Pharmacology Flashcards
1
Q
Pharmacokinetics
A
What the body does to the drug
2
Q
Pharmacodynamics
A
Mechanism of drug action - what the drug does to the body
3
Q
Factors Affecting Drug Action
A
- Physiochemical Properties
- Acid-Base Properties (dependent on ionization)
- Water Solubility (dependent on ionization and H bonding) - Stereochemistry: Stereoisomers are molecules that differ in their 3D arrangement of atoms in space
- Enantiomers: nonsuperimposable mirror images, cannot be separated by standard chromatography
- Diastereomers: nonsuperimposable non mirror images, exhibit different physiochemical properties
4
Q
Water Solubility
A
- Important for all ADME
- At the molecular level, it is the true mixing of two materials
- More interactions with water leads to greater solubility
- BUT when ionic groups or ion-dipoles are close in proximity for possible interactions in the same molecules, water may not be able to interact –> molecules less soluble than predicted
- Two major factors
1. H Bonding - contributes to hydrophilicity of molecules
2. Ion-Dipole Interactions - develops between cation/anion and a formal dipole; ions must be dissociable to be soluble
5
Q
Medicinal Chemistry
A
- Concerned with how the physiochemical properties of a drug affect its biological activity
- Invention, discovery, design, identification, and preparation of biologically active compounds, study of their metabolism, interpretation of their mode of action at the molecular level and understanding the relationship between the chemical structure and pharmacological activity
6
Q
Receptors: Lock and Key
A
- Receptor: A molecular target; usually a protein expressed on the cell surface “receptor” or a soluble intracellular protein “enzyme”
- Ligand: A chemical substance that binds to a receptor
7
Q
Affinity
A
- Drugs must be attracted to a receptor, to bind and exert a biological effect
- Drugs that are attracted to a receptor are said to have affinity for that receptor
- Various chemical bonds allow for the interaction of drug and receptor (van der Waals, ionic, H, covalent)
- Drugs with affinity may be either agonists or antagonists
- Agonists bind and exert positive biological effect
- Antagonists bind and do not produce biological effect
8
Q
Efficacy
A
- Ability to produce a response
- Agonists have both affinity and efficacy, while antagonists do not have efficacy, only affinity
9
Q
Drug-Receptor Interactions
A
-Most drugs bind transiently and reversibly
-Combination of a variety of bonds make binding energetically favourable
-Reversible bonds
+Ionic - two ions of opposite charge are attracted to each other; strong enough to support initial interaction (5 kcal/mol)
+H bonds - bond not strong enough to support a drug-receptor interaction alone but can confer stability (2-5 kcal/mol)
+van der Waals - occur between non-polar organic materials and contribute to stabilizing drug-receptor complex (0.5-1 kcal/mol)
-Irreversible bonds: covalent - two molecules share a pair of electrons (50-150 kcal/mol)
10
Q
Theories of Drug-Receptor Interaction
A
- Occupancy Theory: Response proportional to number of receptors bound (mo’ receptors, mo’ response)
- Rate Theory: Response proportional to number of D-R per unit time
- Induced-Fit Theory: As drug approaches, receptor changes conformation to accommodate drug and induce desired effect
11
Q
Dose-Response Relationship/Curve
A
-Potency: Concentration of drug required to produce desired effect, usually measured by EC50 (concentration of drug that produces 50% effect); higher EC50, lower potency
-Effect of Antagonists: Potency of an agonist is decreased in the presence of an antagonist
+Agonist + Competitive Antagonist –> still reaches maximal efficacy, but you need more drug to get there (decrease in potency/increase in EC50)
+Agonist + Non-Competitive Antagonist –> EC50 increases and efficacy is reduced significantly
12
Q
Signal Transduction
A
- Process by which an extracellular signal exerts a change in the activity of the target cell
- A sequence of biochemical reactions are carried out by enzymes, proteins and ions
13
Q
Molecular Targets: G-Protein Coupled Receptors
A
- 7 transmembrane-spanning domains (heptahelical)
- Signal is transduced by heterotrimeric G-proteins
- Cell has ability to turn off signal once alpha interacts with effector by GTP hydrolysis back to GDP + Pi
14
Q
Alpha G Subunits
A
- Gs: stimulates adenylyl cyclase and calcium channels
- Gi: inhibits adanylyl cyclase and activates potassium channels
- Gq: stimulates phospholipase C activity
- G12: regulates Na+/H+ ion exchanger
15
Q
Molecular Targets: Enzymes
A
-Inhibition of an enzyme is a challenging process due to the likelihood of redundancy in biological systems
-Enzymes are slightly easier to crystallize compared to intrinsic membrane proteins, therefore designing drugs is theoretically easier
