaths or other undesirable effects
o More accurate estimate of the margin of safety of the drug
o LD1 = lethal dose in 1% of population
o ED99 = effective dose in 99% of population
o CSF > 1: safe
o CSF close to 1 or less than 1 is not safe
Standard Safety Margin (SSM)
o Shows the percentage by which the drug dose can be increased before 1% will die of overdose
SSM = [(LD1 - ED99)/ED99] x 100
The study of the influence of heredity on the pharmacokinetic and pharmacodynamic responses to drug
Pharmacogenetics
o Study of qualitative and quantitative variations in drug response due to genetics
Study of genetic traits affecting primarily the metabolism of
environmental and industrial chemicals
Ecogenetics
E.g. individuals with deficiency of α1-antitrypsin are more prone to develop emphysema
REMEMBER
Declining rate in renal and hepatic function
- 20 y/o: renal function starts to decline
- 75 y/o: renal function is down by 50% (there is a 10% decline every decade beginning at 20)
The most important family of CYP 450:
CYP3A4
o Responsible for 50% of metabolism of clinically available drugs
CYP2D6
o Responsible for 30-40% of drug metabolism
o Predominant of drugs metabolized are basic compounds: beta blockers, antidepressants, antipsychotics, opioid analgesics
CYP2C19
o Responsible for 2-10% of drug metabolism
o Preferentially metabolizes acidic drugs: proton-pump inhibitors, antidepressants, antiepileptics, antiplatelet drugs
CYP2D6 Deficient in : - Caucasians (1-7%) - Asian and Afro-Americans (1-3%) Antipsychotic drugs (substrate) not metabolized => dyskinesias
CYP2C19
Deficient in :
- Caucasians (1-3%)
- Asians (30%) Advantage of having CYP2C19 deficiency for patients with peptic ulcers => heal faster when treated with proton-pump inhibitors (Omeprazole)
Variations due to Genetic Factors
Defect: Abnormal Plasma
Drug: Succinylcholine
Clinical consequence:
Variations due to Genetic Factors
Defect: Abnormal Plasma
Drug: Succinylcholine
Clinical consequence: Prolonged apnea
Variations due to Genetic Factors
Defect: Hydroxylation
Drug: Debrisoquine
Clinical consequence:
Variations due to Genetic Factors
Defect: Hydroxylation
Drug: Debrisoquine
Clinical consequence: Orthostatic hypotension
Variations due to Genetic Factors
Defect: Hydroxylation
Drug: Sparteine
Clinical consequence:
Variations due to Genetic Factors
Defect: Hydroxylation
Drug: Sparteine (anti-arrhythmic)
Clinical consequence: Cytotoxic symptoms
Variations due to Genetic Factors
Defect: Hydroxylation
Drug: Mephenytoin (anti-epileptics)
Clinical consequence:
Variations due to Genetic Factors
Defect: Hydroxylation
Drug: Mephenytoin (anti-epileptics)
Clinical consequence: Overdose toxicity (nystagmus, ataxia)
Variations due to Genetic Factors
Defect: Slow acetylation
Drug: Isoniazid (anti-TB) (Phase 2 to Phase 1)
Clinical consequence:
Variations due to Genetic Factors
Defect: Slow acetylation
Drug: Isoniazid (anti-TB) (Phase 2 to Phase 1)
Clinical consequence: Peripheral Neuropathy
Variations due to Genetic Factors
Defect: Slow acetylation
Drug: Hydralazine, INH, Sulfonamides
Clinical consequence:
Variations due to Genetic Factors
Defect: Slow acetylation
Drug: Hydralazine, INH, Sulfonamides
Clinical consequence: S.L.E. like symptoms
Variations due to Genetic Factors
Defect: Oxidation
Drug: Ethanol
Clinical consequence:
Variations due to Genetic Factors
Defect: Oxidation
Drug: Ethanol
Clinical consequence: Facial flushing CVS symptoms
People with red cell enzyme deficiency (G6PD) causing dec. in RBC, dec. in glutathione when given these drugs will suffer drug-induced hemolysis
Primaquine (antimalarial), Sulfonamide, Nitrofurantoin
In people with abnormal calcium release in sarcoplasmic reticulum, inhalation of ______ will induce malignant hyperthermia with muscle rigidity
anesthetics (e.g. halothane/succinylcholine)
People with elevated D-amino levulinic acid synthetase when given these drugs will have poryphyria
barbiturates
Insulin
- Interacts with insulin receptor (tyrosine kinase)
- Beneficial: decrease blood glucose level
- Toxic: hypoglycemia
Anticoagulants (warfarin, dicoumarol, heparin parenteral)
- Acts on the enzyme that reduces vitamin K (vitamin K epoxide reductase or VKORC)
- Beneficial: prevents further clotting (reaction of thrombus)
- Toxic: uncontrolled bleeding or hemorrhage
