Pharm & Tox M1 Study Guide PDF

**Section 1** Pharmacology -- the study of the effects of chemical substances on the function of living systems Drug -- a chemical substance of known structure, other than a nutrient or essential dietary ingredient, which, when administered to a living organism, produces a biological effect ***Ph...

**Section 1** Pharmacology -- the study of the effects of chemical substances on the function of living systems Drug -- a chemical substance of known structure, other than a nutrient or essential dietary ingredient, which, when administered to a living organism, produces a biological effect ***Pharmacogenetics*** - the study of genetic influences on responses to drugs ***Pharmacogenomics*** - individual genetic information guides the choice of drug therapy ***Pharmacoepidemiology*** - the study of drug effects at the population level ***Pharmacoeconomics -*** a branch of health economics that aims to quantify in economic terms the cost and benefit of drugs used therapeutically **Section 2** Majority of protein drug targets are classified as: - receptors - ion channels - enzymes - carrier molecules (transporters) exceptions like colchicine bind to other proteins. Binds to tubulin and depoarlizes microtubules. Neutrophils develop "drunken walk" as they are not able to migrate to join site receptors are "sensing elements" that bind to chemical messengers - hormones - neurotransmitters - other mediators (growth factors etc.) agonist -- molecule that binds and ACTIVATES receptor - e.g. noradrenaline activates β-adrenoreceptor in heart and increases heart rate antagonist -- molecule that binds and PREVENTS receptor activation - e.g. propranolol is a beta blocker that reduces cardiac contraction ligand -- any agonist or antagonist molecule agonist have different functions - direct physiological effect: opening/closing ion channel - transduction mechanism: enzyme activation/inhibition, ion channel modulation, DNA transcription ligand-gated ion channels -- ion channels with an agonist binding site - opened when occupied by agonist - e.g. benzodiazepine bind to GABA receptor/chloride channel which makes them open more and reduce firing in brain. Causes a calming sensation voltage-gated ion channels -- ion channels that allow ions to flow across cell membrane - open in response to changes in voltage across cell membranes - e.g. lidocaine bind to channel pore of voltage-gated sodium channels which blocks ion permeation and reduce neuron firing. Reduces pain reception competitive inhibitor -- drug molecule that is analogue of the enzyme false substrate -- drug binds to enzyme and an abnormal product is formed and reduces the efficiency of the enzyme - e.g. fluorouracil binds to enzyme that make thymine (uracil is precursor) to prevent DNA synthesis and cell division - e.g. amphetamine competes with noradrenaline for transport back into nerve terminal which cause more noradrenaline to be bind to receptors pro-drug -- drugs that require enzymatic degradation to convert them from an inactive form to an active form transporters -- membrane proteins that transport ions and small molecules (e.g. glucose) across membranes - e.g. tricyclic antidepressants and cocaine inhibit noradrenaline uptake at the presynaptic nerve terminal in brain amphetamine-like drugs: meth, MDMA effects - locomotor stimulation - euphoria and excitement - rise in blood pressure withdrawal -- depletion causes them not to attach to the receptor leading to negative mood - lethargic - depressed and anxious - hungry toxicant -- any harmful substance toxin -- a naturally produced toxicant - interact with same targets as drugs (proteins, lipids, nucleic acids) - cause symptoms related to their primary action or related to a downstream affect toxin on enzymes - inhibition is a common mechanism - inhibition may be reversible or irreversible toxin on receptors and ion channels - may be agonist or antagonist - e.g. nicotine is agonist for acetylcholine receptor - e.g. curare is antagonist for receptors and causes paralysis toxin on lipids - organic solvents and anesthetic gases are lipid soluble - changes membrane integrity and effect membrane