-Soluble enzymes vs drug receptors (antagonists) in terms of efficacy
+Receptors present on cell surface are the first step in a multi-step process (amplification) –> targeting receptor is not good at turning off the whole cascade because of further amplification versus enzyme which can shut down the cascade at multiple steps
16
Q
Molecular Targets: Ion Channels
A
Both ligand-gated and voltage-gated ion channels have an important role in the nervous system
17
Q
Molecular Targets: Nuclear Receptors
A
Drugs binds to receptor and forms a dimer –> ligand complexes and goes to nucleus –> binds directly to DNA and changes protein synthesis
18
Q
Somatic Nervous System
A
- Signals to skeletal muscle
- Voluntary movement
- No ganglia present
19
Q
Autonomic Nervous System
A
-Signals to organs, smooth muscle, blood vessels, etc
-Involuntary movement
-Has ganglia (sites where preganglionic fibres synapse with postganglionic neurons)
1. Parasympathetic - Rest and digest, craniosacral, trophotropic
+Ganglia usually lie close to target organ
+Preganglionic fibres often will synapse in a one-to-one ration with postganglionic neurons
2. Sympathetic - Fight or flight, thoracolumbar, ergotropic
+Broader distribution through the body
+More general and more persistent stimulation
+Preganglionic cells synapse with many postganglionic neurons
+EXCEPTION: sweat glands are innervated only sympathetically
20
Q
Neurotransmitters of the ANS
A
-Both systems use ACh at the preganglionic nerve, binding to nAChR on the postganglionic nerve
-Differ at the NT which is released from the postganglionic nerve
+Sympathetic releases noradrenaline (NA)
+Parasympathetic releases ACh, which binds to mAChR at target
-EXCEPTIONS: The sympathetic has some nerves which the postganglionic nerve releases ACh (sweat glands and some blood vessels to skeletal muscle)
-Skeletal muscle is important area for nAChRs, distinct from the preganglionic ones
21
Q
Endocrine Effects of Sympathetic Nervous System
A
Adrenal medulla is associated with the kidneys and the preganglionic sympathetic fibre is received here and then produces adrenaline (hormone), which goes directly to the blood stream
22
Q
Acetylcholine Receptors
A
Nicotinic
- Ionotropic
- Ganglionic junctions, adrenal medulla, neuromuscular junction (skeletal muscle)
- Two subtypes: muscular and neuronal
- Subtypes based on differing subunit composition
- Effects blocked by tubocurarine
Muscarinic
-Metabotropic
-Postganglionic parasympathetic synapses, certain postganglionic sympathetic synapses (ex. sweat glands, skeletal muscle vasculature)
-5 Subtypes
+M1 expressed predominantly in neuronal tissue; coupled to Gaq (stimulates PLCbeta ultimately increases calcium)
+M2 expressed predominantly in the heart; coupled to Gai (inhibited AC and decreases cAMP)
23
Q
Muscarinic Receptor Effects
A
- Eye
- Cardiovascular
- Respiratory
- GI Tract
- Genitourinary Tract
24
Q
Pharmacology of Cholinomimetics
A
Direct Acting Agents (agonists acting at muscarinic receptors) -Natural alkaloids \+Muscarine \+Pilocarpine -Synthetic analogues \+Carbachol \+Methacholine \+Bethanechol
Indirect Acting Agents
-Acetylcholinesterase inhibitors: More selective than cholinergic agonists because they target only active synapses
+Reversible
1. Physotigmime
2. Neostigmine, Pyridostigmine, Amenonium
3. Endorphonium
+Irreversible
25
Cholinomimetics Toxicity
-Toxic effects are exaggerated forms of their pharmacological actions
+Vomiting, diarrhea, salivation, sweating, bronchial constriction, meiosis
-Commonly caused by pesticides - there are 100+ organophosphate inhibitors used in the US
TREATMENT
- Maintenance of vital signs
- Decontamination to prevent further absorption
- Parenteral ATROPINE
26
Antimuscarinics: Natural Compounds
ATROPINE (hyoscyamine)
-Found in Atropa belladona (deadly nightshade) and Datura stramonium (jimsonweed)
SCOPOLAMINE
-Found in Hyoscyamus niger (henbane) and Scopolia carniolica
27
Antimuscarinics: Chemical Properties
- Synthetic tertiary ammonium analogs can be synthesized by esterfying atropine bases with acid
- Tertiary antimuscarinics can be converted to the quaternary analog by the addition of a methyl group
- Tertiary antimuscarinics are well absorbed and readily enter the CNS therefore they are usually used topically for opthamologic uses
- Quaternary antagonists tend to be more potent than tertiary antagonists and do not enter the CNS readily therefore they are used more often for systemic indication
- Antihistamines, antipsychotics, and antidepressants have similar structures and similar antimuscarinic effects
28
Anticholinergic Effects
Decreased GI motility --> Constipation
```
Decreased secretions (eg. saliva, sweat, bronchial, GI)
Dysregulation of body temperature, dry mouth, etc.