Methyldopa
- Combines with the α2 receptors in the brain, causing decreased sympathetic outflow
- For gestational hypertension
- Beneficial: anti-hypertensive
- Toxic: hypotension
Digoxin (cardiotonic glycoside)
- B1 myocardial stimulant
- Treatment for congestive heart failure (CHF)
- Beneficial: increased myocardial function (contractility); improve cardiac muscle contraction
Toxic: GIT (diarrhea, nausea, GIT irritation), eyes (visual disturbances, changes in color vision)
Cimetidine (H2 blocker)
- Beneficial: anti-gastric acid secreting drug
- Toxic: causes reversible gynecomastia in men taking high doses
Steroids
- Beneficial: anti-inflammatory
- Toxic: a lot of negative effects like excessive growth of hair in females. Can also cause allergies, arthritis and neurologic disease (e.g. Cushing’s syndrome)
Epinephrine
- Beneficial: β2 receptor => bronchodilation
- Toxic:
1. α1 receptor => vasoconstriction => increase BP; may precipitate cerebrovascular accident (CVA)
2. β1 receptor => affects heart => increase HR => provokes arrhythmias
Propranolol (β-blocker)
Binds with β1 receptors and competes with epinephrine for the receptor sites
- Beneficial: β1 receptor => anti-arrhythmic, anti-hypertensive
- Toxic: β2 receptor => bronchospasm => dangerous for asthmatic patients. **Don’t give propanolol (β-blockers) to hypertensive and asthmatic patients
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Absorption - Interference with GIT absorption
Interference with GIT absorption
Atropine (anti-cholinergic) or opiate – inhibits/slows down gastric emptying time
Metoclopramide – hastens gastric emptying time thus hastening gastric absorption
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Absorption - Formation of insoluble complexes
Formation of insoluble complexes
o Antacids containing Ca, Al, Mg salts, Fe and tetracycline – chelation forming insoluble complex
o Ca + Fe = insoluble complex
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Absorption - Binding to drugs
Binding to drugs
o Cholestyramine (for hypercholesterolemia) – binds to Warfarin (anti coagulant) and Digoxin (cardiac stimulant)
o Salbutamol – β2 adrenergic agonists; bronchodilator and muscle relaxant
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Absorption - Decreased blood flow (vasoconstriction)
Decreased blood flow (vasoconstriction)
o Epinephrine, Norepinephrine, Phenylephrine + Procaine (local anesthetic) => decreased procaine absorption (prolonging duration of action and minimizing toxic effects)
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Absorption - Alterations of pH
Alterations of pH
o Antacids + acidic drugs (barbiturates, mefenamicacid, anticoagulants, sulfonamides) => decreased effect of acidic drug (ionized at alkaline pH this leaving it less absorbed)
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Distribution and Binding
- Displacement from binding sites in the plasma or tissues transiently increases free or unbound drug followed by high elimination
Examples:
Mefenamic acid and Sulfonamides increases antimicrobial activity
ASA (aspirin), an oral anticoagulant => hemorrhage
ASA and Methotrexate => pancytopenia (bone marrow toxicity)
Sulfonamides and bilirubin => kernicterus
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Metabolic Clearance - Induction of drug metabolism enzymes
Induction of drug metabolism enzymes
Rifampicin + Warfarin = decreases warfarin
Phenobarbital in premature neonates with increased bilirubin: stimulates glucuronyltransferase decreasing the rate of kernicterus
Barbiturates + oral anticoagulants: decrease anticoagulant action
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Metabolic Clearance - Inhibition of drug metabolizing enzymes
Inhibition of drug metabolizing enzymes
Chloramphenicol + Phenytoin: nystagmus
Chloramphenicol + Tolbutamide: hypoglycemia
Disulfiram + Warfarin: increases Warfarin effects
Ketoconazole + Terfenadine/Astemizole/Cyclosporine: cardiotoxicity
Erythromycin + Theophylline/Warfarin: increased theophylline level
Disulfiram + Alcohol: prolongs alcohol-like effects
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Renal Function - Alteration of protein binding
Alteration of protein binding
Decrease in protein binding favors metabolism as well as excretion of the drug