proteins - e.g. halogen hydrocarbons form free radicals that attack fatty acids in plasma membrane toxin on DNA - mutagens: toxicants that interact and produce changes in DNA - e.g. mustard gas add alkyl groups to bases - e.g. nitrous acid delete portions of bases Section 3 Four types of receptors - ligand-gated ion channels - G-protein-coupled receptors - Kinase-linked receptors - Nuclear receptors Nicotinic acetylcholine receptor - Ligand-gated ion channel; conducts sodium ions - Found on muscle (regulates contraction) and on neurons (regulates firing) - Made up of 5 subunits anchored to the plasma membrane in a ring - five subunits come together forming a pore - The 2 acetylcholine binding sites lie on the interface of adjacent subunits - When acetylcholine binds it causes a conformational change in the channel. Both sites have to bound and there is cooperativity (one being bound makes the other easier) - This causes the pore to become larger allowing ions to flow into the cell Mechanism of nicotine acetylcholine receptor activation - binding of ACh to both binding sites first causes localized disturbances at the binding sites. - These disturbances are then communicated through small rotations of the subunits, to the structure of the membrane spanning domains. - The M2 helices communicate the rotations to the gate, drawing them away from the central axis, which opens the channel Each subunit contains: - a binding domain at the N-terminus (which is extracellular) - hydrophobic amino acids that interact with the plasma membrane - The protein chain of a single subunit passes through the plasma membrane 4 times - These regions or domains are named M1-M4 and they are hydrophobic M2 - faces the pore of the channel - forms the lining of the channel pore - has the kink that forms the channel gate - amino acid with bulky chains that form the gate - negatively-charged amino acids help Na+ how the structure of a ligan-gated ion channel dictate its function - The N-terminus outside the cell as it allows the neurotransmitters to bind to the receptor - The ligand-gated subunits have M1-M4 that are hydrophobic in order for the subunits to embed itself in the plasma membrane - M2's kink to control the opening of the channel. It has amino acids that have bulky side chains to make up the gate. i.e. closing the channel when it is not activated Other ligand-gated ion channels with similar structure to nicotinic acetylcholine receptor - the GABA~A~ receptor channel; it conducts Cl however - the 5-HT~3~- (serotonin) receptor channel in vomit center of the brain - the glycine receptor channel. Antagonist - **Tubocurarine** - blocks receptor; causes paralysis; competes with acetylcholine at binding site; may enter channel pore - Used as a poison (curare) on arrow tips by Amazonian hunters - **Atracurium** similar to above but is used clinically - **α-bungarotoxin** from cobra venom. Blocks receptor; causes paralysis - **Picrotoxin**; from fishberry; binds within the channel pore to block ion channel flow Agonists/Modulators - **Nicotine**; activates nicotinic acetylcholine receptors - **Benzodiazepines** [(modulator):] binds to GABA receptor and enhances the action of GABA - Causes relaxation - **Muscimol**: from a hallucinogenic mushroom; binds and opens GABA receptor channel GPCRs consist of a single polypeptide chain of up to 1100 amino acids - N-term binding domain - Intracellular C-term - 7 transmembrane domains M1-M7 - A G-protein coupling domain GPCR signalling - When agonist binds to the receptor a conformational change occurs in its cytoplasmic domain - causing it to bind to the αβγ-trimer - This causes the bound GDP in the α-subunit to dissociate and is replaced with GTP - This change causes dissociation of the trimer, releasing the α-subunit from the βγ-subunits - the G-proteins diffuse in the membrane and can activate or inhibit various targets (eg. enzymes and ion channels) - The process is terminated when GTP is converted to GDP through the GTPase activity of the α-subunit. - The resulting α-subunit with GDP then dissociates from the target and reunites with the βγ-complex, completing the cycle GPCR can be inhibitory