```
Mydriasis and cycloplegia --> Impaired near vision, photophobia and may result in glaucoma
Tachycardia --> May result in heart failure
29
Antimuscarinics: CNS Effects and Indications
-At normal doses ATROPINE has a little effect in the CNS, but at toxic doses it stimulates the CNS which causes restlessness and disorientation
-At normal doses, SCOPOLAMINE causes CNS depression resulting in drowsiness, fatigue and amnesia, and also causes hallucinations
-SCOPOLAMINE crosses the BBB more readily than atropine resulting in greater effects
-Extrapyramidal effects caused by some antipsychotics and tremor associated with Parkinson's; can be treated with antimuscarinics
-Prevention of vestibular disturbances and motion sickness
+SCOPOLAMINE very effective
30
Antimuscarinics: Pre-Operative Medications Effects and Indications
- Rationale: Produce sedation and decrease secretions
- SCOPOLAMINE administered with morphine reliably produce pre-anaesthetic sedation
- SCOPOLAMINE administered with morphine reliably produce pre-anaesthetic sedation
- Reduce vagal-induced reflex bradycardia that may occur during surgery
- Eg. ATROPINE, SCOPOLAMINE, and GLYCOPYRROLATE
31
Antimuscarinics: Ocular Effects and Indications
-Mydriasis (pupillary dilation)/cyclopegia (paralysis of accommodation)
+Eg. ATROPINE, CYCLOPENTOLATE, HOMATROPINE
-Antimuscarinics may dangerously increase intraocular pressure in patients with narrow-angle glaucoma
32
Antimuscarinics: Respiratory Effects and Indications
-ATROPINE causes some bronchdilation and reduction in secretion
-These effects are more pronounced in asthmatics, and less pronounced in beta-receptor agonists
-IPRATROPIUM is the agent mostly used
+Given as an aerosol therefore less likely to demonstrate systemic effects
-Patients with COPD (chronic obstruction pulmonary disease) respond very well to ipratropium (more effective than beta-receptor agonists)
33
Muscarinic Receptor Effects: Eye
- Constriction of the pupillary sphincter muscle
- Contraction of the ciliary muscle (paralysis of accommodation or loss of far vision)
- Both of these effects facilitate outflow of aqueous humor
34
Muscarinic Receptor Effects: Cardiovascular
- Vasodilation (indirect effect that occurs through increased NO)
- Decreased chronotropy and ionotropy
35
Muscarinic Receptor Effects: Respiratory
- Smooth muscle constricts upon treatment with muscarinic agonists
- Tracheobronchial gland secretion is stimulated
36
Muscarinic Receptor Effects: GI Tract
- Increase in secretion and motor activity of the gut
- Stimulation of salivary and gastric gland secretion, smaller stimulation of pancreatic and small intestine glandular secretion
- Relaxation of sphincters
37
Muscarinic Receptor Effects: Genitourinary Tract
- Stimulation of the detrusor muscle, relaxation of bladder sphincter
- No effects on uterine smooth muscle
38
Muscarine
MUSCARINIC AGONISTS: Natural Alkaloids
-Muscarine (Amanita muscaria)
+Not used therapeutically
+Poisoning can be treated with antagonists such as atropine
39
Pilocarpine
```
MUSCARINIC AGONISTS: Natural Alkaloids
-PILOCARPINE
+From South American Pilocarpus shrub
+Has some nicotinic activity
+Increases in salivation and sweating
+Predominantly used in glaucoma to produce meiosis and to potentiate drainage of fluid to decrease intraocular pressure
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40
Carbachol
MUSCARINIC AGONISTS: Synthetic Analogues
-CARBACHOL
+Muscarinic-selective at therapeutic doses (very narrow TI, so at slightly higher concentrations is can bind to nAChR)
+Selective urinary and GI tract stimulation
+Similar effects on the eye as pilocarpine
41
Methacholine
MUSCARINIC AGONISTS: Synthetic Analogues
-METHACHOLINE
+Much more muscarinic-selective than carbachol
+Used primarily to diagnose bronchial hyper-reactivity in asthma (very short duration of action, making it ideal for testing for hyperactivity)
42
Bethanechol
MUSCARINIC AGONISTS: Synthetic Analogues
-BETHANECHOL
+Smooth-muscle "selective" effects
+Increases GI and urinary motility after surgery
43
Physotigmime
```
CHOLINESTERASE INHIBITORS: REVERSIBLE
-PHYSOTIGMIME
+Calabar bean alkaloid
+Will enter the CNS at high levels
+Mostly used in the eye to reduce intraocular pressure
```
44
Neostigmine, Pyridostigmine, Ambenonium
CHOLINESTERASE INHIBITORS: REVERSIBLE
-NEOSTIGMINE, PYRIDOSTIGMINE, AMBENONIUM
+Quaternary ammonium cholinsterase inhibitors, do not cross the BBB
+Taken orally for myasthenia gravis (autoimmune condition whereby antibodies attack nAChR at neuromuscular junction)
45
Endorphonium
```
CHOLINESTERASE INHIBITORS: REVERSIBLE
-EDROPHONIUM
+Used IV for myasthenia gravis
+Very brief duration of action (3-4 minutes)
-DONEPEZIL, RIVASTIGMINE, GALANTAMINE
+Used to treat Alzheimer's
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46
Irreversible Cholinesterase Inhibitors
- Not generally used therapeutically
- Most are organophosphate derivatives that undergo a reversible followed by an irreversible phase (aging phase where enzyme becomes phosphorylated and covalently modified)
- Can be reversed by PRALIDOXIME
1. ECHOTHIOPHATE
+One of the few clinically used organophosphates used for open-angle glaucoma
2. Insecticides are designed to be relatively more toxic to insects vs. mammals and many need to be converted to phosphates prior to activation
47
Clinical Uses of Muscarinic Receptor Effects
1. Ocular
2. GI and Urinary Tract
3. Respiratory System
4. Myasthenia Gravis
5. Alzheimer's
48
Clinical Uses of Muscarinic Receptor Effects: Ocular
- Glaucoma
