Drugs Block 12 Flashcards
Chloroquine
- Chloroquine is a antimalarial drug that is used off label to treat Rheumatoid Arthritis
- The mechanism of action of antimalarials in the treatment of patients with rheumatoid arthritis is unknown but is thought to involve changes in antigen presentation or effects on the innate immune system.
Hydroxychloroquine
- Hydroxychloroquine is an antimalarial drug which is relatively safe and well-tolerated agent for the treatment of rheumatoid arthritis.
- The mechanism of action of antimalarials in the treatment of patients with rheumatoid arthritis is unknown but is thought to involve changes in antigen presentation or effects on the innate immune system.
- A period of 2 to 4 months is usual. Most agree that if a patient shows no response after 5-6 months that this should be considered a drug failure.
SIDE EFFECTS:
The most important toxicities are on the eyes:
-corneal deposits
- extraocular muscular weakness
- loss of accommodation (and sensitivity to light)
- retinopathy that may progress to irreversible visual loss.
- Patients with underlying retinopathies or risks may not be good candidates for antimalarial drugs.
Azathioprine
Drug class: immunosuppressant
Indication: used to prevent renal transplant rejection, treat rheumatoid arthritis, crohns disease and ulcerative collitis.
Mechanism:
- inhibition of purine synthesis
- inhibition of B cells and T cells
Contraindications:
Side effects:
- Only used for severe Rheumatoid Arthritis
Diclofenac
Drug Class: NSAID
Indications:
Pain in various inflammatory conditions
- Osteoarthritis
- Rheumatoid Arthritis
MOA:
- inhibits COX-1 and COX-2 which are the enzymes responsible for the production of prostaglandin
Celecoxib
Drug Class: NSAID
Indications:
Pain in:
- treat osteoarthritis
- rheumatoid arthritis
- acute pain
- menstrual symptoms,
- reduce polyps is familial adenomatous polyposis.
MOA:
- selective noncompetitive inhibitor of cyclooxygenase-2 (COX-2) enzyme.
Cyclophosphamide
Drug class: chemotherapy drug
Indication:
- cancer and Rheumatoid Arthritis
Mechanism of action: DNA Alkylation -> DNA crosslinking -> decreased DNA replication
Side effects: - hemorrhagic cystitis (bleeding in bladder)
- Doctors typically use this medication to treat severe RA, specifically vasculitis, which is inflammation in the blood vessels.
Ciclosporin
Drug class: immunosuppressant
Indication: organ and bone marrow transplants as well as inflammatory conditions such as ulcerative colitis, rheumatoid arthritis and atopic dermatitis.
Mechanism:
1. Calcineurin inhibitor that inhibits T -cell activation.
2. Cyclosporin binds to the receptor cyclophilin and forms a complex called cyclosporine-cyclophilin.
3. This complex inhibits calcineurin, which stops the dephosphorylation and activation of (NFAT) that produce cytokines and inflammatory reactions.
Side effects:
- hypertension
- hyperlipidemia
- hirsutism ( excessive hair growth)
- hyperuricemia ( gout)
Aurothiomalate
Sodium aurothiomalate is a disease-modifying antirheumatic drug (DMARD) indicated for the symptomatic treatment of arthritis.
Drug Class: DMARD
Indication: Arthritis
MOA:
The precise mechanism of action is unknown. It is known that sodium aurothiomalate inhibits the synthesis of prostaglandins. The predominant action appears to be a suppressive effect on the synovitis of active rheumatoid disease.
Methotrexate
Drug Class: can also be DMARD
Indication: very effective at treating Rheumatoid Arthritis
MOA:
- Methotrexate enters tissues and is converted to a methotrexate polyglutamate by folylpolyglutamate
- In rheumatoid arthritis, methotrexate polyglutamates inhibit AICART more than methotrexate.
- This inhibition leads to accumulation of AICART ribonucleotide, which inhibits adenosine deaminase, leading to an accumulation of adenosine triphosphate and adenosine in the extracellular space, stimulating adenosine receptors, leading to anti-inflammatory action
Sulfasalazine
Drug Class: DMARD
Indication:
- Rheumatoid Arthritis
- It has been shown to reduce the signs and symptoms of RA and slow radiographic damage.
Indication:
- Crohns disease
- Ulcerative Colitis
- Rheumatoid Arthritis
MOA:
- Although the exact mechanism of action of sulfasalazine is not fully understood, it is thought to be mediated through the inhibition of various inflammatory molecules
- can inhibit leukotrienes and prostaglandins by blocking the cyclo-oxygenase and lipoxygenase pathway.
RA triple therapy
- Sulfasalazine
- Methotrexate
- Hydrochloroquine
Prednisolone
Drug class: Intermediate ( medium) acting glucocorticoids
Indications: orally, intravenously and topically
treat adrenocortical insufficiency, inflammatory conditions, endocrine, rheumatic and dermatologic.