or stimulatory Inhibitory -- muscarine acetylcholine receptors Stimulatory - β-adrenoceptors - Regulate heart contraction - Epinephrine is agonist; glycogen metabolism in liver Both -- AC enzyme - Ac makes cAMP; a chemical messenger made from ATP - GPCR regulate conc of cAMP in cell - cAMP bind and activates protein kinases and these kinases regulate functions such as: transporters, ion channels and other enzymes other targets for G-proteins phospholipase C - IP~3~ increase free cytosolic Ca^2+^ by releasing Ca^2+^ from intracellular compartments increased free Ca^2+^ initiates many events, including contraction, secretion, enzyme activation - DAG activates protein kinase C, which in turn controls many cellular functions by phosphorylating a variety of proteins. Calcium, potassium and sodiem channels Section 4 Receptor - A protein that is activated by an agonist (found naturally in the body) to produce a physiological response and can interact with antagonists Affinity -- tendency of a drug or any molecule to bind to the receptor Efficacy -- tendency of a drug to activate the receptor High Potency -- high affinity for receptors and occupy a significant proportion Agonists can have BOTH affinity and efficacy Antagonists have ONLY affinity To determine affinity - use of a radiolabelled drug - Various concentrations radiolabeled drug are incubated with a homogenate of tissue that has the receptors of interest - Measure the amount of drug binding to receptor at each drug concentration ***binding curve*** = relationship between drug concentration (X~A~) and the amount of drug bound (*B*) - Affinity (K~A~) is equal to the concentration of drug where you see 50% of the maximal binding OR 50% of binding sites occupied - higher the affinity of the drug for the receptor, the lower the K~A~ - binding capacity (Bmax) -- density of receptors (or binding sites) in the tissue where all the receptors are occupied by drug (saturation) - when in straight line: slope is K~A~ and x-intercept is Bmax - [\$B\\ = \\ \\frac{\\text{Bmax}\\ \\times X\_{A}}{X\_{A} + \\ K\_{A}}\$]{.math.inline} - B= amount of drug bound - X~A~= concentration of drug - K~A~= affinity - So if we make X~A~ = K~A~ then; [\$B\\ = \\ \\frac{\\text{Bmax\\ }}{2}\$]{.math.inline} K^+1^ - rates at which drugs **bind** to the receptor K^-1^ - rate at which drug **dissociate** from the receptor \ [\$\$K\_{A} = \\ \\frac{K\^{- 1}}{K\^{+ 1}}\$\$]{.math.display}\ K^+1^ high, K~A~ low K^-1^ low, K~A~ low To determine effect - Binding DOES NOT measure effect - illustrated by a concentration-response curve - (*E*max) = the maximal response that the drug can produce - EC~50~ or ED~50~ = the concentration or dose (y-axis) needed to produce a 50% maximal response (x-axis) full agonists - produce a maximal response partial agonists - only produce a sub-maximal response competitive antagonists compete with agonist for the binding site - E.g. propranolol is antagonist that competes with isoprenaline - Increasing propranolol causes a shift in the curve which means more isoprenaline is needed for a response. - Isoprenaline is becoming less effective as you increase conc of propranolol. Noncompetitive antagonist block part of the chain of events that lead to the physiological response - E.g. drug that blocks ion channel that is activated by a GPCR Receptor desensitization - Once receptors are activated by agonists there is a gradual decrease in responsiveness even if agonist is still bound to the receptor - In the case of ligand-gated ion channels, the channel closes even if agonist is still bound - Receptors linked to GPCRs are phosphorylated to become inactive Down Regulation - Prolonged exposure to agonists often results in a gradual decrease in the number of receptors expressed on the cell surface - Removed by endocytosis from the cell surface if they no longer want to be activated Toxicology testing - Measured though LD50: Median Lethal Dose = Dose lethal to 50% of animals tested - Acute Toxicity = single exposure to substance - Sub-acute Toxicity = substance delivered though repeated doses ( \< 14 days) - Sub-chronic Toxicity = repeated doses for 90 days - Chronic Toxicity = testing continuous for \> 90 days Categories of Toxicity - Dose: expressed as mg/kg (milligrams of toxin per kilogram of body mass) - Extremely Toxic = LD50 \< 1mg/kg - Highly toxic = \< 50mg/kg - Moderately toxic = \< 500 mg/kg - Slightly toxic = \> 500 mg/kg - Mixed substances may be more or less toxic than predicted from individual components Toxicity increased Synergism Decreased Antagonism Determining Hazard Hazard -- actual risk of poisoning Variables - Toxicity = may not be possible to reduce due to inherent properties - Potential level of human exposure = possible to reduce by reducing risk of exposure Section 5 There are four main ways by which small molecules cross cell membranes: - by diffusing through the lipid - by diffusing through aqueous pores formed by special proteins (\'aquaporins\'): not important as drug distribution is not abnormal in patients with genetic diseases affecting aquaporins - transmembrane carrier protein - by pinocytosis: important for the transport of some macromolecules (e.g. insulin) but not for small molecules (drugs) lipid Mediated Transport -- non-polar substances penetrate cell membranes freely by diffusion Lipid solubility will influence: - Rate of absorption from the gut - Penetration into the brain and other tissues - Extent of renal elimination PKa is an equilibrium constant; the pH where 50% of the drug is ionized (charged) Only the uncharged species (the protonated form for a weak acid; the unprotonated form for a weak base) can diffuse across lipid membranes pH partition -- different drugs become more concentrated in different parts of the body - Weak acids tend to accumulate in compartments relatively high pH (alkaline) - Weak bases accumulate in compartments with low pH (acidic) They are ionized and become trapped in those compartments Urinary acidification: ↑ excretion of weak bases and ↓ excretion of weak acids. Urinary alkalinisation: ↓ excretion of weak bases and ↑ excretion of weak acids. Increasing plasma pH (e.g. by administration of sodium bicarbonate) causes weakly acidic drugs to be extracted from the CNS into the plasma. Reducing plasma pH causes weakly acidic drugs to become concentrated in the CNS, increasing their neurotoxicity. Carrier mediated transport - involve a transmembrane protein which binds one or more molecules or ions - E.g. p-glycoprotein eliminates environmental toxins; responsible for multidrug resistance in cancer cells; found in renal tubules, microvessels in brain and gastrointestinal tract Extensive plasma protein binding slows drug elimination (ie, metabolism and/or excretion through kidneys) Blood brain barrier - Capillaries that are outside the brain are made up of endothelial cells that have small gaps between them This allows some drugs to pass between these gaps - Capillaries in the brain are made up of highly packed endothelial cells Therefore, drugs with low lipid solubility are unable to pass through. Absorption - passage of a drug from site of administration into the plasma Factors affecting gastrointestinal absorption - Strong acids or bases are poorly absorbed because they are fully ionized E.g. curare is poorly absorbed in intestine so hunters can still eat meat - gastrointestinal motility high GM caould cause drugs to pass through before proper absorption - splanchnic blood flow: higher the blood flow near intestine the greater the absorption - particle size and formulation Drug capsules with slow and fast release particles; resistant coating on tablets - physicochemical factors Certain drugs may bind ions that impair absorption Volume of Distribution (Vd) - volume of fluid required to dissolve a dose of drug at the same concentration as detected in the blood plasma Vd= Dose/\[Drug\]plasma For example, if you administered 400 mg of a drug then measured the \[plasma\] to be 0.01 mg/L Vd =400mg/0.01mg/L or 40,000L It takes 40 000L of plasma to dissolve 400 mg of drug to a concentration of 0.01 mg/L Vd is high for drugs distributed into muscle, fat etc like morphine Vd is low for drugs that are retained in blood like insulin Drug metabolism - involves the enzymatic conversion of one chemical entity (drug) to another (metabolite) - Takes place mainly in the **liver** by a group of enzymes called **cytochrome P450** There are two phases to drug metabolism - **Phase I reactions** (by P450) often introduce a relatively reactive group, such as hydroxyl, into the molecule - P450 contains a ferric iron (Fe^3+^) - Combines with a molecule of drug (DH) - Receives an electron from NADPH-P450 reductase - This reduces the iron to Fe^2+^ - Combines with molecular oxygen, a proton and a second electron to form an Fe^2+^OOH·DH complex - Eventually DOH is produced and released from the complex - OH serves as the point of attack for **phase II** system to attach a substituent such as glucuronide by another enzyme - This forms an inactive, readily excretable product - Both phases increase water solubility Variations in P450 Activity - Genetic polymorphisms: individual variations of genes - Environmental influence: enzyme inhibitors and inducers are present in the diet and environment e.g. Brussels sprouts and cigarette smoke induce P450 enzymes Metabolism can alter drug properties - E.g. aspirin hydrolyzed to salicylic acid has an anti-inflammatory effect Drug Elimination - Renal excretion is the most common form of elimination 20% of drug, cross the glomerular filter of the kidney. 80% is transported from the peritubular capillaries to the tubules by active transport - Lipid-soluble drugs are passively reabsorbed by diffusion across the tubule back to the blood - Because of pH partition, weak acids are more rapidly excreted in alkaline urine, and vice versa. - Urine pH affects drug response and plasma concentration Pharmacokinetic Plots - plot of the plasma (blood) concentration of a drug over time - Half-life is the time where 50% of drug is eliminated from body - Depends on drug, not the dose Toxicokinetics - Body is first exposed to poison - Poison undergoes movement throughout the body Includes absorption, distribution and elimination Metabolism (detoxification) - Can also refer to drugs because many clinically important drugs are moderately toxic - Some well-known poisons are therapeutic at low doses e.g. Botulinum toxin (cosmetic; BOTOX) - Lipophilic Toxicants (pesticides) are slowly excreted by the body; Highly lipid soluble compounds (DDT) can accumulate in fat - Some toxicants have a high affinity for certain tissues Liver, kidney and bone hold heavy metals - Kidney is major route of excretion for most toxicants Section 6 Autonomic Nervous System - conveys all of the outputs from the central nervous system (CNS) to the rest of the body except for skeletal muscle contraction - involved in involuntary control - contraction and relaxation of smooth muscle - all exocrine (secretions via duct) and certain endocrine (ductless) secretions - the heartbeat - energy metabolism, particularly in liver and skeletal muscle. The autonomic nervous system comprises three divisions: - sympathetic Sympathetic ganglia are found as paravertebral chains and midline ganglia Sympathetic activity increases in stress - parasympathetic Parasympathetic ganglia usually lie close to or within the target organ Parasympathetic activity predominates during satiation and repose (digest and rest) - enteric Sympathetic and parasympathetic have a basic (two-neuron) pattern How information is relayed - An impulse from the CNS travels down a **preganglionic neuron** causing release of a chemical that can bind to a receptor on the cell body of the **postganglionic neurons** - This excites the **postganglionic neurons** and will release chemicals that bind to receptors on the target organ Chemicals in ANS The two main chemicals are: - Acetylcholine - Noradrenaline Some general rules - All neurons leaving the CNS release acetylcholine, which act on **Nicotinic Ach receptors** - In **parasympathetic system** all postganglionic neurons release acetylcholine, which acts on muscarinic acetylcholine receptors - In **sympathetic system**, all postganglionic neurons release noradrenaline, which may act on either α- or β-adrenoceptors; except in the sweat gland Nicotinic receptors fall into 3 main classes. They are ligand-gated ion channels - Muscle receptors are confined to the