- Primary respond well to muscarinic agonists
- Muscarinic agonists or cholinesterases inhibitors contract the ciliary body to allow enhanced aqueous humour outflow
49
Clinical Uses of Muscarinic Receptor Effects: GI and Urinary Tract
- GI smooth muscle stimulant
| - Urinary bladder smooth muscle stimulant
50
Clinical Uses of Muscarinic Receptor Effects: Respiratory System
- Testing for bronchial hyperreactivity and asthma
| - METHACHOLINE
51
Clinical Uses of Muscarinic Receptor Effects: Myasthenia Gravis
- Caused by a reduction in the number of nicotinic receptors at the motor end plate (likely due to binding by anti-receptor antibodies)
- Anticholinesterase drugs provide partial improvement by increasing ACh at end plate
- PYRIDOSTIGMINE + NEOSTIGMINE
52
Clinical Uses of Muscarinic Receptor Effects: Alzheimer's Disease
- Usually indirect cholinomimetics are used to treat mild to moderate Alzheimer's
- TACRINE, DONEPEZIL, GALANTAMINE
53
Antimuscarinics: Genitourinary Tract Effects and Indications
- Relaxation of smooth muscle and decreased motility, used to treat incontinence and enuresis
- Overactive bladder system is due to overactivity of muscarinics in the bladder --> antimuscarinics can help to decrease the tone in the muscles
- No effect on the uterus
- DRUGS: OXYBUTININ and TOLTERODINE
54
Antimuscarinics: GI Tract Effects and Indications
-Decreased salivation
-Decreased GI secretion (enteric nervous system is not cholinergic, and therefore not susceptible to complete atropine blockage)
+Makes it attractive for pre-op
-Relaxation of smooth muscle to treat GI spasm
+DRUG: SCOPOLAMINE
-Antimuscarinics may be combined with LOPERAMIDE in anti-diarrheal preps because both decrease GI activity
55
Cholinesterase Regenerator Compounds
-Agents that can regenerate active cholinesterase from the organophosphate-cholinesterase complex, if caught before the aging phase
-DRUGS: oximes (=NOH) --> PRALIDOXIME (PAM) and DIACETYLMONOXIME
+These drugs are extremely nucleophilic and outcompete the organophosphates for cholinesterase --> Used for organophosphate poisoning
56
Neuromuscular Junction: Overview
- Junction between the axon terminal of a lower motor neuron and the motor end plate of the muscle fibre plasma membrane
- NT is ACh and binds to post-synaptin NICOTINIC receptors in the motor end plate
- 2 ACh molecules bind to 2 alpha subunits on the nAChR
- When the membrane potential reaches 15 mV, an action potential is generated in the sarcolemma of the muscle fibre
57
NMJ Blocking Groups
1. Non-Depolarizing
- Competitive antagonists at nAChR, preventing depolarization
- Usually ionized
- DRUG: TUBOCURARINE (curare)
2. Depolarizing
- Activate nAChR constitutively
- Not broken down by AChE, but rather by plasma cholinesterases
- Binds and activates the receptors and keeps it open (Phase I Depolarizing) so that there is initial contraction followed by flaccid paralysis --> Un-excitable area develops around the motor end plate (Phase II Desensitizing)
- DRUG: SUCCINYLCHOLINE
58
Clinical Effects of NMJ Drugs
- Muscle relaxation for surgery without deep anesthesia
| - Larger muscles are more resistant than smaller muscles --> diaphragm is the last muscle to be affected
59
Adverse Effects of Depolarizing NMJ Drugs
1. Hyperkalemia: Increased potassium in the circulation, which may lead to cause cardiac arrests
2. Increase in intraocular pressure
3. Increase in intragastric pressure, which may cause vomiting
4. Muscle pain
5. Malignant hyperthermia
60
Reversal of Non-Depolarizing Effects
Cholinesterase inhibitors will increase levels of ACh to such an extent that they will out-compete the non-depolarizing nicotinic antagonists
61
Toxins that Block the NMJ
1. Botulinum Toxin
2. Bungarotoxins
3. Black Widow Spider Venom (Latrotoxin)
4. Conium Alkaloids
5. Curare
62
Botulinum Toxin
TOXIN BLOCKING NMJ
- Produced by bacterium: Clostridium botulinum
- One of the most toxic substances known
- Causes muscle weakness, respiratory paralysis and death
- Toxin prevents pre-junctional release of ACh, which prevents muscle contraction
- Used cosmetically to induce local muscle relaxation in specific locations
63
Bungarotoxin
TOXIN BLOCKING NMJ
- Produced by the Bungarus Multicinctus krait snake
- ALPHA targets the nAChR and produces a neuromuscular blockade
- BETA induces a rapid release of ACh thereby depleting stores and also inhibits the high affinity choline transporter in the presynaptic membrane
64
Black Widow Spider Venom
TOXIN BLOCKING NMJ
- One component of the venom causes release of ACh from the motor neurons in the NMJ, resulting in both ACh depletion and a depolarizing blockade (mostly in the back, abdomen, and thigh muscles)
- Treat symptomatically with pain medications and muscle relaxants
65
Conium Alkaloids
TOXINS BLOCKING NMJ
- From poison hemlock (Conium maculatum)
- Used to execute Socrates
- Conium resembles nicotine and stimulates the nAChR
- Symptoms of toxicity mimic those of nicotine toxicity --> CNS stimulation including headaches, ataxia, sweating, salivation, and tachycardia
- Prolonged toxicity results in depressive stage characterized by bradycardia, respiratory failure and death
66
Tubocurarine
TOXINS BLOCKING NMJ
- Curare is an extract that is obtained from indigenous plants in South America (Chondodendron and Strychnos)
- Active component of curare in d-tubocurarine
- Added to the tips of darts for hunting and warfare
- First used as muscle relaxant in 1940s
- Non-depolarizing relaxant