Mechanisms:
- The short term effects of corticosteroids are decreased vasodilation and permeability of capillaries, as well as decreased leukocyte migration to sites of inflammation
Glucocorticoids inhibit neutrophil apoptosis and demargination; they inhibit phospholipase A2, which decreases the formation of arachidonic acid derivatives; they inhibit NF-Kappa B and other inflammatory transcription factors; they promote anti-inflammatory genes like interleukin-10.
Acetazolamide
Acetazolamide is a carbonic anhydrase inhibitor used to treat edema from heart failure or medications, certain types of epilepsy, and glaucoma.
Drug Class: Antidiuretic and Anticonvulsant
Indication:
For adjunctive treatment of: edema due to congestive heart failure; drug-induced edema; centrencephalic epilepsies; chronic simple (open-angle) glaucoma
The anticonvulsant activity of Acetazolamide may depend on a direct inhibition of carbonic anhydrase in the CNS, which decreases carbon dioxide tension in the pulmonary alveoli, thus increasing arterial oxygen tension.
The diuretic effect depends on the inhibition of carbonic anhydrase, causing a reduction in the availability of hydrogen ions for active transport in the renal tubule lumen. This leads to alkaline urine and an increase in the excretion of bicarbonate, sodium, potassium, and water.
Timolol
Drug Class: non-selective beta blocker
Indication:
- elevated intraocular pressure in occular hypertension or open angle glaucoma.
- given as eyedrop solution also given as tablet to treat hypertension.
MOA:
TO DECREASE BP:
- competes with adrenergic neurotransmitters (epinephrine) for binding to beta-1 receptors in the heart
- also competes with beta-2 receptors in the vascular and bronchial smooth muscle
- This leads to diminished actions of catelcholamines, which would normally bind to adrenegic receptors and exert sympathetic effects - like increase heart rate and pressure.
- So the beta blocker effect - decreases heart rate and cardiac output
- Also decreases systolic and diastolic blood pressure
TO DECREASE OCCULAR PRESSURE:
- exact way timilol reduces occular pressure is unknown
- probably because it decreases the amount of aqueous humor in the eye.
Mannitol
Drug Class: Osmotic Diuretic (sugar alcohol)
Indication:
- reduce intracranial pressure and intraocular pressure
- measure the glomerular filtration rate (GFR)
- manage pulmonary symptoms associated with cystic fibrosis
MOA:
- Is a osmotic diuretic which is metabolically inert in humans
- Occurs naturally as sugar alcohol in fruits and vegetables
- Elevates BLOOD PLASMA OSMOLALITY - resulting in enhanced flow of water from tissues, including the brain and cerebrospinal fluid into interstitial fluid and plasma.
- As a diuretic it also causes the excretion of water.
Propofol
Drug Class: General Anesthesia
Indications:
- is an intravenous anaesthetic agent used for induction and maintenance of general anaesthesia.
MOA:
- positive modulation of the inhibitory function of the neurotransmitter gama-aminobutyric acid (GABA) through GABA-A receptors.
Side effects:
- vasodilation
- decreased cardiac function which can lead to hypotension
- Propofol infusion syndrome
Donepezil
Drug Class: Acetylcholinesterase inhibitor
Indication:
- behavioral and cognitive effects of Alzheimers disease and other types of dementia
- given orally or transdermal delivery system
- It is also available as an extended-release capsule in combination with memantine for the treatment of moderate-to-severe dementia of the Alzheimer’s type in patients previously stabilized on 10mg of donepezil hydrochloride once daily
MOA:
- Donepezil selectively and reversibly inhibits the acetylcholinesterase enzyme, which normally breaks down acetylcholine.
- The commonly accepted cholinergic hypothesis proposes that a portion of the cognitive and behavioral decline associated with Alzheimer’s are the result of decreased cholinergic transmission in the central nervous system.
Suxamethonium (AKA succinlycholine)
Drug Class: Muscle relaxant, onset one min, effects last for 10 min
Indication:
- is a depolarizing skeletal muscle relaxant used adjunctly to anesthesia and for skeletal muscle relaxation during intubation, mechanical ventilation, and surgical procedures
MOA:
- Succinylcholine is a depolarizing neuromuscular blocker, meaning it causes a prolonged period of membrane depolarization in order to exert its therapeutic effects.
-It binds to the post-synaptic cholinergic receptors found on motor endplates, thereby inducing first transient fasciculations followed by skeletal muscle paralysis
Side effect:
- hyperkalemia - which is find in normal patients but not fine for burn patients where it can cause asystole.
SUXAMETHONIUM
PHASE 1 block: It binds to the post-synaptic cholinergic receptors found on motor endplates, thereby inducing first transient fasciculations followed by skeletal muscle paralysis
PHASE 2 block:
- Eventually the sodium channel closes and the membrane repolarises
- however because of the continued stimulation by suxamethonium the receptor becomes desensetised to acetylcholine, therefore preventing the formation of further action potentials.