skeletal neuromuscular junction - Ganglionic receptors are responsible for transmission at sympathetic and parasympathetic system - CNS-type receptors are widespread in the brain Parasympathetic - Acetylcholine leaves preganglionic neuron - Binds to nicotinic acetylcholine receptor - Depolarizes and possible action potential in postganglionic neuron - Acetylcholine released and binds to muscarinic acetylcholine receptor Sympathetic - Acetylcholine leaves preganglionic neuron - Binds to nicotinic acetylcholine receptor - Depolarizes and possible action potential in postganglionic neuron - Noradrenaline released and binds to adrenoreceptor Agonist that affect ganglionic nicotine receptors - Nicotine and DMPP will activate nicotinic AChR on the of the ganglion neuron, exciting the neuron - stimulate almost all transmission in the autonomic nervous system - effects are: tachycardia and increase of blood pressure variable effects on gastrointestinal motility and secretions - This will affect a variety of downstream tissues and organs and so have little therapeutic use Antagonist of ganglionic nicotine receptors - hexamethonium, trimetaphan and tubocurarine - Block all autonomic ganglia. - Effects are: hypotension and loss of cardiovascular reflexes inhibition of secretions - Clinically obsolete, except for occasional use of trimetaphan to produce controlled hypotension in anaesthesia. Muscarine Ach Receptors are GPCRs. There are two main types: - M2-receptors (\'cardiac\') cause mainly *inhibitory* effects Found on the heart Cause decrease in cardiac rate and force of contraction (mainly of atria) - M3-receptors (\'glandular/smooth muscle\') cause mainly *stimulatory* effects Found on various glands and smooth muscle Cause secretion and contraction of visceral smooth muscle M2 mAChRs inhibit the heart in two ways - G-protein can activate a K^+^ channel directly causing hyperpolarization This inhibits muscle contraction of the heart - inhibit Ca^2+^ channels These channels are normally opened by cAMP-dependent protein kinases reduces Ca2+ channel opening by inhibiting adenylate cyclase This decreases cAMP concentration Therefore, decreases Ca2+ conductance M3 mAChRs stimulates glands and smooth muscle - response to acetylcholine - found on exocrine glands, smooth muscle and blood vessels - stimulates by increasing conc of IP~3~ - The main role of IP~3~ is to release Ca^2+^ from intracellular stores causing depolarization M3 mAChRs cause [smooth muscle contraction and gland secretion ] - Acetylcholine binds to the M3 mAChR - Stimulates G-protein to activate phospholipase C - Phospholipase C produces IP~3~ - IP~3~ activates a Ca^2+^ channel (in the ER or SR) - This increases the concentration of intracellular Ca^2+^ - Ca^2+^ interacts with the contractile machinery leading to contraction and/or secretion from glands mAChRs agonists - **Acetylcholine**: The natural ligand activates all receptors - **Muscarine**: activates all receptors; from poisonous mushrooms; can reproduce the actions of acetylcholine (produces many different affects) - **Pilocarpine**: used as eye drops for the treatment of glaucoma (high intraocular pressure) - Contracts the constrictor pupillae muscle (smooth muscle) in the eye reducing intraocular pressure - **Bethanechol**: stimulates smooth muscle of the bladder and GI track. Helps bladder emptying. mAChRs antagonists - **Actropine**: a poison from the deadly nightshade plant. Blocks all mAChRs Inhibits secretions (M3 inhibition) Relaxes smooth muscle of the bronchi, bile ducts and urinary tract (M3 inhibition) Causes tachycardia (M2 inhibition) - **Ipratropium:** M3 antagonist used to treat asthma. Relaxes smooth muscle of the bronchi Drugs and toxins that affect acetylcholine concentration at the presynaptic nerve terminal Ach is released via exocytosis - **Botulinum toxin**: one of the toxins is a peptidase that cleaves proteins involved in exocytosis AChE regulates free ACh by converting it back into choline and acetate - **Ecothiopate**: antiAChE used to treat glaucoma; as eye drops Section 7 **Agents causing contraction may:** - release intracellular Ca^2+^ by the ER or SER by IP~3~ - allow