- Has some activity at nAChR in autonomic ganglia (causing respiratory depression) and also causes release of histamine from mast cells (causing fall in blood pressure)
- Often replaced by PANCURONIUM
67
Catecholamines
- Adrenergic receptor agonists
- Noradrenaline, adrenaline, dopamine
- Drugs that mimic them are known as SYMPATHOMIMETIC DRUGS
68
Adrenergic Receptors
-GPCRs
-Desensitization occurs via down-regulation of receptors - some f the signaling factors go back to the receptor to act on it and ultimately down regulate the receptor, usually via phosphorylation
-Agonist therapeutic effects will decrease over time due to this
-Types and Subtypes
+ALPHA Adrenergic Receptors: ALPHA 1 and ALPHA 2
+BETA Adrenergic Receptors: BETA 1, BETA 2, and BETA 3
69
Alpha 1 Adrenergic Receptor
- Postsynaptic
- Causes smooth muscle contraction
- Expressed in most vascular smooth muscle (arterial and venous) - activation results in contraction and increased peripheral resistance and decreased venous capacitance, leading to increased BP
- Vessels of the skin and nasal mucosa predominantly express alpha 1 receptors (nasal decongestants)
- Contract pupillary radial (dilator) muscles
70
Alpha 2 Adrenergic Receptor
- Presynaptic
- Inhibit neurotransmitter release
- In the CNS, they are expressed postsynaptically and can cause decrease in BP
71
Beta 1 Adrenergic Receptor
- Predominantly expressed in the heart
- Positive chronotropy and ionotropy
- Juxtaglomerular cells increase renin secretion
72
Beta 2 Adrenergic Receptor
- Smooth muscle relaxation (respiratory, uterine and vascular)
- Liver - stimulates glycogenolysis
- Pancreas - increases insulin and glucagon production
- Eye - regulates aqueous humour production
73
Beta 3 Adrenergic Receptor
- Expressed in adipose tissue and in the bladder
| - Recently being used for overactive bladder
74
Adrenergic Agonists: Cardiovascular Effects
```
HEART
-Positive ionotropy
-Positive chronotropy - increased automaticity and shortened refactory period
VASCULAR SMOOTH MUSCLE
-Alpha 1 - vasoconstriction
-Beta 2 - vasodilation
-Alpha 2 - vasodilation
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75
Baroreflex
-Any effect a sympathomimetic drug has on BP can induce a compensatory baroreflex aimed at restoring homeostasis
-Baroreceptors are located all over and they sense the change in BP and by way of a very simple reflex, sends signal straight to the MEDULLA, which immediately sends a signal back to the heart to invoke change
+Increase in BP --> PARASYMPATHETIC signal --> mAChR decreases BP and HR
+Decrease in BP --> SYMPATHETIC signal --> adrenergic receptors increase HR and BP
76
Cardiovascular Effects of Noradrenaline
- Causes significant vasoconstriction due to ALPHA 1 AGONISM and because it has low affinity for beta 2
- Reflex bradycardia overrides the agonism at beta 1
77
Cardiovascular Effects of Adrenaline
- Variable effects on peripheral resistance due to agonism at both BETA 2 and ALPHA 1 receptors
- Initial increase in BP due to ALPHA 1 effect and then the HR increases due to BETA 1 (but the effect is not as high as isoproterenol because there is the baroreflex acting to decrease HR)
- Rapid infusion can result in baroreflex induced bradycardia
- Slower infusion may escape baroreflex
78
Cardiovascular Effects of Isoproterenol
- Selective for only BETA receptors
- Decreases peripheral resistance due to BETA 2 effects (BP decreases)
- Increases HR and contractility due to direct BETA 1 effect and due to baroreflex induced tachycardia
79
Cardiovascular Effects of Phenylephrine
- Selective for only ALPHA receptors
- Significant vasoconstriction due to ALPHA 1 AGONISM (BP increases)
- Baroreflex-induced bradycardia (HR decreases)
80
Adrenergic Agonists: Metabolic Effects of Lipids
Lipolysis
- Stimulated by BETA 3
- Inhibited by ALPHA 2
81
Adrenergic Agonists: Metabolic Effects of Carbohydrates
Glycogenolysis
- Stimulated by ALPHA 1 and BETA 2 receptors in the liver
- Increases glucose release in the liver
82
Adrenergic Agonists: Metabolic Effects of the Endocrine System
- INSULIN secretion is stimulated by BETA 2, but inhibited by ALPHA 2 activation
- RENIN secretion is stimulated by BETA 1, which is very important for controlling BP by setting off cascade to produce angiotensin (leading to eventual increase in BP)
83
Adrenergic Agonists: Metabolic Effects of the CNS
- Endogenous catecholamines are restricted by the BBB
| - Effects of exogenous include: nervousness, fear, anxiety, and euphoria
84
Alpha 1 Agonists
USES - Treat hypotension, nasal decongestant, produce mydriasis
Drugs
1. METHOXAMINE increases peripheral resistance to treat hypotension
2. PHENYLEPHRINE treats hypotension, topically used to produce mydriasis, as well as decongestant
85
Alpha Agonists
OXYMETAZOLINE is used topically as a decongestant
86
Alpha 2 Agonists
USES - Treat essential hypertension
- Receptors present in the CNS in CV control centers reduce sympathetic outflow and subsequently decrease sympathetic vascular tone (decrease peripheral resistance)
- In periphery, agonists inhibit the release of catecholamines (predominant effect is to decrease peripheral resistance)
Drug: CLONIDINE is antihypertensive agent that has a long duration of action because mechanism involves CNS
-Adverse effects: dry mouth, sedation, sexual dysfunction
87
Beta 1 Agonists
USES - Treat congestive heart failure and post-myocardial infarction
Drug: DOBUTAMINE strongly increases ionotropy, therefore useful in increases cardiac output
-Low affinity for beta 2 receptors ensures little decrease of peripheral resistance, which is important for keeping BP levels normal