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Renal Function - Inhibiting tubular secretion
Inhibiting tubular secretion
Competition with the same carrier
Probenecid + Penicillin/Azidothymidine: increases Penicillin level
GENERAL MECHANISM OF PHARMACOKINETIC INTERACTIONS
Renal Function - Altering urine pH
Altering urine pH
Alkalanizing the urine: increases the secretion of weak acid and vice-versa
rapidly diminishing response to successive doses of a drug, rendering it less effective
Tachyphylaxis
Supersensitivity
- Smaller doses of the drug already produces an effect greater than expected
Hyperreactivity
- Expected therapeutic dose of the drug causes profound effects greater than expected
Drug-drug interaction
Additivity: 1 +1 = 2
- The effect of administration of 2 drugs is simply the sum of their individual effects
E.g. paracetamol (anti-pyretic) + ibuprofen (anti inflammatory, anti-pyretic) = reduce fever more rapidly
Drug-drug interaction
Synergism: 1 + 1 = 3
- The combination of the drugs results in an enhanced effect that is greater than the sum of the effects
E.g. Aminoglycosides (antimicrobials) + penicillin (antimicrobials) = more effective in eliminating infection
Drug-drug interaction
Potentiation: 1 + 0 = 3
- A drug with known effect to a particular condition combined with a drug with no known effect will result in greater effectivity
E.g. Amoxicillin (antimicrobial) + clavulanic acid (β-lactamase inhibitor) = Co-amoxiclav; prolongs the effect of amoxicillin owing to reduced degradation secondary to inhibition of β-lactamase
Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases
This class of receptor molecules mediates the first steps in signaling by insulin, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), atrial natriuretic peptide (ANP), transforming growth factor-β (TGF-β), and many other trophic hormones.
These receptors are polypeptides consisting of an extracellular hormone-binding domain and a cytoplasmic enzyme domain, which may be a protein tyrosine kinase, a serine kinase, or a guanylyl cyclase
The receptor tyrosine kinase signaling pathway begins with binding of ligand, typically a polypeptide hormone or growth factor, to the receptor’s extracellular domain. The resulting change in receptor conformation causes two receptor molecules to bind to one another (dimerize) , which in turn brings together the tyrosine kinase domains, which become enzymatically active, and phosphorylate one another as well as additional downstream signaling proteins
Inhibitors of receptor tyrosine kinases are finding increased use in neoplastic disorders in which excessive growth factor signaling is often involved. Some of these inhibitors are monoclonal antibodies (eg, trastuzumab, cetuximab), which bind to the extracellular domain of a particular receptor and interfere with binding of growth factor. Other inhibitors are membrane-permeant “small molecule” chemicals (eg, gefitinib, erlotinib), which inhibit the receptor’s kinase activity in the cytoplasm.
Ligand-Regulated Transmembrane Enzymes Including Receptor Tyrosine Kinases
A number of regulators of growth and differentiation, including TGF-β, act on another class of transmembrane receptor enzymes that phosphorylate serine and threonine residues.
ANP, an important regulator of blood volume and vascular tone, acts on a transmembrane receptor whose intracellular domain, a guanylyl cyclase, generates cGMP
Cytokine receptors respond to a heterogeneous group of peptide ligands, which include growth hormone, erythropoietin, several kinds of interferon, and other regulators of growth and differentiation.
These receptors use a mechanism closely resembling that of receptor tyrosine kinases, except that in this case, the protein tyrosine kinase activity is not intrinsic to the receptor molecule. Instead, a separate protein tyrosine kinase, from the Janus kinase (JAK) family, binds noncovalently to the receptor
Ligand- and Voltage-Gated Channels
Many of the most useful drugs in clinical medicine act by mimicking or blocking the actions of endogenous ligands that regulate the flow of ions through plasma membrane channels
The natural
ligands are acetylcholine, serotonin, GABA, and glutamate. All of these agents are synaptic transmitters.