Ca^2+^ entry through ligand-gated calcium channels. The ligand is actually ATP which is released from autonomic nerves - depolarize the membrane and thus allow Ca^2+^ entry through voltage-gated calcium channels How Ca^2+^ cause smooth muscle contraction - Ca^2+^ bind to calmodulin - Calmodulin activates myosin-light chain kinase - MLCK phosphorylates myosin so it detaches from actin causing contraction How does muscle contration get reversed - cAMP activates a PK that inhibits MLCK---leading to relaxation - cGMP activates a PK that further activates myosin phosphatase (MP) - MP dephosphorylates myosin\-\--leading to relaxation Agents causing relaxation may: - Inhibit receptors that activate PLC that produces IP~3~ - Inhibit Ca^2+^ entry through voltage-gated calcium channels either directly or indirectly by hyperpolarizing the membrane - increase intracellular cAMP or cGMP concentration One way to cause vasodilatation is to block V-gated Ca^2+^ channels - A drug called **nifedipine** is an antagonist for voltage- gated Ca^2+^ channels The drug blocks Ca^2+^ flow into the cell and reduces the probability of contraction The drug is used to treat hypertension and angina Another way of vasodilation is using α~1~-adrenoceptors - Drugs such as **Prazosin**, **Terazosin** and **Doxazosin** block α~1~-adrenoceptors on vascular smooth muscle α~1~-adrenoceptors are activated by noradrenaline When activated, activates phospholipase C which release IP3 Leading to calcium channel activation and release of Ca Are therefore used to treat hypertension Potassium ion channels can also be used for vasodilation - **Cromakalim** opens membrane potassium channels causing hyperpolarization This makes the membrane potential less positive This switches off voltage-gated calcium channels Vascular tone is also regulated by the endothelial cells - NO secreted by the endothelial cell activates **guanylate cyclase** which produces cGMP cGMP activates myosin phosphatase that cause relaxation - PGI~2~ produced by the endothelial cell binds to a IP receptor which activates **adenylate cyclase** producing cAMP cAMP inhibits myosin-light-chain kinases that cause contraction. ACE are on plasma membrane - ACE converts a circulating peptide angiotensin I into angiotensin II angiotensin II binds to a AT1, a GPCR, on smooth muscle AT1 activates PLC producing IP~3~ IP~3~ activates Ca^2+^ channels in the ER increasing intracellular Ca^2+^ causing muscle contraction - Captopril binds to the active site of ACE in place of angiotensin I angiotensin I cannot be converted into angiotensin II Used to treat hypertension, cardiac failure and has other clinical uses - **Losartan** is an antagonist for the AT1 receptor Blocks the receptor so you do not get IP3, do not get calcium and causes muscle relaxation Categories of vasodilator drugs - ACE inhibors -- captopril - Nitrates -- glyceryl trinitrate - Calcium channel antagonists - nifedipine - Sympathetic transmission blockers - α1-adrenoceptor antagonists - Potassium channel activators -- cromokalin - AT1 antagonists -- losartan - β2-adrenoceptor agonists -- adenosine Beta2-adrenoreceptor & IP receptor lead to vasodilation when activated Apla1-adrenorecptor & AT1 lead to vasodilation when inhibited Potassium ion channel lead to vasodilation when activated Calcium ion channel lead to vasodilation when inhibited cGMP is better for vasodilation than Ca2+ ACE and myosin light chain kinase are enzymes that lead to vasodilation when inhibited Toxicants on vascular system - Industrial nitrates can also activate guanylate cyclase---increasing cGMP causing vasodilatation Side effects such as headaches and dizziness Tolerance may develop Stopping exposure suddenly may trigger vasoconstriction Toxicants on blood cells - Bone marrow -- decrease in red or white cells or stem cells can't produce new cells - Lindane and benzene can cause this Toxicant on hemoglobin - **Lead** inhibits the enzyme ALA-D that is important for heme production - **Carbon monoxide** binds to iron in heme - **Nitrites, nitrates and aromatic amines o**xidize heme molecules converting iron from the ferrous to ferric state Ferric iron cannot bind oxygen