88
Beta 2 Agonists
USES
1. Asthma and COPD
- Pulmonary receptors are targeted by inhalation, and so B2 stimulation results in bronchodilation and also decreased leukotriene and histamine release from pulmonary mast cells
2. Premature labour
3. Anaphylactic shock
Drugs:
1. RITODRINE is administered systemically to stop premature labour
- Effects last several days which is long enough to treat mother with corticosteroids to reduce risk neonatal respiratory distress
2. Short acting B2 agonists: METARAMINOL, ALBUTEROL, TERBUTALINE are used to treat asthma flare ups
3. Long acting B2 agonists: FORMOTEROL, SALMETEROL are used chronically to avoid flare ups
89
Epinephrine
USES - Treat anaphylactic shock
Anaphylaxis is characterized by bronchospasm, mucous membrane congestion and severe hypotension
-Epinephrine is very effective in treating these symptoms
90
Indirect Sympathomimetics
- Indirectly increase noradrenaline neurotransmission by increasing levels in the synapse
1. AMPHETAMINE
2. EPHEDRINE
91
Amphetamine
INDIRECT SYMPATHOMIMETIC
-Stimulates release of NA from nerve terminal
-Uses
+CNS stimulant
+Stimulates respiration centres
+Decreases perception of fatigue
+Euphorant
+Appetite suppressant
-Therapeutic uses are now limited due to strong abuse potential of the drug
-METHYLPHENIDATE (Ritalin) used to treat ADHD and narcolepsy
92
Ephedrine
INDIRECT SYMPATHOMIMETIC
-Stimulates release of NA and is an agonist of alpha and beta receptors
-Uses
+Used for millenia (herbal sources)
+High bioavailability and long duration of action
+May enter the CNS and has some stimulant activity
+Increases HR and cardiac output
+Causes bronchodilation
-One of its enantiomers, PSUEDOEPHEDRINE, is commonly used as a decongestant
93
Alpha 1 and Alpha 2 Antagonists
USES
- Treat pheochromocytoma
- Very effective in decreasing hypertension resulting from high adrenergic tone
- Mixed alpha receptor antagonists are given pre-operatively or during surgery to prevent/treat hypertension
DRUGS
- PHENTOLAMINE
- PHENOXYBENZAMINE
94
Pheochromocytoma
- Tumour of the adrenal medulla that secretes large amounts of adrenaline and noradrenaline
- Symptoms reflect high sympathetic tone (hypertension, sweating, etc.)
95
Alpha 1 Antagonists BP and HR
PHENTOLAMINE ONLY
- Decreases BP, but not by much UNLESS someone has hypertension
- Increases HR due to baroreflex
EPINEPHRINE BEFORE PHENTOLAMINE
- Increase in BP (peripheral resistance, alpha 1) and cardiac output (beta 1)
- Increase in HR
EPINEPHRINE AFTER PHENTOLAMINE
- Decrease in BP
- Increase in HR (beta 1) + baroreflex
96
Phentolamine
ALPHA 1/2 SELECTIVE ANTAGONIST
- Reduces BP due to decreased peripheral resistance
- Major adverse effects are tachycardia due to baroreflex and orthostatic hypertension
- Used in the treatment of pheochromocytoma
97
Phenoxybenzamine
ALPHA 1/2 SELECTIVE ANTAGONIST
- Irreversible
- Due to irreversible activity, its duration of activity is longer than reversible antagonists
- Adverse effects include tachycardia, orthostatic hypertension and nasal stuffiness
98
Alpha 1 Antagonists
USES
- Essential hypertension (almost always given with diuretic)
- Benign prostatic hyperplasia (hyperactive smooth muscle of the bladder and prostate --> feel the need to pee all day err day)
- Raynaud's phenomemnon
CV Effects - most common adverse effect
- Decrease arteriole and venous tone
- Decreased venous tone results in venous pooling and reduced venous return to heart
- Venous pooling can result in orthostatic hypotension --> trigger reflex-induced tachycardia
DRUGS
- PRAZOSIN
- DOXAZOSIN
- TAMSULOSIN
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Prazosin
ALPHA 1 SELECTIVE ANTAGONIST
- Moderate bioavailability
- Half life is about 3 hours
- Used primarily in treatment of essential hypertension, and also benign prostatic hyperplasia
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Doxazosin
ALPHA 1 SELECTIVE ANTAGONIST
- Used for both essential hypertension and BPH
- Half life about 22 hours and therefore requires less frequent dosing
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Tamsulosin
ALPHA 1 SELECTIVE ANTAGONIST
- Primarily used to treat BPH (due to alpha 1 subtype specificity of bladder and prostate)
- Relatively greater potency in inhibiting contraction in prostate smooth muscle vs. vascular smooth muscle
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Beta-Blockers
Can be:
1. Nonselective B1 + B2 (PROPANOLOL and TIMOLOL)
2. Nonselective B1 + A1 (LABETOLOL)
3. Cardioselective B1 only (METOPROLOL, ATENOLOL, ACEBUTOLOL)
USES
1. Hypertension
+Used alone or in combo with vasodilator or diuretic
+Mechanism not well characterized
2. Stable angina pectoris (ischemic heart disease)
+Reduce frequency of anginal attacks and increase exercise tolerance in patients with angina
+Slows and regulates HR
3. Arrhythmias (class 1B anti-arrhythmic)
+Useful for treating both supraventricular and ventricular arrhythmias
4. Secondary prevention of myocardial infarction
5. Glaucoma
+Reduce intraocular pressure via decrease aqueous humor production
6. Hyperthyroidism (symptomatic treatment)
7. Migraine prophylaxis
8. Psychiatric disorders (performance anxiety)
Respiratory Effect
- Blockage of B2 receptors may lead to increased bronchoconstriction, especially in asthmatics
- B1 selective antagonists have limited blockade of B2, although adverse effects may still be seen in severe asthmatics
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Propanolol
NON SELECTIVE BETA BLOCKER