GENERAL ANASTHETICS
Used for:
- unconsciousness
- sedation
-analgesia
- amnesia
How do they work:
- general anesthetics depress the central nervous system. In other words, they diminish the total amount of action potentials that are constantly firing in the brain.
- The generation of these action potentials depends on excitatory and inhibitory synapses
- EXCITATORY: The main neurotransmitter involved is glutamate, which binds to postsynaptic NMDA receptors, so some general anesthetics work by blocking these receptors.
- INHIBITORY: Inhibitory synapses, on the other side, do the opposite; they release the inhibitory neurotransmitter called GABA, which binds to the postsynaptic neuron and keep it from firing.
So certain anesthetics work by stimulating these GABA receptors or by increasing their sensitivity to GABA.
GENERAL ANASTHETICS
-There are two main phases in anesthesia: induction, which is when the patient enters the anesthetic state; and maintenance, when the anesthetic state is prolonged for as long as required.
- some anesthetics are better for induction, while others are better for maintenance.
- Now, depending on how they’re administered, there are two classes of general anesthetics: PARENTERAL and INHALATIONAL anesthetics
Parenteral anesthetics
- Parenteral anesthetics are given by injection into a vein.
- They’re highly lipophilic agents that are commonly used for anesthetic induction in a single intravenous injection, although some of them, in special situations, can be used for maintenance by continuous intravenous infusion.
- Once in the bloodstream, these medications travel through the body to highly lipophilic tissues that receive a lot of blood, like the brain and spinal cord. There, they can induce the anesthetic state.
- After this, the medications diffuse back into the bloodstream, get metabolized by the liver, and then excreted by the kidneys.
Inhaled general anesthetics
Inhaled anesthetics are gases or volatile liquids given through a mask or a tracheal tube for the patient to inhale. The anesthetic then goes from the alveoli of the lungs into the blood, and finally to different parts of the body.
When the anesthetic agent has a high lipid solubility, it accumulates over time in the body fat, increasing its potency.
On the other hand, inhaled anesthetics with high blood solubility will bind to blood proteins and tend to have slower onset and recovery.
Each one of the inhaled anesthetics is better suited for specific patients according to their side effects.
Neuromuscular drugs
- Neuromuscular blocking drugs are mainly in surgery as an adjunct to anaesthetic agents.
- They cause muscle paralysis which is necessary prerequisite for mechanical ventilation.
- Competitive antagonism of post-synaptic nicotinic receptors (bind to the acetycholine/nicotinic receptors but do not depolarise only block so that acetylcholine cannot bind).
- Stop depolarisation of the muscle membrane and therefore stop muscle contraction
Opiods
- Normally, in the absence of endorphins, inhibitory neurons secrete a neurotransmitter called gamma-aminobutyric acid, or GABA, that prevents nearby neurons from releasing neurotransmitters like dopamine, serotonin, and norepinephrine.
- Now, let’s say someone goes to play a rigorous game of badminton. Exercise releases endorphins which activate the three major opioid receptors located on the inhibitory neurons, called the mu, kappa, and delta receptors.
- As endorphins bind to these receptors, they block the inhibitory neuron from releasing GABA, allowing the dopamine, serotonin, and norepinephrine secreting neurons to freely unload their neurotransmitters, which then get picked up by another neuron in the same area.
What do all opiods do ?
- inhibition of GABA release.
- however some are full agonist and some are partial agonists
ANTICONVULSANTS
The main excitatory neurotransmitter in our brain is glutamate which can bind to several types of receptors that are basically ligand-gated ion channels, which open up and allow Na+ and Ca2+ to flow in, and K+ to flow out.
In the end, when it’s all added up, there’s an influx of positive charge that makes the cell less negative,and the neuron becomes depolarized. This causes nearby voltage-gated Na+ channels to open on the surface of the membrane, causing more Na+ to enter. This in turn triggers other nearby voltage-gated Na+ channels to open.
Inhibitory Neurons
These neurons release the main inhibitory neurotransmitter called gamma-aminobutyric acid or GABA, which binds to GABA receptors on other neurons.
These GABA receptors are also ligand-gated ion channels, but they open up to let the negatively charged Cl-, into the cell.
The influx of negative ions causes hyperpolarization where the cell’s membrane potential becomes more negative, which means it’s much more difficult for it to depolarize and fire off an action potential.
Medications that block voltage gated sodium channels
BENZODIAZAPINES
- So one way we can decrease the excitatory signals is by enhancing the effect of inhibitory neurons through medication like benzodiazepines.
- There is short acting, intermediate acting and long acting
Diazepam
Drug class: Long acting benzodiazapine
Indications: severe anxiety, panic disorders, alcohol withdrawal and seizures
MOA:
- bind to the BZ site of GABA receptors
- binds to GABBA receptors to a different space to which GABBA binds to which increases the inhibitory effect of GABBA
Side effects: DROWSINESS, LOW CONCENTRATION, LOW REACTION TIME (should not be taken before driving)