- Prototypical beta blocker
- Short half life, so often used in hospitals
USES
1. Essential hypertension
2. Angina
3. Certain arrhythmias
4. Migraine prophylaxis
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Timolol
NON SELECTIVE BETA BLOCKER
- Ocular Use: Treatment of glaucoma
- Systemic effects are common even after local application
- Contraindications: asthmatics and congenital heart failure
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Metoprolol and Atenolol
SELECTIVE BETA 1 BLOCKER
- As potent as propanolol at B1 receptors
- Used to treat angina and hypertension
- Safer in those with asthma or diabetes because they have no B2 action
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Acebutolol
SELECTIVE BETA 1 BLOCKER
- Partial B1 agonist
- Less efficacious than antagonists but are less likely to cause bradycardia and affect plasma lipids
- Aka "beta blockers with intrinsic sympathomimetic activity"
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Labetolol
NONSELECTIVE B1 + A1 ANTAGONIST
- Decreases BP without reflex tachycardia (A1 treats hypertension, B1 blocks reflex)
- Useful in treating hypertensive emergencies and pheochromocytoma
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Beta-Blockers: Toxicity
CNS
- Sedation
- Sleep disturbances
- Depression
- Precipitation of asthma
- Exacerbation of hypoglycemia
Cardiac
-In patients after myocardial infarction or with CHF, cardiac output may be highly dependent on sympathetic signaling
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Reserpine
INDIRECT ACTING SYMPHATHOLYTIC
-Alkaloid Rauwolfia serpentina
-Reduces the storage of catecholamines in nerve terminals
-Used occasionally for hypertension
-Depletion of catecholamines decreases BP over several days, the lack of catecholamine signaling causes an upregulation in adrenergic receptors and creates a super sensitivity to adrenergic agonists --> can be bad news bears
-Adverse effects
+Excessive bradycardia, flushing of skin, congestion, and postural hypotension
+Parkinsonism (depletion of dopamine)
+Depression (depletion of 5HT)
+Abdominal cramps and diarrhea
OTHER DRUGS
- Guanethidine
- alpha-Methyldopa
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Endocrine Pharmacology
Study of drugs that are hormones or hormone derivatives, or drugs that may modify the synthesis or action of normally secreted hormones
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Hypothalamus and Pituitary
- Portal venous system carries small regulatory hormones from the hypothalamus to the ANTERIOR PITUITARY
- POSTERIOR PITUITARY hormones are synthesized in the hypothalamus and transported by neurosecretory fibres (hypophyseal tract) into the stalk of the posterior pituitary where they are released into circulation
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Posterior Pituitary Secretions
Neurohormones
- Oxytocin
- Vasopressin
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Anterior Pituitary Secretions
- FSH/LH
- ACTH
- TSH
- GH
- Prolactin
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Growth Hormone
- Produced by somatotropes in the anterior pituitary
- Release is stimulated by GH releasing hormone and inhibited by somatostatin
- Half of circulating GH is bound to a specific protein and binding results in decreased clearance and 10X increased half-life
- Plasma protein binding also reduces biological activity
- Estrogen and obesity increase plasma protein concentration
- Secretion varies throughout life but is highest during childhood, reaches maximal levels as puberty and declines during adulthood
- Secreted in pulsatile, irregular rhythms
- Amplitude of pulsatile secretion is greatest at night and begins shortly after the onset of deep sleep
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Regulators of Growth Hormone Secretion
POSITIVE
- DA
- 5-HT
- Alpha2 Agonists
- Hypoglycemia
- Exercise
- Stress
NEGATIVE
- Beta Agonists
- IGF-1
- GH
- Free Fatty Acids
- Glucose
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Effects of Growth Hormone
- During childhood, GH is necessary for longitudinal bone growth (before epiphyseal closure)
- In adults, GH increases bone density
- In adults and children, GH increases lipolysis and gluconeogenesis (in liver)
- Most effects are mediated through IGF-1
- Growth promoting effects are mediated by increased IGF-1 secretion from liver
- Stimulates IGF-1 production in bone, cartilage, muscle and kidney where IGF-1 has an autocrine role
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Growth Hormone Deficiency
-May be idiopathic or may be due to damage to the pituitary or hypothalamus
-In children, deficiency results in short stature, adiposity and low growth velocity
-In adults, GH deficiency is associated with increased mortality predominantly due to CV causes
+increased circulating lipids
+reduced exercise tolerance due to reduced muscle mass
+obesity
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GH Replacement Therapy
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Prader-Willi Syndrome
+Autosomal dominant disease
+Growth failure
+Obesity
+Carbohydrate intolerance
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Turner Syndrome
+Treatment with GH increases height 4-6 inches
Any condition where there is a deficiency in GH, will respond much better to replacement therapy than conditions with no deficiency
-Children of short stature only respond modestly to therapy
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Growth Hormone Preparations
- GH available in recombinant human form (rhGH)
- Two main preparations
1. SOMATOTROPIN - Identical to endogenous GH
2. SOMATREM - Same as endogenous GH but with added methionine
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Growth Hormone Toxicity
- Generally well tolerated
- Sometimes increased intracranial hypertension
- Scoliosis due to rapid growth
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Mescasermin
- Growth Hormone Treatment of Short Stature
- Complex of recombinant hIGF-1 and IGFBP-3
- Children with short stature may also be due to IGF-1 deficiency, or GH receptor failure
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Growth Hormone Antagonists
-GH producing tumors cause acromegaly in adults and gigantism in children
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Treatment of Excess Growth Hormone
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Method 1: Indirectly inhibit GH
OCTREOTIDE
-Somatostatin analog
-Inhibits GH release
-45X more potent and half-life is 80 minutes
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Method 2: Target GH receptor (more direct)
PEGVISOMANT
-GH receptor antagonist
-Has high affinity but little efficacy for GH receptor
-Used in treatment of acromegaly
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Vasopressin and Oxytocin
-Short peptide hormones (9 aa) only differ by 2 aa
-Cyclic peptides
-Synthesized in the cell bodies of hypothalamic neurons
+SON - vasopressin
+PVN - oxytocin
-Transported to nerve termini that terminate in posterior pituitary
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Vasopressin
-Anti-Diuretic Hormone
-Released by posterior pituitary in response to changes in or the presence of
1. Decreased BP/blood volume (volume depletion)
2. Increased blood osmolality (hyperosmolality)
3. Certain drugs including nicotine
4. Pain/nausea
-Release inhibited by
+increased blood volume
+hypo-osmolality
+alcohol
+cold exposure and emotional stress
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Vasopressin: Mechanism of Action
- 3 types of receptors (V1, V2, V3) that are all GPCRs
- V1 and V3 through Gq11
- V2 through Gs
- V1 is found in vasculature, causing vasoconstriction
- V2 is found in distal convoluted tubule, reabsorbing H20
- V3 is found in pituitary
-Binds to receptor and results in increase in cAMP, which stimulates insertion for aquaporins on the apical border --> water absorption in nephrons
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Vasopressin: Effects
-Stimulates water reabsorption from collecting ducts (via V2 receptors; increases BP)
-Stimulates smooth muscle contraction (V1 receptors)
+In vasculature results in vasoconstriction
+increases intestinal motility
+stimulates uterine and cervical contractions
-Blood coagulation increases clotting factor VIII and von Willebrand factor
-ACTH secretion increases ACTH release from AP (V3)
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Effects of Other Drugs on Vasopressin
- PGE1 and LITHIUM act as antagonists at V2 receptors
| - ASA and INDOMETHECIN may potentiate the effects of vasopressin
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Desmopressin
- Synthetic analogue of vasopressin
- Greater selectivity for V2 than V1 (ADH:Pressor 1:4000)
- Can be administered IV, SQ, intranasally or PO
- Half life is 1.5-2.5 hours (compared to 15 minutes for vasopressin)
- Nasal bioavailability is 3-4%
- Oral bioavailability is hypotensive crisis
- Promotes release of factor VIII in the blood coagulation cascade - used for surgery in those with factor VIII deficiency
- May be used to try and control excessing bedwetting
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Diabetes Insipidus
- Vasopressin deficiency
- Can be congenital or result from lesions in hypothalamus, posterior pituitary or pituitary stalk
- Characterized by dilute urine and extreme thirst
- Serum is hyper osmotic due to either decreased release or kidney insensitivity to ADH
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Other Conditions Involving Vasopressin
- Syndrome of inappropriate ADH secretion (SIADH) results in ADH excess and water intoxication, hyponatremia etc
- Treatment of heart failure; V2 receptor antagonists are thought to reduce water retention and improve blood hemodynamics for individuals with heart failure
- Excessive sodium excretion and decreased serum osmolality (vaptans used to treat)
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Vasopressin Receptor Antagonists
- Vaptans
- Used for treatment of hypervolemic and euvolemic hyponatremia
- CONIVAPTAN was first to be approved by FDA but does not differentiate between V1 and V2
- TOLVAPTAN targets V2
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Oxytocin Effects
1. Milk Ejection - primary physiological action is release of milk
2. Uterine Contraction - in the pregnant uterus and stimulates prostaglandins that further stimulate contractions
3. CNS Effects - acts as a NT and may be involved in social recognition and bonding
4. Vascular Effects - Relaxation of circular smooth muscle fibres and lowers BP
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Oxytocin Uses
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-Labour induction/contraction promotion
+Given IV
+Short half life allows for increased control of effects
-Control of post-partum bleeding
-Stimulation of milk ejection
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Oxytocin Toxicity
-Tetanic contractions that can result in fetal hypoxia
